final cover 240909 · dr. pankaj seth 22 dr. ellora sen 26 dr. shiv kumar sharma 32 dr. anirban...

Annual Report2009-10

National Brain Research CentreManesar, Haryana, INdIA

Contents

Mandate & Objectives vii

From the Director’s Desk viii

Research Reports

Molecular and Cellular Neuroscience Division ● Dr.NiharRanjanJana 5

● Dr.ShyamalaMani 11

● Prof.V.Ravindranath 16

● Dr.PankajSeth 22

● Dr.ElloraSen 26

● Dr.ShivKumarSharma 32

● Dr.AnirbanBasu 37

● Dr.RanjitKumarGiri 46

Systems and Cognitive Neuroscience Division ● Dr.AdityaMurthy 54

● Dr.RemaVelayudhan 61

● Prof.NeerajJain 64

● Dr.SoumyaIyengar 69

● Dr.NarenderK.Dhingra 75

● Dr.YoganarasimhaDoreswamy 78

Computational Neuroscience and Neuroimaging Division ● Dr.NandiniChatterjeeSingh 83

● Prof.PrasunKumarRoy 87

● Dr.PravatKumarMandal 95

Publications & Patents 102

Presentations 109

Distinctions, Honours & Awards 117

Externally Funded Research Projects 121

Core Facilities ● DistributedInformationCentre(DIC) 127

● AnimalFacility 128

● DigitalLibrary 130

DBT’s Electronic Library Consortium (DeLCON) 133

National Neuroimaging Facility 141

Translational Research: Clinical Unit 147

Meeting and Workshops 151

● PerceptionEngineeringWorkshop2009

International Collaborations and Networking ● InternationalCollaborations

● Networking 141

Invited Lectures 161

Academic Programmes ● Ph.D.inNeuroscience 169

● IntegratedPh.D.inNeuroscience 169

● SummerTrainingandShort-termProgrammes 170

General & Academic Administration 171

Institutional Governance Structure & People at NBRC ● NBRCSociety 177

● GoverningCouncil 178

● FinanceCommittee 179

● ScientificAdvisoryCommittee 180

● ResearchAreaPanel 182

● BuildingCommittee 183

● AcademicCouncil 184

● BoardofStudies 186

● M.Sc.NeuroscienceCo-ordinationCommittee 187

● ScientificStaff 189

● OtherStaff 193

vMandate & Objectives

MAnDAte • Pursuebasicresearchtounderstandbrainfunctioninhealthanddisease.• Generatetrainedhumanresourceswiththecapabilitytocarryoutinter-disciplinary

researchinneuroscience.• Promote neuroscience in India through networking among institutions across the

country

oBJeCtIVes• Toundertake,aid,promote,guideandcoordinateresearchofhighcaliberinbasicand

clinicalneurosciencerelatedtodiseasesanddisordersofthenervoussystem.• TodevelopNBRCasthenationalapexcentreforneuroscienceresearchandpromote

neuroscience researchatdifferent centres in the countryand toprovide consultingservicestootherinstitutions,agenciesandindustries.

• To promote, encourage and augment effective linkages, alliances and affiliationsbetweentheCentreandNationalandInternationalScientificandResearchInstitutions,bodies,agencies/laboratoriesandotherorganizationsworkinginthefieldofbrainandneurosciencesresearch.

• ToestablishoneormoresatellitecenterstoservedifferentregionsofthecountryforefficientachievementoftheobjectivesoftheCenter.

• Tocollect,assimilate,publishanddisseminatedataandinformationonaspectsrelevanttoneurosciencetothescientificcommunity.

• Toestablish,operateandmaintainstate-of-the-artfacilitiesanddatabaseforcarryingresearchanddevelopmentactivitiesandmakesuchfacilitiesanddatabaseavailabletoscientistsandresearchersfromalloverthecountryandabroad;

• ToprovideforinstructionsandtraininginsuchotherbranchesoflearningastheCentremaydeemfit.

• Toprovidefacilitiesfortheadvancementresearchanddevelopmentforadvancementoflearningandfordisseminationofknowledge.

• Toundertakeextramuralstudies,extensionprogrammesandfieldoutreachactivitiestocontributetothedevelopmentofsociety.

• Topromote,develop,collaborateorotherwiseassistinprovidingservicesofresearch,training,consultingorguidancerelatedtoneurosciencesactivitiescomprisingbiological,psychological,sociologicalandclinicalaspects;and

• TodoallsuchotheractsandthingsasmaybenecessaryordesirabletofurthertheobjectivesoftheCentre.

MAnDAte & oBJeCtIVes

vi Annual Report 2009-10

Itisthebrainanditsemergentprocess,themind,whichisthebasisofallthatistrulyhumanandthewellspringofall our deepest abilities and desires,ranging from consciousness andcognition to communication andcreativity.Oftendescribedasthefinalfrontierforscientificenquiry,thestudyofthebrainisprobablytheonlysubjectthat needs the full gamut of humanknowledge for its comprehension,spanning across biology,medicine,computing and the humanities. Notonly does the brain challenge theintrepid molecular biologists intodecipheringthelabyrinthinepathwaysthatexistonly in thebrain,butalsodefies the abilities of an ingeniouselectronics engineerwhoattempts todevelopan intelligentsupercomputerthat would recognize a human facewhichaninfantcaneffortlesslydo.

Inthecurrentyear,NBRC,truetoitsfounding vision, has scaled furtherheights in its quest for excellenceacrossitsfourmainareasofactivity:Molecular and cellular neuroscience,Systems and cognitive neuroscience,Computational neuroscience andneuroimaging, and Translationalandclinicalneuroscience.Acrosstheyears,thecentrehasevolvedauniqueendeavour towardsunity indiversity

From the Director’s Desk

inbothresearchandteaching,namelystriving to show the broad unifyingtheme of integrative neuroscience,that ties the different componentsof the discipline together, from theion-channeltoneurontobehaviortolanguage. Needless to say, we havegiven emphasis to both aspects ofNBRC’smandate, academic researchas well as educational training inneuroscience, both of which willplay its part to enable the usheringof a talented and trained pool ofyoungresearchersinneuroscienceinthe country.Harnessing the uniqueopportunityaffordedbytheinstitute,theseresearchershavebeennurturedin the fertile soil of interdisciplinarytraining across the breadth of thedifferentareasrelevanttoneuroscience,rangingfromfundamentalgeneticstobehavioralpsychobiology.

Inthe Indianscenario, twopertinentfields demand immediate attention,namely basic and applied researchpertaining to neuroinfection andneurodegeneration.Amongstinfectionsaf f l ic t ing the brain, Japaneseencephalitis is a critical problemin several parts of India, especiallythe northern and north eastern,accountingforseveralthousanddeathsand many more individuals with

From the Director’s Desk vii

residualdeficits,duringthemonsoonseason every year,mostly amongstchildren.NBRCisinitiatingaclinicaltrial on Japanese encephalitis usinga polycyclic antibiotic, onwhich thefaculty is having an active researchprogram for several years, besidessecuring the patent therein.On theotherhand,degenerativeconditionsofthebrain,suchasAlzheimer’sdiseaseandotherdementia-likeconditions,areaprecipitouslyloominghealthproblemin India, that would be affectingabout 8million Indians in the year2040 according toWHO estimates.Our faculty has pursued incisiveinvestigations into indigenous plantextractsthatcanmarkedlydiminishthecerebralamyloidplaques,thehallmarkof Alzheimer’s disease, whenceforththe intellectual property rights havebeenobtainedbyNBRC,alongwiththecollaboratinginstitutionsinvolved.

Anewareaofsynthesisofneuroscienceand computer engineering has beenushered in worldwide under thename of neuroinformatics and brainmachinecomputation. It isherethatneurobiologists and technologistschallenge each other to develop thenext generation of brain-inspireddevices and neuromorphic systems.Our faculty have also developed abrain computer interface device thatcandecodeelectricalsignalsfromthebrainandaccordinglyinstructaroboticarmtomoveasintendedbythebrain.Itisafascinatingsighttodiscernhowamerewishorintentioncanbemadetoactuateacomplexmovingmachine.Neurorobotics is actually a decisiveareaintheemerginginterdisciplinaryf ields of neuroengineering andneuroprosthetics, and has seminal

implicationsforrehabilitationmeasuresin brain or spinal cord damagedindividualsanddisabledsubjects.

Tobeattheforefrontoffacilitiesrequiredforadvancedresearchinneuroscience,the Institute is establishing moreadvanced microscopy se tups ,including additional functionalitiesin the neuroimaging systems andhippocampalneuronavigationfacility.To assure full utilization of theseinfrastructures, NBRChas seamlesscollaboration with other NationalInstitutes/Universities and leadingclinicalcentersoftheregion,therebypromotingactivecooperativeresearch,training and sharing of resources. Aworkshop on PerceptionEngineeringunder the auspices of theMinistryof Communications & InformationTechnology was held in the centreinNovember 2009 to brainstorm ondeveloping an approach program forharnessing neurophysiological andneurocomputationalmethodologiestospawnthenewergenerationofperceptualsystems.Theinstitute’sscientistswerejoinedbypremierresearchgroupsinthe country, as that from IITs, IIITand some universities and centres,and NBRC has been partnered asthe resource centre f rom theneurosciencesector,inthisnational-levelinitiative.

ThisyearhasseenNBRCmatureintoa complete campus. ThehonourableMinister of Science and TechnologyMr Prithviraj Chavan inauguratedthe residential complex at NBRC inDecember.Asnecessary,thecampusnowprovidesaccommodationtostaff,officers and some facultymembers.Additionally,wehavetwootherbuildings

viii Annual Report 2009-10

toprovideaccommodationtostudents,project assistants and researchassociates.Thesemeasuresdoincreasethe bonding of the employees withthe institute,considering therelativeisolation of the campus. In keepingwith the current practice of regularperformancemonitoring, committeesfrom the Planning Commission andUniversityGrantsCommissionvisitedthe institution for assessment, andNBRCwasalsoevaluatedbytheMinistryof Human Resource Development,Government of India. The NBRCTranslational &Clinical unit at theGurgaon Government Hospital hasnowblossomedacrossthefullgamutof clinical neuroscience: neurology,neuropsychiatry, neuro-surgery andneuropsychology.Additionalconsultantfacultyhavejoinedtheunit.

Fulfillingitsnationalandinternationalobligations, our institutionhas beenanactivecollaboratortotheBiennialCongressoftheFederationofAsianandOceanianNeuroscienceSocieties,whichistobeheldforthefirsttimeinIndia,andNBRCisorganizingtheaccompanyingevent,aSchoolofNeuroimaging,withsponsorshipfromInternationalBrainResearchOrganization.Besides,NBRChas catalyzed Indian participationin International NeuroinformaticsCoordinat ing Faci l i ty and theInternationalHumanFrontierScienceOrganization, and relatedmeetingsin India are soon in the offing. Toshowcase Indian neuroscienceresearch to prospective applicantsto Indian institutions, NBRC co-organized the India NeuroscienceSatellite Symposium, at the SocietyforNeuroscience annualmeeting, inChicagolastNovember.NBRChadan

activegroupparticipationthroughitsvariousfacultymembersandstudents,whohadaproductiveinteractionwithleadinginternationalpeersinthefield.AseriesofmeetingattwelvedifferentcitiesacrossthecountrywasorganizedbyNBRC,duringtheBrain-AwarenessWeekonthemonthofMarch.

AsamemberoftheUniversitysysteminIndia,theinstituteisonacontinuousmonitoring and feedbackmode forenhancement of the integratedMSc-PhDprogram aswell as the regularPhD program. Indeed, several newcurriculartopicshavebeenintroducedorconsolidated,suchasNeuroimaging,Computerprogramming(Matlab)andAnimal Handling. Furthermore, wehaveundertaken further broadeningof thescopeofstudentrotationshipsto includemore laboratories, so thatthe students can samplemore fieldsofneuroscience,beforeembarkingontheir thesis area. To entice the beststudents towards brain research,theNBRCfacultyhasparticipatedinthe student selection process of thesummerfellowshipschemeofthethreescienceacademics,whoseprogramhasbeenfurtheractivelyconsolidated.Thisinvestmentofthefacultyarepayingoff,indeedsomeofthesetalentedscholarsare joining NBRC for their doctoralprograms.

Asthecentrenowcompletesadecadeof its existence, it is now time toreminisce our growth. From itsinitial establishment in 2000 at theICGEB campus inNewDelhi, to itsinterim premises at Gurgaon, andthen through the inauguration ofits idyllic Manesar campus by thePresident of India, the institute has

From the Director’s Desk ix

grown from two students to almostahundred, fromone labto fourteen,from six network centres to fortyeight,andfromacoupleofemployeesto now about a hundred and fifty.Thenumberofpublications,projectsandpresentationsundertakenbytheresearchershasgrownaccordingly.Theinstitutehasgraduatedoutfivebatchesof doctorates, a couple of batchesofMasters, and a steady stream ofother alumni, such as post-doctoralfellows and research associates. Asteachers,wefinditindeedarewarding

experiencetoknowthattheinstituteisspawningsecond-generationstudents,a few of our alumni havematuredas facultymembers elsewhere, andtheirownstudentsareintheprocessof graduating. As the centre growsinto the adolescence of its seconddecade,weareincreasinglyconfidentthatNBRCwouldbeabletotacticallyreinforce its nichewell in basic andappliedneuroscience,andconsolidateitscontribution towards thebuildinga criticalmass of neuroscientists sonecessaryinthecountry.

Prof. Prasun K. RoyDirector (in-charge)

ReseaRch RepoRts

Molecular and Cellular neuroscience

systems and Cognitive neuroscience

Computational neuroscience and neuroimaging

Molecular & Cellular Neuroscience

Dr. Nihar Ranjan Jana

Dr. shyamala Mani

prof. V. Ravindranath

Dr. pankaj seth

Dr. ellora sen

Dr. shiv Kumar sharma

Dr. anirban Basu

Dr. Ranjit Kumar Giri

Molecular & Cellular Neuroscience 5

Principal Investigator

dr. Nihar Ranjan Jana

Research Fellows

Shalaka Mulherkar, Swetha K. Godavarthi, Megha Maheswari

Project Assistants

Parthanarayan de, Anannya Samanta

Technical Assistants

Ankit Sharma, Mahendra Singh

ThegeneproductofUbe3acalledE6associated protein (E6-AP) belongsto theHECT (Homologous to E6-APC-terminus) domain family of E3ubiquitin ligases. E6-AP, the bestcharacterizedproteininthisfamily,tagsubiquitinmoleculestoproteinsthataredestined tobedegraded through theproteasome.Lossoffunctionmutationsor deletions of maternal Ube3a isknowntocauseAngelmansyndrome(AS).Recentlycopynumbervariationofthisgeneisalsoreportedinautism.Characteristicsofthesyndromeinclude

Understanding the Function of the Autism And Autism spectrum Disorders Associated Ubiquitin Ligase, Ube3a/e6-AP

motordysfunction,seizuresandmentalretardation.Inthebrain,thematernalallele of Ube3a is predominantlyexpressedasaresultoftissuespecificimprinting.Mature neurons exhibitmaternal allele-specific expressionalthough traces of paternal allele-specificexpressionarealsodetected.Biallelic expression is restricted toGFAPpositivecellsliningtheventriclesand absent from GFAP positiveastrocytesinotherregionsofthebrain.In the brain, Ube3a predominantlyexpresses in the cerebellar Purkinjecells,neuronsinthehippocampusandthecortex.Atthecellularlevel,E6-APis localized inthenucleusaswellasinthecytoplasm.ExpressionofE6-APwas also found in both presynapticand postsynaptic compartments inculturedofhippocampalneuronsUbe3amaternal deficientmice (Ube3am-/p+)exhibit learning andmemorydeficitsaswell asmotor abnormalities. ThemotorabnormalitiesintheseUbe3am-/

p+micearesofarbeenshownduetodysfunctionofthecerebellum.PaternaldeficientUbe3amice(Ube3am+/p-)failtoshowthesetypicalcharacteristics.

SinceE6-APisanubiquitinligase,itishypothesizedthattheASorautisticphenotypemightbecausedbyfailureof ubiquitination and subsequent

6 Annual Report 2009-10

degradation of the variety of targetsubstrate proteins of E6-AP. Loss ofcoactivator functionmight also belinkedwiththediseasepathogenesis.Therefore identification of substrateprotein of E6-AP and the defectivesignaling cascades could open anew avenue in understanding thepathogenicmechanismofAS.

Major objectives of this project are(1) identification and functionalcharacterization of novel substratesof E6-AP, (2) study the altered geneexpressionprofileandsignalingcascadesintheE6-APdeficientmice, (3)studythemolecularmechanismofcognitiveimpairmentusingmicemodel.

RecentlywehavepublishedaseriesofpapersthatsuggestE6-APmightfunctionas a cellular quality control ligase. Itenhances the clearance of expandedpolyglutamineproteinsandalsomutant-synuclein.Nowweare studying therole of E6-AP in the progression ofHuntington’sdiseaseusing transgenicmice. This yearwe have found thatmaternallossofUbe3a(Ube3am-/p+)inthe

mousemodelleadstomotordeficitsthatcouldbeattributedtothedysfunctionofthenigrostriatalpathway.ThenumberoftyrosinehydroxylasepositiveneuronsinthesubstantianigrawassignificantlyreducedinUbe3am-/p+miceascomparedto the wild type counterparts. TheUbe3am-/p+mice performed poorly inbehavioral paradigms sensitive tonigrostriataldysfunction.Eventhoughthe tyrosinehydroxylase stainingwasapparently same in the striatum ofboth genotypes, the presynaptic andpostsynaptic proteins were highlyreduced in Ube3am-/p+ mice. ThesefindingssuggestthattheabnormalityinthenigrostriatalpathwayalongwiththecerebellumproducestheobservedmotordysfunctionsinUbe3am-/p+mice.

This year we have also found thatE6-AP interacts with and promotesproteasome-mediated degradation ofcyclin-dependentkinaseinhibitorp27.E6-APalsodirectlyubiquitinatesp27in an in vitro ubiquitination assay.PartialknockdownofE6-APincreasesthe level of p27 leading to cell cyclearrest.Interestingly,partialknockdown

Figure.MotordeficitsinUbe3am-/p+miceduetonigrostriataldysfunction.A,B) Ube3am-/p+mice showed hind limbclaspingwhileUbe3am+/p+miceheld theirhindlimbsoutwardswhensuspendedbythetail.C)Poletest.Micewereplacedona50cmverticalpoleandthe timetakentodescendwasrecorded.Ube3am-/p+micetook significantly longer to descend fromthepole than thewild typemice.D)Foradhesiveremovaltest,smalladhesivetapewasputonthesnoutoftheanimalsandthetimetoremovethetapewasrecorded.TheUbe3am-/p+micetooklongertoremovetheadhesivethantheUbe3am+/p+mice.Datarepresentedasmean±SEM;(n=6).*p<0.05incomparisonwiththewildtypemice.


also increases the transcription ofp27. Finally, we have demonstratedtheincreasedlevelsofp27inE6-AP-maternaldeficientandnullmicebrain.Our result suggests that E6-AP notonlyenhancesthedegradationbutalsoregulatestheexpressionofp27anditslossoffunctioninAngelmansyndromemightcausecellcyclealterationleadingtodiseasepathogenesis.

Publications:

1. S.Mulherkar andN. R. Jana(2010). Loss of dopaminergicn e u r o n s a n d r e s u l t i n gbehavioural deficit in mousemodel of Angelman syndrome.Neurobiology of Diseases. (InPress)

2. N. R. Jana (2010). Role ofubiquitin-proteasome systemandautophagyinpolyglutamineneurodegenerative diseases.Future Neurology,5,105-112.

3. R.Maity, J Sharma andN. R. Jana (2010).Capsaicin inducesapoptosis through ubiquitin-proteasomesystemdysfunction.Journal of Cellular Biochemistry,109,933-942.

4. S.Mulherkar,J.SharmaandN. R. Jana(2009).TheubiquitinligaseE6-AP promotes degradationof α-synuclein. Journal of Neurochemistry, 110, 1955-1964.

5. Mishra, S. K. Godavarthi andN. R. Jana (2009).UBE3A/E6-AP regulates cell proliferationby promoting proteasomaldegradationofp27.Neurobiology of Diseases,36,26-34.

Presentations:

1.S. Godavarthi and N. R. Jana:Angelman Syndrome CandidateProtein-E6AP, is a Coactivator ofGlucocorticoidHormoneReceptor,IAN,Jaipur,2009.

2.N.R.Jana:Toxicproteinaggregationinneurodegenerativediseases.NationalInstitute of Advanced Research,Ahmedabad,2010.

3.N. R. Jana: Understanding thefunctionalroleofE6-AP–anubiquitinprotein ligase and steroid receptorcoactivator implicated in Angelmanmentalretardationsyndrome.AOSCE,JNU,NewDelhi,2010.

4.N.R.Jana:Toxicproteinaggregationin polyglutamine neurodegenerativediseases.DRDO,NewDelhi,2009.

5.N. R. Jana: Suppress ion o fpolyglutamine neurodegeneration byubiquitin protein ligases. IGIB, NewDelhi,2009.

Funding:

1)Understanding the functional roleofE6-AP-aputativeubiquitinproteinligaseimplicatedinAngelmanmentalretardationsyndrome(DBT).

2)Study the defect in neurogenesisandinitialsynapseformationinmousemodelofAngelmanmentalretardationsyndrome(CSIR).

3)Role of E6-AP in the progressionofHuntington’s disease (DBTCareerDevelopmentAward)

Collaborator:

Dr. Nobuyuki Nukina, RIKENBrainScienceInstitute,Japan.



dr. Nihar Ranjan Jana

Research Fellows

Jaiprakash Sharma, dr. Sudheendra Rao

Project Assistants

diptendu Mukherjee


Ankit Sharma, Mahendra Singh

Lafora disease (LD) is a neurodegenerative epilepsy, characterizedby progressively worsening seizure,myoclonus, dementia and ataxiawithout any gender preference. Theonsetofthediseasetypicallybetween12-17yearsofageandpatientusuallydieswithin 10 years of first seizure.One of the characteristic features ofLD is the cytoplasmic accumulationofLafora inclusionbodiescontainingpolyglucosan in various organsincludingbrain,liverandaxillaryskin.It is an autosomal recessive diseasecausedbymutationsineitheratleasttwogenesEPM2AandEPM2B.EPM2A

Understanding the Physiological Function of Malin, A Ubiquitin Ligase Mutated in Lafora’s Progressive Myoclonus epilepsy

geneencodeslaforin,adualspecificityphosphatase with a carbohydratebinding domain and EPM2B geneencodes malin, an E3 ubiquitinligase of the ubiquitin proteasomesystem. Patients withmutations inmalin or laforin are phenotypicallyindistinguishable and Lafora bodiesare found across all LD patients.Currentunderstandingsuggeststhatboth laforin andmalin regulate theglycogenmetabolism and thereforetheirlossoffunctionmightleadtotheaccumulationofLaforabodiesthroughderangedglycogenmetabolism.ButhowmutationinthesetwoproteinsinducesneurodegenerationandwhetherLaforabodiesplayanyroleinthisprocessisnotknown.

Since malin is an E3 ubiquitinligase and itsmutation causes LD,it is hypothesized that the improperdegradation and accumulation ofsubstratesofmalinmightleadtodiseasepathogenesis.Therefore,identificationof substrates ofmalin could open anew avenue in understanding thepathogenicmechanismofLD.

In the proposed project, we plan toidentify and characterize the newsubstrates ofmalin. Additionally,wewill also study the involvement of


molecularchaperonesandubiquitin-proteasomesysteminthepathogenesisofLD.

Thisyearwehavefoundthatmalinisspontaneouslymisfoldedandtendstobeaggregated,degradedbyproteasomeand forms not only aggresomes butalso other cytoplasmic and nuclearaggregates in all transfected cellsupon proteasomal inhibition.Malinalso interacts with Hsp70. Severaldiseasecausingmutantsofmalinarecomparatively more unstable thanwildtypeandformaggregatesinmosttransfected cells even without theinhibitionofproteasomefunction.Thesecytoplasmicandnuclearaggregatesareimmunoreactivetoubiquitinand20Sproteasome.Interestingly,progressive

proteasomaldysfunctionandcelldeathis alsomost frequently observed inthemutantmalinover-expressedcellscompared to wild type counterpart.Finally,we demonstrate that the co-chaperone CHIP stabilizesmalin bymodulating theactivityofHsp70.Alltogether,ourresultsuggeststhatmalinisunstableandaggregateproneproteinandco-chaperoneCHIPcanmodulateitsstability.

Thisyearwehavealsoobservedthatthe Lafora bodies in axillary skinand brain stain positively for theubiquitin,the20SproteasomeandthemolecularchaperonesHsp70/Hsc70.Interestingly,mutantmalinsthataremisfolded also frequently colocalizeswithLaforabodiesinskinbiopsysample

FigureLocalizationofubiquitin,20SproteasomeandHsc70/Hsp70chaperonesintoLaforabodies.AxillaryskinbiopsysamplesfromtheclinicallyandgeneticallyconfirmedcasesofLDwereeitherprocessedforPASstainingorimmunohistochemicallystainedwithantibodiesagainstubiquitin,20SproteasomeandHsc70/Hsp70.ArrowindicatesPASpositiveLaforabodiesthatarealsopositivelystainedwithubiquitin,20SproteasomeandHsc70/Hsp70inbothEPM2A(laforin)andEPM2B(malin)mutantLDpatients.


ofrespectiveLDpatient.TheexpressionofdiseasecausingmutationsofmalininCos-7cellsresultsintheformationof profuse cytoplasmic aggregatesthat colocalize with Hsp70/Hsc70chaperonesand20Sproteasome.Themutantmalin expressing cells alsoexhibit proteasomal dysfunction andcelldeath. OverexpressionofHsp70decreases the frequency ofmutantmalin aggregation and protects frommutantmalin-inducedcelldeath.Thesefinding suggest that Lafora bodiesare consisting of abnormal proteinsincludingmutantmalin, targeted bychaperones or proteasome for theirrefolding or clearance, and failure ofthese quality control systems couldleadtoLDpathogenesis.Ourdataalsoindicates that theHsp70 chaperonecouldbeapotentialtherapeutictargetofLD.Currently,weareactivelyinvolvedin identifying thenovelsubstratesofmalin.

Publication:

1. RaoS.N.,SharmaJ.,MaityR.andJana N. R.(2010).Co-chaperoneCHIP stabilizes aggregate pronemalin,anubiquitinligasemutatedin Lafora disease. Journal of Biological Chemistry, 285,1404-1413.

Presentations:

1. S. Rao, J. Sharma, R. Maity.S.K.Shankar.P.SatishchandraandN.R. Jana. Lafora diseaseand ubiqui t in-proteasomedysfunction, PME Conference,Venice,Spain,2010.

2. J.SharmaandN.R.Jana.Laforadisease associated ubiquitinligase,malin interactswithandpromotes proteasome-mediateddegradation of neuronatin. IAN,Jaipur,2009.

3. S. Rao, J. Sharma and N. R.Jana.CHIP stabilizes aggregatepronemalin,anubiquitinligasemutated inLaforadisease. IAN,Jaipur,2009.

Collaborators:

Drs.S.K.ShankarandP.Satishchandra,NationalInstituteofMentalHealthandNeurosciences,Bangalore.



dr. Shyamala Mani

Research Fellows

Parthiv Haldipur, Rupali Srivastava, Pavan Kumar Rambatla

The cerebellum is a part of thehindbrain that accounts for morethanhalfoftheneuronsofthebrain.Ithelps in the integrationofsensoryinformation, coordination andmotorcontrol.Althoughconsiderableamountofworkhasbeendoneoncerebellumdevelopment in several animalmodels, very little is known aboutthemechanisms involved in humancerebellum development. Previousstudiesinmicehaveimplicatedsonichedgehog(Shh)signallingasamajorcontributortocerebellumdevelopment.Thereforewesetouttocharacterizethissignalingpathwayinhumancerebellumdevelopment.WecarriedoutthestudyincerebellarautopsysamplesobtainedfromArmyBaseHospitalandtheAllIndia Institute ofMedical Sciences,New Delhi. Our results indicate asimilarpatternofdevelopmentasseen

Development of the cerebellum

duringmousecerebellumdevelopment.Duringthegestationalperiodbetweenthe14thweektoterm,Shhisdetectedpredominantly in the PL, while itsdownstreamcomponentsaredetectedin the outer EGL. Sonic hedgehogcontinues to express itself in the PLeven postnatally, until the 8-12thmonth. The decrease in expressioncoincideswith theobliterationof theEGL.Wealso lookedcarefullyat thecasesofgestationalage10-13weeks.Thehistogenicprofileseenduringthisperiodisuniquetohumans.Duringthe10-13thweek,thereisnoconspicuouspurkinje layer, although the EGL isformed.Suchastageisnotseenintherodentmodel.We found that duringthe10-13thweek,Shhwasproducedby the EGL itself, which possiblyacted in an autocrinemanner. ThiscontinuedtilladistinctPLwasformed,followingwhichthepurkinjecellstookoverthetaskofShhrelease.Thisisanimportantfindinginthecontextofmedulloblastomas, where the exactreasonbehindtheoriginisunknown.Our results comparingmouse andhumanmedulloblastomas seem toindicate that in humans followingbirthalthoughtheEGLdoesdisappearover time, in some individuals, insome regions of the cerebellumEGLproliferationmaycontinuetopersist.


Persistent autocrine Shh signallingof the EGL or recapitulation of Shhdependentontogeny,inthepostnatalcerebellum could possibly be one ofthe reasons whymedulloblastomasoccur.Itishenceabefittingexampleof ontogeny gone wrong, leading tooncogeny.

We have also studied how thenormal developmental program ofthecerebellumismodifiedbychangein the environment due to pretermdelivery. We addressed the changesatthelevelofindividualcelltypesthatcannot be detected byMRI analysis.

To address the issue of how thenormal developmental program isperturbed due to premature birth,severalmorphologicalparametersandmolecularmarkerswereanalyzedinthecerebellumofpreterminfantswhohadsurvived in an ex-utero environmentandcomparedwithcontrolsinwhichthedevelopmentofthecerebellumhastakenplacein-utero.ThestudyreportsaselectivechangeinthedifferentiationofgranulecellsandtheBergmanngliaduetotheex-uteroenvironmentthatcould havemajor consequences forlateroutcomes.



dr. Shyamala Mani

Duringdevelopmentofnervoussystem,avastarrayofneuronsandgliaforminappropriatenumberandatdesiredpositions.Thisprocessdependsbothon the cell’s intrinsic programmingand the environment in which it ispresent. Proneural genes are one ofthemost important classes of genescoding for the basic helix-loop-helixcontainingtranscriptionfactors,whichare both necessary and sufficient toinitiateneurallineageandtopromotegenerationofprogenitorscommittedtodifferentiatefromtheectoderm.Theyalso integrate positional informationinto the neurogenesis process andcontribute to the specification ofprogenitor-cel l identity duringneurogenesis.Thegeneshavealsobeenshown to specify neuronal subtypes.MATH-1,abHLHgene,hasbeenshownindispensible for the development ofoneofthemostabundantcellsofthebrain,cerebellargranulecells (CGC).Cerebellum is important for variousfunctionslikemovementcoordinationandbalance, sensorydiscrimination,cognitiveprocessingandothers.Many

Embryonic stem cell differentiation into cerebellar granule neurons

cerebellar disorders are associatedwith progressive loss of its neurons.For treatmentof suchdisorders, cellreplacement therapy seems to be animportantapproach.

Embryonic s tem ce l ls are thepluripotent cells derived from theblastocystofthedevelopingembryo.Theyholdabigsignificancebecauseof their two important properties,firstly they can be maintained intheir undifferentiated state fortechnicallyunlimitedtimeperiod,andsecondly because of their potentialtodifferentiateinalmostanytypeofbodycell.Duetotheseproperties,theyare visioned as clinically importantfor the cell replacement therapies.Also, they hold significance in thefield of research to understand thedevelopment process during earlystages,whichisverydifficultotherwiseduetolimitedmodelsystems

Theprojectinourlabaims

• To generate amouse stem cellline which could conditionallyoverexpressMATH-1gene

• To study the effect of transientMATH-1overexpressiononthefateofcellsobtainedbydifferentiationofthecellline


ConditionalMATH-1 expressing celllinewasmadewith TET-ON systemof expression, in which the gene ofinterest (MATH-1) is only expresseduponDoxycyclineaddition.Tostudythe effect ofMATH-1 overexpressionduring differentiation, Doxycyclineinduction was given transiently atone of the stages of differentiation.VariousstagesofdifferentiationwerecharacterizedbyusinggeneralneuronalmarkerslikeNestin,Tuj1,Map2,GFAPandabatteryofgranulecellmarkerslikeTag1,Zic1,Zic2,Pax6,En1,Meis1using real time PCR method andimmunohistochemistry. Our resultssuggest that the timing of Math-1induction is crucial in the extentandnumberofgranuleneuronsthatare induced.Math-1was induced atvarioustimesduringthedifferentiationofEScellsandwefoundthatMath-1wasmostefficientininducinggenesofthegranuleneuronlineagewhenitwasinducedduringtheperiodofembryoidbodyformationitis.

Publications:

1. ShaileshKumarGupta, KarinaMeiri2,KashifMahfooz1,UpasnaBharti1 andShyamala Mani.(2010) Coordination betweenextrinsicextracellularmatrixcuesandintrinsicresponsestoorientthe centrosome in polarizingcerebellar granule neurons.Journal of Neuroscience,30(7):2755–2766.

2. Angela M. Kaindl, SandrinePassemard Pavan Kumar ,BenedicteGerard,AlainVerloes,Shyamala Mani and PierreGressens(2010).Manyroadsleadto primary autosomal recessive

primarymicrocephaly.Progess in Neurobiology,90(3):363-83.

3. JenniferL.Moran,EmilyT.Shifley,John M. Levorse, Shyamala Mani,KristinOstmann,AriadnaPerez,DawnM.Walker,ThomasF.Vogt,andSusanE.Cole(2009).Expressionanddeletionanalysesof Manic fringe indicates thatit isnot required for embryonicdevelopment, and that FRINGEproteins are not functionallyredundant. DevelopmentalDynamics, Developmental Dynamics,238(7):1803-1812.

4. Kim-DaDestot-Wong,KunLiang,ShaileshKumarGupta,GéraldineFavrais, Leslie Schwendimann,Michael Spedding, VincentLe l i èvre , Shyamala Maniand Pierre Gressens (2009).The AMPA receptor positiveallostericmodulator,S18986,isneuroprotectiveagainstneonatalexcitotoxic and inflammatorybrain damage through BDNFsynthesis.Neuropharmacology,57:277-286.

Presentations:

Parthiv Haldipur, Upasna Bharti,Chitra Sarkar, Corinne Alberti,Soumya Iyengar, Pierre Gressens,ShyamalaMani:Pretermdeliveryaltersthe developmental program of thecerebellum.FrontiersinOrganogenesis,Kobe, Japan. 23rd – 25th March2010

Funding:

NBRCCorefunds

DepartmentofBiotechnology,India


Principal Coordinator 2006-2009:BasicBiologyofNeuralStemCells.

Aprogramgrantunderwhichthereare8sub-projectsthatdealwithvariousaspects ofunderstandingbasic stemcellbiologyandapplicationsinretinal,spinal and stroke injurymodels inrodents.

Indo–French Centre for the Promotion of Advanced Research

Principal Investigator; 2009-2012:Neural differentiation of embryonicstemcells.

Themajorgoalofthisprojectistostudythedirecteddifferentiationofhumanembryonicstemcellsintoneurons.

Collaborator:

Prof.PierreGressens,INSERMU676,France

Degrees Awarded (Ph.D.):

ManojKumar2009


Prof. V. Ravindranath

Research Fellows

Varsha Agarwal, Neha Sehgal

Theunifyinggoalofthelaboratoryistounderstandpathogenicmechanismsunder ly ing neurodegenerat i vedisorders thatwouldpotentially leadto identification of drug targets thatcanbeusedtodeveloprationaldiseasemodifying therapies. To this effect,we adopt a combinatorial approachinvolvingbiochemicalandhistochemicaltechniquestoelucidatepathogenicallyimportantcellularpathwaysinanimalmodelsofParkinson’sandAlzheimer’sdisease.Fromthetherapeuticangle,wearealsodefiningthemodeofactionoftraditionalmedicinalpreparationsusedinthetreatmentofneurodegenerativedisorders,particularlyseniledementia,which help us to screen naturalproducts that can be developed aspotential drugs. Drug targets alonedonotensuresuccessfultherapeuticstrategies,asinsitudrugmetabolisminthebrainiscriticalfordrugaction.Inthisregard,weareidentifyingandcharacterizingbrainCYP450enzymes

Cytochromes P450 dependent metabolism of drugs in brain

with particular emphasis on brain-specificbiotransformationpathwaysofbothdrugsandendogenouscompoundsthat play a role in pathogenicphenomena,suchasinflammationinthebrain.

CytochromeP450(P450),asuperfamilyof heme proteins is involved in themetabolism of xenobiotics andendogenous compounds.While liveris themajororgan involved inP450-mediatedbiotransformation,functionalP450enzymesarealsopresentinthebrainwhereintheymetabolizeavarietyofcompounds.TheP4504Fsubfamilycomprisesof7functionalenzymesinhumans, 4 in rat and5 inmice. AlloftheenzymesoftheP4504Ffamily(Cyp4f) catalyze at varying rates thehydroxylation of the inflammatorycascade prompt leukotriene B4(LTB4)toitsinactive20-hydroxylatedproduct.LTB4 isaproductofactionof5-lipoxygenaseonarachidonicacid,while another class of inflammatoryprompts, the prostaglandins areformedfromarachidonicacidbycyclo-oxygenases to epoxy products. TheCyp4f subfamily can alsometabolizehydroxyeicosa-tetraenic acid (HETE)and hydroperoxyeicostetraenoic acid(HPETE), which are alsometabolicsignals for vasoconstriction/dilation


or other functions.Cyp4fs thus playa significant role inmodulating theinflammatorycascadebyhydroxylatingandinactivatingbothleukotrienesandprostaglandins.WhileCyp4fenzymeshave previously been shown to bepresentinhumanandratbrain,whatislesscleariswhethertheCyp4fsplayaneuroprotectiveroleinbrainduringaninflammatoryinsult.OurworkinghypothesisisthatbraincytochromesP-450 4Fs play an important rolein the metabolism of endogenouscompoundsandthereforecaninfluencethe inflammatory response. Thelong-term objective of the proposedproject is to understand the role ofin situmetabolism in the brain indetermining the pharmacologicalresponse to psychoactive drugs aswell as endogenous compounds thatregulateimportantcellularresponses,suchasinflammation.

InflammatoryprocessesareinvolvedinpathogenesisandprogressionofCNSdisorders,suchasinfection,traumaticbrain injury, and neurodegenerativediseases. Eicosanoids includingleukotrienes, particularly leukotrieneB4 (LTB4) mediate inflammatory

responsebyinitiatingandamplifyinggenerationofcytokinesandchemokines.Cytochrome P450 (Cyp), a family ofheme proteinsmediatemetabolismof xenobiotics and endogenouscompounds, such as eicosanoids.We demonstrate thatmouse brainCyp4fsareexpressedubiquitouslyinseveralcelltypesinthebrainincludingneuronsandmicroglia,andmodulateinflammatory response triggered byLPS,invivoandinmicroglialcells,invitrothroughmetabolismofLTB4totheinactive20-hydroxyLTB4. ChemicalinhibitororshRNAtoCyp4fsenhanceinflammatory response,while PPARagonist,fenofibrateinducesCyp4fsandattenuatesit.Thus,catalyticactivityofCyp4fsisanoveltargetformodulatingneuroinflammationandwe identifyanew application for the well-knowndrug,fenofibrate.

Funding:

ThisworkissupportedbyNIH-RO1.

Collaborator:

Henry Strobel, University of TexasMedicalSchool,Houston



Research Fellows

Lalitha, Uzma Saeed, Ajit Ray

Pa rk i n s on ’ s d i s e a s e ( PD ) , aneurodegenerat ive d isorder ischaracterizedbylossofdopaminergicneuronsinthesubstantianigraparscompacta. Idiopathic Parkinson’sdisease(PD)asopposedtoheritableforms of Parkinson’s disease (PD)accountsforgreaterthan90%oftheParkinson’sdisease incidenceworldover.Oneofthecompellingquestionsinunderstandingthepathogenesisofneurodegenerative disorders is theselectivevulnerabilityofspecificcelltypestoneurodegeneration.Theredoxstatusofproteinsregulatesignalingpathwaysthatgovernbothcellsurvivalanddeath.Itisourhypothesisthatproteinthiolmodification,occurringasaresultofoxidativestressresultsinmitochondrialdysfunctionandalteredredoxsignalingleadingtoactivationofcelldeathandsuppressionofsurvivalpathways. Our overall aim is tounderstanddifferentialvulnerabilityofselectivecellpopulations,suchasthe

Cell specific redox driven apoptotic signaling in Parkinson’s disease

dopaminergicneuronsofsubstantianigratoneurodegeneration.

ImpairmentofAktphosphorylation,acriticalsurvivalmoleculehasbeenimplicated in the degeneration ofdopaminergicneuronsinParkinson’sdisease(PD).However,themechanismunderlyingpAkt loss isunclear.Wehavedemonstratedtheselectivelossof pAkt in the ventralmidbrain inmice treatedwith the dopaminergicneurotoxin,MPTP and showed thattheprimarymechanismofpAktlossis due to increased association ofoxidatively modified Akt with thephosphatase, PP2A resulting inenhanceddephosphorylationofAkt.MicetreatedwithMPTPshowoxidationofcysteineresidue(s)inAktbothaftersingle and chronic exposure that isreversed by pretreatmentwith thiolantioxidants.MaintainingtheproteinthiolhomeostasispreventsthelossofreducedAktandeventuallypredservespAktlevels.Further,overexpressionof glutaredoxin in human primaryneurons helpsmaintain the redoxstatus of Akt and abolishes pAktloss caused byMPP+ exposure.Wedemonstrate that oxidative stress,a criticalmediator of dopaminergiccell death in PD downregulatesAkt cell survival pathway through


redox modification of Akt, whilePTEN,theredoxsensitiveupstreamphosphatase that antagonizes Aktsurvival pathway is not modified.Maintenance of redox homeostasis

by thiol antioxidants and enhancedexpressionofGrx1couldslowdownthe progress of Parkinson’s diseasebypreventingthedysregulationofthepAktcellsurvivalpathway.



Research Fellows

Neha Sehgal, Alok Gupta

Traditionalsystemsofmedicinesuchas, Ayurveda offer a knowledge basethat can beutilized for developmentfortherapeuticinterventionstrategiesfor treatment of neurodegenerativedisorders,suchasAlzheimer’sdisease.Neuropharmacologicaleffectsofplants,whichareusedintraditionalsystemofmedicine for treatmentofage-relateddementiaincludingAlzheimer’sdiseasearebeingexaminedinanimalmodelsofAlzheimer’sdiseaseandthemolecularmechanismsunderlying their actionarebeingidentified.

Oral administration of semi-purifiedplant extract reversed behavioraldeficits, accumulation of plaquesand oligomers, and lowered levels ofβ-amyloid peptides 40/42 (Aβ40/42)in brain of bothmiddle-aged (9-10months) and old (22-24 months)Alzheimer’sdiseaseTgmice(APPswe/PS1∆E9).DecreaseofAβ42monomers

evaluation of the molecular basis of the pharmacological action of traditional medicinal preparations used in the treatment of dementia

inbrainandincreaseinplasmaAβ42was seen after 7 days indicatingincreased transport of Aβ peptidesfrombraintotheperiphery.Increaseinbrainlow-densitylipoproteinreceptor-relatedprotein(LRP),whichisinvolvedintransportofAβ42/40frombraintotheperipherywasseenat14daysandwasrestrictedtomicrovessels.Increaseinneprilysin(NEP),theAβdegradingproteasewas seenmuch later at 21days.However, substantial increaseinliverLRPandNEPwasseenearlierat 7 days. Increase in liver LRPwasaccompanied with enhancement ofplasmasLRPthatisknowntoactasaperipheralsink forbrainAβ40/42.Further, in WT mice, the extractinducedliverbutnotbrainLRPandNEPexpression,whichwas accompaniedby decrease Aβ40/42 in serum andbrain indicating that the increase inliverLRPandplasmasLRP,occurringindependent of the concentrationof Aβ40/42, results in clearance ofAβ from the brain inWTmice. Theremarkable therapeutic effect of theextractmediatedthroughup-regulationofLRPandNEPindicatesthattargetingtheperipheryoffersanovelmechanismforeliminationofAβ42andreversesthebehavioraldeficitsandpathologyseeninAlzheimer’sdiseasemodels.


Funding:

ThisworkissupportedbyDBT.

PCThasbeenfiledfortheabove

Collaborators:

S.C.Jain,DelhiUniversity,P.Balaram,IISc

Presentations

1. N. Sehgal , V. Agarwal , K.Valli, L. Antonovic, H. Strobel,V.Ravindranath.Neuroprotectiverole of cytochrome P4504f inresolution of inflammation inbrain.Presentedatthethe39thannualmeeting of the SocietyforNeuroscience,Chicago,USA.October17–21,2009.

2. RayA,SaeedU,ValliRK,KumarAMRK, Karunakaran S andRavindranathV:Perturbationofproteinthiolhomeostasisthroughdownregulationofglutaredoxin,aproteindisulfideoxidoreductase,results in loss ofDJ-1 throughproteolysis; Poster presented attheXVIIIWFNWorldCongressonParkinson’sDiseaseandRelatedDisorders,Miami Beach, USA.December13-16,2009.

Publications

1. Saeed, U., Ray, A., Valli, R.K.andRavindranath, V (2010)DJ-1 loss by glutaredoxin butnotglutathionedepletiontriggersDaxxtranslocationandcelldeath.Antioxidants & Redox Signaling,13(2):127-144.

2. K a r u n a k a r a n , S . a n dRav ind rana th , V ( 2009 )Activation of p38MAP kinasein substantia nigra leads tonuclear translocation of NF-kBinMPTPtreatedmice:Implicationin Parkinson’s disease. J. Neurochem,109:1791-9.

Patent

Withania somniferaplantextractandmethod of preparation thereof. Jointpatent withUniversity of Delhi andIndianInstituteofScience-Bangalore.



dr. Pankaj Seth

Research Fellows

Mamata Mishra, Pretty Garg and Shaily Malik

Project Assistants

Hena Khalique, Manisha Taneja

Technical Assistant

durgalal Meena

Lab Assistant

Naushad Alam

Research inneurosciencesandmoreso in the area of neurovirologywasstimulated to great extent followingdesignationof1990sas“DecadeoftheBrain”byNationalInstitutesofHealth.During that period clinicians werestrugglingwithanentirelynewimmunecompromising disease, the acquiredimmunodeficiency syndrome (AIDS)caused byhuman immunodeficiency

Cellular and Molecular Mechanisms of HIV-1 neuropathogenesis

virus-1 (HIV-1). One of the majorchallengesofthatera,andeventoday,is to find answers for significantneurological deficits presented inpatients suffering from this dreadeddisease.

Neurological deficits in HIV/AIDSpat ients are character ized byneurodegeneration in frontal cortex,basalganglionandbrainstemregionofhumanbrain.Progressivecognitiveandmotorimpairmentsinvolvingbehavioralabnormalities, deficits in executivefunctionsanddementiaarecommonin AIDS patients. These disordersappear in advanced stages ofHIV-1infection due to irreversible damagetoneuronsbyHIVoritsviralproteinsgp120 and Tat. Such neurologicaldeficits are collectively referred to asHIV-1 associated dementia (HAD) orAIDSdementiacomplex(ADC).Adventofcombinatorialanti-retroviraltherapy(cART)hasgivenanewleaseoflifetomostoftheHIV/AIDSpatientswhohaveaccesstothis“wonderdrug-cocktail”.Inlastfiveyearsorso,severeHADorADCisnotcommonanymorethoughamilder formofdementiaknownasHIVassociatedneurocognitivedisorder(HAND) is becomingmore prevalentamongsuchpatients.TheprevalenceofHANDisbelievedtoincreasefurther


asHIV/AIDSpatients arenow livinglongerduetosuccessfulanti-retroviraltherapy.Moreover,humanbrainservesasa“safeheaven”fortheHIV-1,wheremost of these drugs have very poorpenetrationduetobloodbrainbarrier.DespitethesuccessofcART,thecentralnervous system infectionwithHIV-1andsubsequentdevelopmentofmildtosevereneurologicaldisordersremainachallengeforinvestigatorsworkinginneuroAIDSfield.Basicneuroscientistsandneurologistsareworkingtogetherto get to the crux of these braindisordersinAIDSpatients.

Neuralstem/precursorcellsreplenishageingordamagedbraincellstilllate

in life by forming new neurons orneurogenesis. Neurogenesis occursthroughoutadulthood in thedentategyrusofhippocampus,thecenterforlearning andmemory, unfortunatelyHIV-1hasbeenreportedtoinfecttheseimportantareasofbrain.Inadditiontoitspresenceinastrocytesandmicroglialcells,HIV-1virusisreportedinareasof neurogenesis in autopsy brainsectionsfrompediatricAIDSpatients,suggestingthatHIV-1caninfectandthriveinhumanneuralstem/precursorcells.Several investigators, includingour group have shown that HIV-1canaffectneuralstem/precursorcellfunctionsininvitromodels.

Figure 1: HIV-1 Tat Modulates Expression P r o f i l e o f G e n e s Important for Human Neurogenesis and Neural Stem Cells. A) TattreatedhNPCs show decreasedexpressionlevelsofseveralof the neurogenesis andneural stem cell genes(downwardarrowhead).B)Quantitativeassessmentofintensityoftheexpressedgenes normalized withhouse keeping genes.Geneswithalterationsof20%ormoreoverrespectivecontrolarerepresentedinthefigure.


We used a well characterized cellculture model of human neuralprecursor cells established by us.These neural precursors grow asundifferentiated, highly proliferative,adhered monolayers cultures. Wecultured these cells in presence orabsence of HIV-1 transactivatingproteinTat.HIV-1Tatattenuatedthegrowth,proliferationanddifferentiationcapabilities of human fetal brainderivedneuralstem/precursorcells.

Themajor steps involved in processofregulationofneuralprecursorcellsandneurogenesis are - proliferation,migration, differentiation and axonalguidance, so we used a pathwayspecific cDNAmicroarray comprising263genesspecificallyrelatedtothesefunctions rather than a global geneexpressionprofile.TotalRNAisolatedfromhNPCsundergoingdifferentiation/neurogenesisinpresenceandabsenceofHIV-1Tatfor5dayswereusedforcDNAmicroarray.

AtDay5postdifferentiation,Tatresultedindownregulationofgenescrucialforregulationofcelldifferentiation(ASCL1,JAG1),cellsignalinggenesinvolvedinneurogenesis(JAG1),cellproliferation(JAG1, S100 beta, PTN, SPOCK1),regulationforcellmotilityandmigration(KAL1,MTSS1), cell adhesion (KAL1,MTSS1,SPOCK1,PCDHB-2,-5,-14,-15and -16, ROBO2), synaptic function(S100beta,PCDHB-2,-5,-14and-16),regulation of transcription (ASCL1,CHD6andPBX1),cellcycleregulation(MTSS,PTN,KAL-1andSPOCK1)andgrowthfactorsandcytokines(CSPG5,FGF13,JAG1,NRG1andPTN).ThesefindingssuggestthatHIV-1Tataffects

at various levels of neural stem cellfunctionswhich affects its stemnessaswell as the neurogenesis relatedgenes.

Mountingevidencesuggeststhatdrugsof abuse accelerate the incidenceand progression of HIV-1 inducedneurological complications in AIDSpatients.DrugabusingHIV-1positiveindividuals exhibit more severecognitive impairment comparedwiththe non-drug-abusing HIV-positivecounterparts.Hencethereisanurgentneed to investigate the underlyingmechanismsandpathways thatmaylead to increased neuronal damage.We are actively engaged in anotherresearchprojecttodissectoutmolecularmechanisms that may be involvedin neuronal damage by co-exposureof humanneurons toHIV-1Tat andmorphine. Our preliminary resultssuggest that presence ofmorphinewithHIV-1Tatsignificantlyaugmentsthe neuronal cell death. Detailedinvestigations are in progress toinvestigatethesignalingmechanismsfor these observations and to tracethemolecular signatures thatmarkthis event.We are also exploring ifplateletderivedgrowth factor (PDGF)can be helpful in abrogating the co-morbidity of these two agents onhumanneurons.

These findings provide a new facetto HIV-1 neuropathogenesis andprovide the cellular andmolecularbasis ofHIV-1 Tat induced changesonneurogenesisaswellashowdrugsofabuseaggravatetheHIV-1induceddamagetohumanbrain.


Presentations:

1. P.Seth:Invited Speaker,BrainAwarenessWeek,BanarasHinduUniversity,Varanasi,India,March2010.

2. P.Seth:Guest Speaker,NationalScienceDay,KendriyaVidyalaya,Manesar,India,February2010.

3. P . Se th : Guest Facu l ty ,Jawaharlal Nehru UniversityAcademic Staff College Lectureseries for college teachers,NewDelhi,India,January2010.

4. P. Seth: Invited Speaker & Convene r In t e rna t i ona l Symposia, AnnualMeeting ofIndianAcademyofNeurosciences,NIIMSUniv, Jaipur, India,Dec2009.

5. P.Seth:Invited Speaker,AnnualmeetingofInternationalSocietyofNeurovirology(USA),Miami,USA,June2009.

6. P. Seth: Invited Speaker,I n t e rna t i ona l Neu roA IDSResearchMeeting organized byHIV Neurobehavioral ResearchCenter(HNRC),Miami,USA,May2009.

7. P. Seth: Invited Speaker,Annual meeting of Society ofNeuroimmunopharmacology(USA)atWuhan,China,heldinApril2009.

Funding:

ThisworkissupportedbygrantsfromDBT,IndiaandR01GrantfromNIH,USA.

Collaborators:

V Ravindranath, S K. Sharma, N.DhingraandNJain,NBRC,India.

N.ThaparandA.Singh,CivilHospital,Gurgaon,India.

U. K. Ranga, JNCSAR, Bangalore,India.

A Nath, Johns Hopkins University,Baltimore,USA.



dr. Ellora Sen

Research Fellows

Vivek Sharma, Richa Tewari, Nitin Koul, deobrat dixit, Sadashib Ghosh

Project Assistants

Sourav Roy Choudhury, Sourav Ghosh

Technical Assistant

Uttam Kumar Saini

Lab Assistant

Rajesh Kumar Kumawat

Glioblastoma multiformes (GBM)representsoneofthemostmalignantbraintumorscharacterizedbyintenseproliferation,widespread invasion ofpoorly differentiated cells and poorprognosis.Thetumormicroenvironmentplays a major factor in inducingmalignancy and elevated expressionof pro-inflammatory cytokines hasbeen implicated in the progression

Understanding aberrant transcriptional circuitries and signaling cascades in Glioblastoma multiforme

ofGBM. The focus of our laboratoryis to understand the importanceof inflammatory mediators andgrowth factorson the transcriptionalregulation of genes associated withGBM progression and survival. Theaim is to understand how aberranttranscriptional circuitries and signaltransduction pathways contributeto the progression of GBM. Thehighly resistant nature of GBM tochemotherapyhasalsopromptedustoidentifynewtreatmentstrategies.

Objectives

1. Dissecting the role of cytokinesand growth factors in thetranscriptional regulation ofgenes involved in resistance toapoptosis,proliferation,survivalandevasionofimmuneresponseingliomacellsisanactiveareaofresearchinthelab.

2. Understandmechanisms thatconfer resistance of GBM toapoptosis and identify newtreatment strategies that canmanipulatetheaberrantsignalingpathwaystoinduceapoptosis.

Inflammationwhichisanindispensableparticipant in tumor progression isintricatelylinkedwithredoxmodulation.


Thepro-inflammatorycytokineTumorNecrosisFactor(TNF)elevatesreactiveoxygenspecies(ROS)inGBM.TNFalsoelevatesAktphosphorylationingliomacells.WehaveobservedthatincreaseinAktphosphorylationwasconcurrentwith decrease in ROS scavengersuperoxidedismutase(SOD-1)levels.TNFmediated increase inpAktwasdependentonoxidativestressaspAktlevelswasabrogated in thepresenceof ROS inhibitor N-acetylcysteine(NAC)andelevatedincellstransfectedwith SOD-1 siRNA. TNF alteredactin cytoskeletal organization andincreasedCdc42levels.Thisincreasein Cdc42was concomitant with itsincreased interaction with scaffoldprotein IQGAP-1. Also, we havereported for the first time a ROSdependent interaction between pAktand IQGAP-1 in TNF treated cells.Importantly, Akt inhibition not onlyreversed TNFmediated changes in

actincytosketalorganizationbutalsoabrogated anchorage independentgrowth.Together,theseresultssuggestthat TNF induced oxidative stressaffectAktactivationtoregulateactin`organization and growth of gliomacells.

WealsoidentifiedanovelmechanismofinductionofapoptosisinglioblastomacellsbyScriptaid-anHDACinhibitor.ScriptaidreducedgliomacellviabilitybyincreasingJNKactivationanddecreasingtelomeraseactivity.ThoughScriptaidinduced activation of both p38MAPKandJNK,itwastheinhibitionofJNKthat attenuated Scriptaid-inducedapoptosissignificantly.Scriptaidalsoincreasedtheexpressionof(i)p21andp27 involved in cell cycle regulationand (ii) γH2AXandMLH1associatedwithDNAdoublestrandedbreakandmismatchrepairresponserespectively,inaJNKdependentmanner.TreatmentwithScriptaidincreasedRasactivityinglioma cells and transfection of cellswithconstitutiveactiveRasV12furthersensitized glioma cells to Scriptaidinducedapoptosis.Scriptaidmediatedinhibition of telomerase activitywasindependentofJNKactivation.Takentogether, our findings indicate thatHDAC inhibitor Scriptaid inducesgliomacellapoptosisbyelevatingJNKactivationanddecreasing telomeraseactivity.

SincethefarnesyltransferaseinhibitorManumycin isknownto induceROSgeneration,weevaluatedtheeffectofManumycinongliomacells.Manumycininduced glioma cell apoptosis byelevatingROS generation. Treatmentwith ROS inhibitor N-acetylcysteine(NAC) blockedManumycin inducedapoptosis,caspase-3activityandPARP

Figure:TNFincreasesthecolocalizationof Aktwith scaffold protein IQGAP-1 ingliomacellsinaROSdependentmanner.C,TandNACdenoteControl,TNFandN-acetylcysteinerespectively.


expression,indicatingtheinvolvementof increasedROSintheproapoptoticactivityofManumycin.ThisheightenedROS level was accompanied withconcurrent decrease in antioxidantsSOD-1andthioredoxin(TRX-1).SOD-1overexpression protects glioma cellsfromManumycininducedapoptosis.Inaddition,siRNAmediatedknockdownof SOD-1 and TRX-1 also increasedROS generation and sensitivity ofglioma cells toManumycin-inducedcell death. Interestingly, suppressingROSgenerationpreventedManumycininducedRasinhibition.Wereportforthe first time that (i) Ras inhibitionbyManumycin is due to heightenedROSlevels(ii)Manumycininhibitsthephosphorylation of signal transducerand activator of transcription 3(STAT3) and telomerase activity inROSdependentmannerwhichplaysacrucial role ingliomaresistance toapoptosis.InadditionManumycinalsoinducedDNAdamagerepairresponse,affectedcellcycleregulatorymolecules,impaired colony forming ability ofglioma cells in a ROS dependentmanner.

Publications:

1. Ghosh S, Tewari R, Dixit D,Sen E (2010) TNF inducedoxidative stress dependent Aktsignalingaffectsactincytoskeletalorganization in glioma cells.Neurochemistry International56(1):194-201.

2. SharmaV,KoulN,JosephC,DixitD, SGhosh andSen E (2010)HDACinhibitorScriptaidinducesglioma cell apoptosis throughJNK activation and inhibition

of telomerase activity.Journal of Cellular and Molecular Medicine.14(8):2151-61.

3. Dixit D, Sharma V, Ghosh S,Koul N, Mishra PK and Sen E (2009) Manumycin inhibitsSTAT3, telomerase activity andgrowthofgliomacellsbyelevatingintracellular reactive oxygenspecies generation.Free Radic Biol Med.47(4):364-74.

Book Chapter

SharmaV andSen E (2009) Tumormicroenvironmentand inflammation:role in glioblastoma progression.Editors: GP Talwar and OP Sood(NarosaPublishinghouse).

Sen E and Ravindranath V (2010)Neurobiology. ‘Science in India.AchievementsandAspirations’.Editors:HY Mohan Ram and PN Tandon.IndianNationalScienceAcademy,NewDelhi.

Patent:

“Bicyclic triterpenoid Iripallidal as anovelanti-gliomaandanti-neoplastictherapyinvitro”.FiledforIndianpatentthroughDepartmentofBiotechnology(#2915/DEL/2008)andInternationalpatent(PCT/IN09/000336).

Presentations:

1. Vivek Sharma*, Nitin Koul,Veer SinghMehta and ElloraSen: Interleukin-1β inducedHIF- transcriptional activityin glioma cells is regulated byRas via NF-κB. Frontiers inBasicCancerResearchMeeting.Boston,October2009.


2. Ellora Sen: Inflammation andCancer:Romancingdeath.WestBengalStateUniversity,Calcutta,August,2009

3. Deobrat Dixit*, Vivek SharmaandEllora Sen: Casein Kinase2 inhibition induces SOCS-1 expression and sensitizesglioblastoma cells to TumorNecrosis factor (TNF) inducedapoptosis. Indian Academy ofNeuroscience,JaipurDecember,2009.

4. Nitin Koul*, Vivek Sharma,Deob ra t D i x i t , S adash i bGhosh andEllora Sen:Bicyclictriterpenoid Iripallidal inducesapoptosis and inhibits Akt/mTORpathway in glioma cells.International Symposium onCancer Chemoprevention andTranslational Research, NewDelhi,December,2009.

5. VivekSharma,NitinKoul, VeerSinghMehta and Ellora Sen*:3rdInternationalSymposiumonTranslational CancerResearch,Bhubaneswar,December,2009

6. VivekSharma,NitinKoul, VeerSinghMehta and Ellora Sen*:Macbeth’sthreewitchesinglioma:IL-1β,RasandNFκB.MolecularImmunology Forum. Calcutta,January,2010

*Presentingauthor

Funding:

i. InnovativeYoungBiotechnologistsAward(IYBA,2007),toElloraSenbyDepartmentofBiotechnology

ii. DefenceResearch&DevelopmentOrganization,MinistryofDefence.(DLS/81/48222/LSRB-140/EPB/2007)

iii. DepartmentofBiotechnology,(BT/PR/7407/Med/14/934/2006).

Collaborator:

Dr. VS Mehta, Paras Hospitals,Gurgaon

Award:

NASI–SCOPUSYoungScientistAwardconferredjointlybyNationalAcademyofScienceandElseviers2010.



dr. Ellora Sen

Project Assistants

Sk. Sudipta Shaheen

Neural stem cell (NSCs) in themammalian central nervous system(CNS)possesstheabilitytoself-renewaswell as tomaintain the potentialof generating all three major celltypesoftheCNS:neurons,astrocytesand oligodendrocytes.Differentiationof neural precursors into neurons,astrocytesandoligodendrocytestakesplacesequentiallyandextrinsicfactorsplay pivotal role in specifying celllineages inthedevelopingbrain.Thedecisive instructive and permissivesignals,thatgovernthesedevelopmentalchoices,areprovidedbycellexternalcues and cell intrinsic programs.Recent advances in understandingNSCdifferentiationintogliallineageshaverevealedtheimportanceofgrowthfactors and relevant downstreamtranscription factors. These factorsworking through their respectivedownstream transcription factorcombinatoriallyinducethepreferential

Signaling cascades regulating the differentiation of glial progenitors along specific lineages

differentiation of one cell lineagewhile suppressing another. Recentstudiessuggestthathypoxiapromotesthe survival and proliferation ofNSCs.We are investigatingwhetherhypoxia regulates the transcriptomeof bipotential glial progenitors inthe subventricular zone (SVZ), - aregion of the brain that harbors themultipotential neural stem cells/progenitors, to induce preferentialdifferentiationtowardsonelineageattheexpenseofanother.

Objectives

To understand how extrinsic cuesin a hypoxic environment regulatedownstreamtranscriptionfactorsthateffect NSC differentiation towardsastrocyticlineage.

We hypothesized that there isaberrantglialcellgenerationfromthesubventricularzone(SVZ)afterneonatalhypoxiaischemia(H/I)thatcontributesto an increased astrogliogenesiswith concomitant oligodendroglialinsufficiency.MicroarrayandqRT-PCRanalysesofthedamagedSVZofratpupssubjected to hypoxia/ischemia (H/I)showedincreasedexpressionofseveralcytokinesandreceptorsthatareknownto promote astrocyte differentiation,suchasEGF,LIFandTGFßsignaling


components. Using gliospheres tomodeltheneonatalSVZ,weevaluatedtheeffectsofthesecytokinesonsignaltransduction pathways regulatingastrocyte generation, proliferationand differentiation. These studiesdemonstrated that combinations ofEGF, LIF and TGFß1 reconstitutedtheincreasedastrogliogenesis.TGFß1-induced Smad 2/3 phosphorylationand the combination of EGF, LIFand TGFß1 synergistically increasedSTAT3 phosphorylation over singleor double cytokine combinations.Pharmacologically inhibiting ALK5signaling in vitro antagonized theTGFß1-induced increase inastrocytegeneration, and antagonizing ALK5signaling in vivo similarly inhibitedastrogliogenesiswithintheSVZduringrecoveryfromH/I.Ourstudiessuggestthat aberrant specification of glialprecursorswithin the neonatal SVZduring recovery from neonatal H/Iis a consequence of altered cytokinesignaling.

Publication:

1. Bain JM, Ziegler A, Yang Z,LevisonSW*,Sen E*(2010)TGFβ1stimulates over-production ofwhitematterastrocytesfromglialprecursorsofthe“brainmarrow”in a rodentmodel of neonatalencephalopathy.PLoS One, 5;5(3):e9567.

* Co-corresponding Authors

Funding:

Department of Biotechnology (BT/PR6615/MED/14/857/2005).

Collaborator:

Prof.StevenW.Levison,DepartmentofNeurology&Neurosciences,UMDNJ–UHCancerCenter,NewJerseyMedicalSchool,Newark,NJ07103.



dr. Shiv K Sharma

Research Fellows

Chinmoyee Maharana, Kaushik Sharma, Kiran Pandey

Project Assistant

Preeti Yadav

Lab Attendant

Narayanan

Theoverallgoalofmylabistoinvestigatethemolecularmechanismsofsynapticplasticity and memory, and themechanismsthatmaycontributetocelldeathanddeficitsinsynapticplasticityandmemoryintheAlzheimer’sdisease.Inthisregard,weareworkingontworelatedprojects.

The investigation ofmolecular andsynaptic mechanisms of memoryhas received considerable attention.Activity-dependent molecular andsynaptic changes play importantroles inmemory formation. Long-

Molecular Mechanisms of synaptic Plasticity and Memory: Activity-Dependent Protein Modifications

termpotentiation (LTP), a persistentincrease in the synaptic strength iswidely studied as a putative cellularmechanism of memory formation.Despite extensive investigation, themolecular changes involved in LTPandmemoryarefarfromunderstood.Activity-dependent changes in thesignalingmoleculesplaycrucialrolesinLTPandmemory.Inaddition,changesinproteinsynthesisandtranscriptionareinvolvedintheseprocesses.

(I) Activity-dependent regulation of histone acetylation:

GiventherequirementofRNAsynthesisinLTPandmemory,weareinvestigatinghow activity leads to changes inchromatinmodificationswhichmaybe involved inRNA synthesis duringLTPandmemory.Forthesemolecularstudies, we prepare slices from therat hippocampus and stimulatethemwithKCl. KCl treatment leadsto depolarization in the cells andCa++influx.Ca++influxisaprimaryrequisitefordifferentkindsofLTPandmemory formation. Importantly, KClcan induce LTP in thehippocampusandthiseffectrequirestheactivityofNMDA type of glutamate receptors.TheNMDAreceptoractivityiscriticalformany forms of LTP andmemory.


These studies would enhance ourunderstandingofthemechanismsthatcontribute to the regulation of geneexpressionduringLTPandmemory.

Inthenucleus,DNAispackagedwithhistones into nucleosomes. Histonemodifications play crucial roles inregulating the state of chromatin,and thus transcription. Acetylationof histones is associated withtranscriptionalactivation.Earlier,wereportedactivity-dependentregulationofhistoneH2B.Duringtheyear,wehaveperformed additional experiments onH2Bacetylationthathavestrengthenedthefindings.KCldepolarizationleadsto increase in histone acetylation intheCA1 region of the hippocampus(Fig.1).

Since depolarization leads to Ca++influxandCaMKisoneofthekinasesactivatedbyCa++influxandknowntoplaycrucialrolesinLTPandmemory,weexaminedwhetherCaMKactivityisrequiredforH2Bacetylation.WefoundthatwhenCaMKactivitywasinhibitedusing its pharmacological inhibitor(KN-93), depolarization-induced

Figure1 KCl depolarization enhanceshistoneH2Bacetylationinthehippocampalslices. Control or KCl treated acutehippocampal slices were processed forimmunohistochemistryusing acetyl-H2Bantibody. KCl treatment enhancedH2Bacetylationintheslices.CA1regionofthehippocampusisshown.

Control KCI

H2Bacetylationwasabolished. Onfurther examination, extracellularsignal-regulatedkinase(ERK)activitywas found to be critically requiredfor depolarization-induced H2Bacetylation. Our results combinedwithotherstudiespointtoacriticalrole of ERK in activity-dependenthistone modifications. Thus, ERKactivitywhichiscriticalforsynapticplasticity and memory regulateshistone modifications in additionto regulating protein synthesis andtranscription factors. Furthermore,ourstudies revealacritical role forCaMK inactivity-dependenthistoneacetylation. In addition, we foundthatDNAmethyltransferaseactivityisalsoimportantfordepolarization-induced H2B acetylation in thehippocampus Taken together withearlierstudies,ourresultssuggestacrosstalkbetweenDNAmethylationand histone acetylation. ThusH2Bacetylation is regulated by eventsthat play crucial roles in LTP andmemory.

The physiological significance ofd e p o l a r i z a t i o n - i n du c e d H2Bacetylationiscurrentlynotunderstood.It is known that cbp+/-mice showimpairment in LTP and memoryalong with deficits in histone H2Bacetylation. Importantly, histonedeacetylaseinhibitorswhichincreasethe levels of acetylation includingH2B acetylation can ameliorateimpairment in LTP and memory.These results suggest that H2Bacetylation may be important forLTP and memory. We have nowstarted experiments to examineactivity-dependentregulationofotherhistonesofthenucleosome.


(II) Characterization of Acetyl-p55 in the Hippocampus

The level of acetylation in a cell isregulated by the relative activities ofhistone acetylases and deacetylases.Wehad found that treatment of thehippocampal slices with a histonedeacetylase(HDAC)inhibitorleadstoanincreaseinacetylationofaproteinwithamolecularweightofabout55kDa.HDAC inhibition enhances LTP andmemory,andincreasesacetylationofap55intheinsularcortex,abrainregioninvolved in tastememory formation.Importantly,p55acetylationisregulatedduring taste memory formation.Considering these observations, wecharacterized p55 protein inmoredetail,inthehippocampus.Wefoundthatthemobilityofp55isdifferentfromp53,theanti-oncogene.Inaddition,p55isanon-nuclearproteinasopposedtop53.Wefurtherfoundthat(1)p55hasidenticalmobilityasalphatubulin,(2)conditions leading to polymerizationof tubulin,decreaseacetyl-p55 levelsin theremaining fraction, (3)sodiumbutyrate, which does not inhibittubulindeacetylase,doesnotaffectp55acetylation,and(4)bothacetyl-p55andalphatubulinproducesamepatternintwo-dimensional gel electrophoresis.Theseresultsstronglysuggestthatp55is alpha tubulin.We next examinedwhether alpha tubulin acetylationis regulated by activity. We foundthat depolarization of cellswithKClincreasesacetylationofalphatubulinintheCA1regionofthehippocampus.Wearenowexaminingthemechanismsofdepolarization-inducedalphatubulinacetylation.

Publications:

1. MaharanaC,SharmaKP,Sharma SK(2010).DepolarizationinducesacetylationofhistoneH2Binthehippocampus.Neuroscience,167:354-360.

2. Sharma SK (2010). Proteinacetylationinsynapticplasticityandmemory.Neurosci Biobehav Rev.,34:1234-40.

Presentations:

1. Shiv K Sharma, Kiran Pandey,ChinmoyeeMaharanaandKaushikSharma: Histone deacetylaseinhibitor- and activity-inducedacetylationofp55:relevanceforsynapticplasticityandmemory.PosterpresentationattheSocietyfor Neuroscience Conference,Chicago,USA,Oct.17-21,2009.

2. ChinmoyeeMaharana,KaushikP Sharma andShivK Sharma:D e p o l a r i z a t i o n i n d u c e shistoneH2B acetylation in thehippocampus.PosterpresentationattheXXVIIConferenceofIndianAcademy of Neurosciences,Jaipur,Dec.18-20,2009.

3. Kiran Pandey, ChinmoyeeMaharana,KaushikSharmaandShivKSharma:Activity-dependentregulation of alpha tubulinacetylation. Poster presentationattheXXVIIConferenceofIndianAcademyofNeurosciences,Jaipur,Dec.18-20,2009.

Funding:

DBTandNBRCcore.



dr. Shiv K Sharma

Research Fellow

Shilpa Mishra

Project Assistants

Jyoti Chibber, Soumee Bhattacharya

Lab Attendant

Narayanan

Alzheimer’sdisease(AD)isaprogressiveneurodegenerative disorder and acommon form of dementia amongthe elderly. Pathologically, it ischaracterizedbythepresenceofamyloidplaquesandneurofibrillarytanglesindifferent brain regions. The amyloidplaques are extracellular deposits,whereastheneurofibrillarytanglesareintracellular.Amyloidbeta(A-beta)isaprimarycomponentoftheplaques.A-betaisproducedbytheproteolyticprocessingofalargerintramembranepeptide, amyloid precursor protein.A-betaexistsinseveralformssuchasmonomeric,oligomericandthefibrillar

Amyloid Beta and neurodegeneration: Identification of a Curcumin Metabolite as a neuroprotective Agent

form.SeveralstudiesshowthatA-betaoligomerscausesynapticdysfunctionandneuronalcelldeath. Inaddition,thesetoxicspeciescauseimpairmentin long-term potentiation (LTP). LTPis considered a putative cellularmechanismofmemory.Furthermore,injection of A-beta oligomers in thebraincausesmemorydeficit.Despiteextensiveresearch,themechanismsofneurodegenerationandtheimpairmentin synaptic plasticity andmemoryare not clearly understood. In thisproject,currentlyweare focusingonidentifying agents that can protectneuronsfromA-betaoligomerinducedtoxicity,andexaminethemechanismsofneuroprotection.

Celldeathisacommonfeatureinmanyneurodegenerativediseases includingAD.SeveralstudieshaveshownthatA-beta is toxic to the neurons. Thiseffect of A-beta is brought about intwo ways: (1) A-beta acting on theneurons and affecting their survival(directtoxicity),and(2)A-betaactingontheglialcellsleadingtothereleaseoftoxicsubstancesincludingcytokines(indirect toxicity). Thus, significanteffortsaredirectedtowardsidentifyingcompounds especially from herbsanddietary sources that canprotectneuronsagainstA-beta-induceddirect


andindirectcelldeath.Curcuminisoneoftheneuroprotectiveagentsthathasreceivedconsiderableattentionduetoitsantioxidantactivityandsafetyprofile.Using primaryhippocampal culturespreparedfromratembryos,weearlierreportedthatametaboliteofcurcuminshowed neuroprotective propertyagainstoligomericA-beta-inducedcelldeath and the possiblemechanismsinvolved in neuroprotection.Duringthe year, we have performedmoreexperimentstostrengthenthefindingson the curcuminmetabolite. A-betatreatment of the hippocampal cellsleads to cell death. InitiallyweusedMTTreductionassayand found thatthe curcumin metabolite reducedoligomeric A-beta-induced toxicity.This finding was confirmed usinganother assay, the TUNEL staining(Fig.2).TreatmentofhippocampalcellstoA-betaledtoenhancedproductionof reactive oxygen species, reductionofmitochondrialmembranepotentialandcaspaseactivation.

The curcumin metabolite showedprotectiveeffectsinallthesemeasures.Inadditiontoratprimaryhippocampalneurons,curcuminmetaboliteshowedprotective effects in human primary

neurons also againstA-beta-inducedtoxicity. These results suggest thatthe curcumin metabolite protectsneurons by affecting themachineryinvolved in apoptotic neuronal celldeath,andtheantioxidantpropertyofTHCmay contribute to itsprotectiveproperty.AsmentionedearlierA-betaacts on the glial cells and increasestheproductionofsubstancessuchaschemokines,cytokines,ROSandNO.These toxic substances are involvedin indirectly causing neuronal celldeath. WehavestartedexperimentstoexamineindirecttoxicitycausedbyA-betaandneuroprotection.Wehaveobtained some promising results inthisdirectionwhichwearepursuinginmoredetail.

Publication:

Sharma S (2010)Hepatocyte growthfactor in synaptic plasticity andAlzheimer’sdisease.Scientific World Journal,10:457-61.

Funding:

NBRCcore.

Collaborator:

Dr.PankajSeth,NBRC.

Figure 2.CurcuminmetaboliteshowsprotectionagainstoligomericA-beta-inducedcelldeath.Culturedratprimaryhippocampalneuronswereuntreated(control,leftpanel),treatedwitholigomericA-beta(middlepanel)orwitholigomericA-betaandcurcuminmetabolite (rightpanel).TUNELstainingshowsthatoligomericA-betainducedcelldeathwhichwaspreventedbythecurcuminmetabolite.



dr. Anirban Basu

Research Fellows

Sulagna das, deepak Kumar Kaushik, Arshed Nazmi

Research Associate

dr Kallol datta

Project Assistants

Swarupa Chakrabarty, Malvika Gupta

Technical Assistant

Kanhaiya Lal Kumawat

Lab Attendant

Manish dogra

The focus of our laboratory is tounderstand the pathophysiologyand pharmacology of infection andinflammationinCNS.Chronicmicroglialactivation is an important component

Molecular approaches to understand the pathophysiology and pharmacology of infection and inflammatory disorders of Central Nervous system

of neurodegenerative diseases, andthis chronic neuroinflammatorycomponentlikelycontributestoneuronaldysfunction,injury,andloss(andhencetodiseaseprogression)inthesediseases.The recognition ofmicroglia as thebrain’sintrinsicimmunesystem,andtheunderstanding that chronicactivationof this system leads to pathologicsequelae,hasledtothemodernconceptofneuroinflammation.

Ourresearchquestionevolvesaroundthe understanding the molecularbasisofhost-pathogen interaction inViral infection of the brain and thesignalingeventsassociatedwithneuro-inflammation. In last few years ourresearchhavebeenprimarilyfocusedon neuropathology of host pathogeninteraction in Japanese encephalitisVirus (JEV), causative agent ofmostcommon Viral encephalitis in Asia-pacificregion.Increasingexperimental,clinical, and epidemiological studiespointtothepivotalroleofinflammationinthepathogenesisofacuteandchronicneuro-degenerativediseases.Recentlywe have initiated onemore projectto understand the consequences ofenvironmentalpollutantinducedneuroinflammationandneuronaldamage.


JEVamemberoftheflaviviruses,isthemostcommoncauseofarthropodbornehumanencephalitisinAsia.TheprimarysitesforJEVmultiplicationarelikelytobeineithermyeloidandlymphoidcellsorvascularendothelialcells.JEVisabletoinfectneurons,althoughtheirroleinJEVinfectionhasnotbeenclearlydefined.Viralpersistenceinthehumannervous system has been reportedinapproximately5%ofpatientswithJEV associated encephalitis. Thissuggests that, following the acuteinfectionphasepersistentJEVinfectionmight also be responsible, in part,for the neural sequelae occurring inapproximately 70%of survivors. Thehost response to infection is centralto the effective control andultimateclearance of invading pathogens. Adetailedunderstandingofthediseasepathogenesisisthereforecrucialforthepreventionof theneurological sequelmediatedbyJEVinhumanbeings.

We have earlier showed that JEVirus can infect neural stem cells/progenitors (NSPs) and harbor inthem.Interestingly,thevirusdoesnotinduce robust NPC death, but withprogressive infection arrests theirproliferative ability. This eventuallyculminates in depletion of NPC pooluponJEVinfection,whichcouldleadto long-term neurological sequel inJE survivors.Wehave also initiatedwork to investigatewhetherJEvirusinfection induce immunogenecity inNSPs.RecentlywehavereportedthatJapanese encephalitis virus induceimmuno-competencyinneuralstem/progenitorcells.Thekeyfindingofthisstudy is: 1) TheNPC residing in thesubventricularzoneoftheJEVinfectedbrainsshowedaprominentexpression

of MHC-I and the costimulatorymoleculesCD40,CD80,andCD86.2)We have observed increased surfaceexpressionofco-stimulatorymoleculeand MHC class I antigen in NPCupon progressive JEV infection. 3)Moreover, significant production ofpro-inflammatory cyto/chemokineswas detected in JEV infected NPCbyCytokineBeadArray analysis onFlowcytometry.4)Interestingly,NPCswere capable of providing functionalcostimulationtoallogenicTcellsandJEV infection resulted in increasedproliferation of allogenic T cells, asdetectedbyMixedLymphocytereactionandCFSEexperiments.5)WehavealsoreportedIL-2productionbyNPCuponJEVinfection,whichpossiblyprovidesmitogenicsignalstoTcellsandtriggertheirproliferation.

Regarding ourworkwith virus entryinto neural stem/progenitor cells(NSPs)wehavefoundthat lipidraftsplay a critical role in JEV entry intoneural stem cells (C17.2 cells) inat least twoways: (i) association ofthe virus envelope proteinswith thelipid rafts (which possibly helps toconcentratethevirusreceptorspresenton the host cellmembrane) and (ii)activation of SFKs and downstreamPI3K/Akt pathway whichmaintainhost cell survivability in the initialstages of infection. Interestingly, wealso found that though JEVutilisestherafts,however,internalisationintoC17.2 occurs by clathrin-mediatedendocytosisanddonotinvolvecaveolaewhicharemostlyassociatedwiththerafts.TheimportanceofthelipidraftsinotherstagesoftheJEVlifecyclewasobserved,speciallyinvirusreplicationas shown by the association of the


differentcomponentsofthereplicationcomplex(NS1,andNS3)withtheraftsatlatertimepointsofinfection(24hourpostinfection).

Incontinuationofourearlierworkwithminocycline,recentlywehaveshowed

thatminocyclineplaysapivotalroleinregulatingperipheralimmuneresponsefollowingJEvirusinfection.Persistenceofinternalizedviruswithinmacrophageswasvisualizedbyimmunofluorescentstaining. Cytotoxicity assay revealedthattherewasnosignificantcelldeath

Figure1Upregulation of costimulatory molecules and MHC class I in Nestin-positive cells in SVZ during JEV infection.BraincryosectionsfromcontrolandJEVinfectedanimalswerestainedwithantibodiesagainstCD40,CD80,CD86,andMHCclassImoleculesandNestin.IsotypestainingusingratIgG2a□(forcostimulatorymoleculesandMHCclassI)andnormalmouseserum(NMS;forNestin)wasperformedonbothcontrol(A)andJEVinfectedbrainsections(B).Co-localizationofNestin(red)withthecostimulatorymoleculesandMHCclass I (green)wasperformedusingconfocalmicroscopy. IsotypestainingonbothcontrolandJEVinfectedsectionsshownodetectablefluorescence(A-B).TheNestin+vecellsshowadistinctivemorphologicalchangefollowinginfectionfromprocessbearingcellstoround/ovalshapedcells.Nestinpositivecellsincontrolsectionsshowverylessco-localizationwithallthecostimulatorymoleculesandMHCclassI(C, E, G, I).JEVinfectedSVZshowcompleteandincreasedco-localisationofNestinpositivecellswithCD40(D),CD80(F),CD86(H),andMHCclassI(J).Scalebarcorrespondsto20microns.


after24hand72hinfectionwithJEV.Proinflammatorycytokine levelswereelevatedincellsthatwereinfectedwithJEV but it was abrogated followingminocyclinetreatment.ReactiveoxygenspecieslevelwasalsoincreasedafterJEV infection.Nitric oxide levelwasfoundtoincreaseafter72hpostinfectionbutremainedunchangedafter24h.Thecellular levels of signalingmoleculessuch as PI3 kinase, phophoAkt andphosphop38MAPkinasewere foundto be altered after JEV infectionand minocycline treatment. JEVinfection also affected the VEGF-MMP pathway. Increased activity ofMMP-9wasdetectedfromJEV-infectedmacrophageculturesupernatantsafter72h;minocycline treatment resultedin reduced activity. Thus it seemsthatminocyclinedampensperipheralimmune reactions by decreasingproinflammatory cytokine releasefrom infectedmacrophages and thevirus survives withinmacrophageslong enough to be carried into theCNS,eventhoughminocyclineinhibitscell survival.Wehave further shownthat the levels of T cell activatingcytokineIL-12andMCP-1levelsweresignificantly elevated in JEV-infectedtissue samples in a time dependentmanner.CorrespondingtothisincreasewastheincreaseinnumberofCD3andCD11bpositivecellsinthetissuesofinfectedanimals.Minocyclinetreatmentabrogatedthesechanges.Minocyclinetreatment also resulted in gradualdecreaseinthenumberofCD11b(butnotCD3) positive cells in the lymphnodeand inspleen,eventhoughthevirus persisted in these organs.Wealso observed structural changesin the spleen followingminocyclinetreatment.

FromthesestudieswehavefoundthatminocyclinehasdifferentialactivitiesondifferentorgansofthebodythatareinfectedbyJEV.Inthebrainitservesasaprotectiveagentbyreducingtherelease of proinflammatory cytokinesand preventing the accumulationof cells of monocyte/macrophagelineage. Intheperipheryminocyclinestimulates thegenerationof immuneresponse within the spleen that istargetedtowardsthevirus,butisnotsufficienttopreventitsspreadintotheCNS,inourexperimentalmodel.Apartfromthispreliminarystudy,theroleofminocyclineinmodulationofperipheralresponsesneedstobestudiedindetailforabetterunderstandingofitsanti-JEVactivities.

BaseduponourfindingsrecentlyNBRCdecidedtofundJE-MinocyclineclinicaltrialatDeptofPediatrics,CSMMedicalUniversity (Erstwhile King GeorgeMedicalCollege),Lucknow.ThisclinicaltrialwillbesupervisedbyProfRashmiKumar, Head of the department,Pediatrics.ThetrialprotocoliscurrentlyunderconsiderationofDrugControllerGeneralofIndia.

Earlierwehaveinitiatedaworktostudythe role of different environmentalpollutant in neuroinflammation andsubsequent neuro-degeneration.Recently we have showed that acommon carcinogen Benzo[a]pyrene(B[a]P) causes neuronal death inmouse via microglial cctivation.Using neuroblastoma cell line andprimary cortical neuron culture, wedemonstratedthatB[a]Phasnodirectneurotoxiceffect.Weutilizedboth invivoandinvitrosystemstodemonstratethatB[a]Pcausesmicroglialactivation.Usingmicroglialcelllineandprimary


Figure2JEV gpE co-localise with CTB, but not with caveolin at the plasma membraneC17.2cellsgrownin8-wellchamberslideswereinfectedJEVat5MOIandincubatedwith10ug/mlofbiotin-conjugatedCTBfor45minsat4ºC.Cellswereshiftedto37ºCfor30minsandthenfixedwith2%PFA.Streptavidin-Alexa594wasaddedtodetectCTB,followedbystainingwithJEVgpE(FITC).Bothcontrol(a)andinfectedcells(b)showCTBexpression.Discreteareasofco-localisationofgpEwithCTBwereobserved(b).Similarly,control(c)andJEVinfectedcells(d)werealsodouble-stainedforgpE(FITC)andcaveolin-1(Alexa594)orCD71(Alexa594,red).CellswerecounterstainedwithDAPIandvisualisedunder40XmagnificationofZeissApotomemicroscope.Noco-localisationofgpEwithcaveolin-1inJEVinfectedcells(d)wasobserved.Scalebarcorrespondsto20microns.

microglialculture,weshowedforthefirst time that B[a]P administrationresultsinelevationofreactiveoxygenspecieswithin themicroglia therebycausing depression of antioxidantproteinlevels;enhancedexpressionof

inducible nitric oxide synthase, thatresultsinincreasedproductionofNOfromthecells.Synthesisandsecretionof proinflammatory cytokines werealso elevated within themicroglia,possibly via the p38MAP kinase


Figure3 Photomicrographs showing effect of B[a]P treatment on N2a, primary neurons, BV-2 and primary microglia.Lightmicroscopicimagesofprimarycorticalneurons,growninpoly-D-lysinecoatedchamberslidesthatweretreatedwith80μMofB[a]P,didnotrevealanysignificantmorphologicalalterationswhencomparedtocontrol(A).Toconfirmthisfinding,immunofluorescentstainingoftheB[a]Ptreatedprimaryneuronsweredone.TheslideswerestainedforbetaIIItubulin,aprimaryneuronalmarker,andglialacidicfibrilaryprotein(GFAP),amarkerforactivatedastrocytes,followedbymountingwithDAPI.TheimageshowsthatnosignificantchangecanbevisualizedintheB[a]Ptreatedneuronswhencomparedtocontrol(B).Thescalebarscorrespondto50μandmagnificationis20×.LightmicroscopicimagesofBV-2aftertreatmentwithvaryingdosesofB[a]Pfor48hshowsmorphologicalsignsofactivationatall threedoses (C).ToseewhetherprimarymicrogliaalsobecameactivatedduetoB[a]P,cellswerecultureandthenseededontochamberslidesandtreatedwith0.2μMB[a]Pfor48h.Theslideswerethenprocessedtobestainedwithanti-CD11bantibodyandmountedwithDAPI.ImageswerecapturedusingZeissAxioplan2fluorescencemicroscope.FigureS1DclearlyshowsmorphologicaldifferencebetweenB[a]Ptreatedanduntreatedcells.Scalebarcorrespondto50μinboth(C)and(D).Magnificationis20×inbothfigures.


pathway.Allthesefactorscontributedto bystander death of neurons, invitro.Whenadministeredtoanimals,B[a]Pwas found to causemicroglialactivation and astrogliosis in thebrain with subsequent increase inproinflammatorycytokinelevels.

Publications:Research article:

1. KDutta,MKMishra,ANazmi,K L Kumawat and A Basu(2010)MinocyclineDifferentiallyModulatesMacrophageMediatedPeripheral Immune ResponseFollowingJapaneseEncephalitisVirusInfection.Immunobiology.(InPress)

2. KDutta,DGhosh, ANazmi, KLKumawat,andA Basu(2010)ACommonCarcinogenBenzo[a]pyreneCausesNeuronalDeathinMouseviaMicroglialActivationPLoS One,5(4):e9984.

3. DNandi,MKMishra,A Basu,andBBishayi (2010)Protectiveef fects of Interleukin-6 inLipopolysaccharide(LPS)inducedexperimental endo-toxemia arelinkedtoalterationinhepaticanti-oxidantenzymesandendogenouscytokines. Immunobiology,215:443-451.

4. RMukhopadhyay,MKMishra,A Basu,andBBishayi(2010)Effectofparticularantigenicstimulationor in vivo administration ofInterleukin-6 on the level ofsteroidogenicenzymesinadrenalglands and lymphoid tissues ofmicewith parallel alteration inendogenousinflammatorycytokine

level.Cellular Immunology,261(2010)23–28.

5. S Das, D Ghosh, andA Basu(2009) Japanese encephalitisvirusinduceimmuno-competencyinneuralstem/progenitorcells.PLoS One,4(12):e8134.

6. *MKMishra,KDatta,SKSaheb,andA Basu(2009)Understandingthe molecular mechanism ofbloodbrainbarrierdamageinanexperimentalmodel of JapaneseEncephalitis: Correlation withminocycline administrationas atherapeuticagent.Neurochemsitry International,55(8):717-233.

7. *KDatta,DGhosh,andA Basu(2009)CurcuminprotectsneuronalcellsfromJapaneseEncephalitisvirusmediatedcelldeathandalsoinhibits infective viral particleformation by dysregulation ofUbiquitinproteasomesystem.J Neuroimmuno Pharmacology,4(3):328.

Review:

8. KDutta, ANazmi, andA Basu(2010)ChemotherapyInJapaneseEncephalitis:AreWeThereYet?Infectious Disorders - Drug Targets.(InPress)

9. S Chakraborty, D K Kaushik,M Gupta, andA Basu (2010)InflammasomeSignalingAtTheHeartofCentralNervousSystemPathology. J Neurosci Res.,88:1651-1631.

10. SChakraborty,ANazmi,KDutta,andA Basu (2010) “NeuronsUnder Viral Attack: VictimsOrWarriors?” Neurochemsitry International,56:727-735.


11. KDutta,PNRangarajan,SVrati,andA Basu (2010) JapaneseEncephalitis: Pathogenesis,Prophylactis and Therapetucis.Current Science,98(3):22-30.(Special section: Biology andpathogenesisofVirus)

12. *D Ghosh andA Basu (2009)Japanese Encephalit is - APatho log ica l and C l in ica lPerspective PloS Neglected Tropical Diseases,3(9)e437.

*In press last year

Presentations:

1. S Das, and A Basu: JapaneseEncephalitisVirusarrestsNeuralstemcellproliferationandconfersthemwithimmunogenicproperties.2ndBangaloreMicroscopyCourse,NCBS, Bangalore, 21st-28thFebruary,2010.

2. ABasu:Immuno-competencyofNeural stem cells: Neuro-tropicViralinfectionasamodelsystem.Molecular Immunology Forummeeting.FortRadisson,Raichak(NearKolkata),15-17thJanuary,2010.

3. ABasu: JapaneseEncephalitisViruscauses“doubletrouble”tobrain.GuhaResearchConference.Summer Sand Beach Resort,Ullal, Mangalore. 19th -23rdDecember,2009.

4. K Dutta, K L Kumawat, M KMishra,andABasu:MinocyclinemodulatesJapaneseEncephalitisVirus entry in the centralnervous system. XXVII AnnualconferenceofIndianAcademyofNeuroscience. NIMSUniversity,Jaipur,18-20December,2009.

5. S Chakraborty, S Das, and ABasu: Lipid rafts play a criticalrole in Japanese EncephalitisVirus entry into neural stemcells.XXVIIAnnualconferenceofIndianAcademyofNeuroscience.NIMSUniversity, Jaipur, 18-20December,2009.

6. DK kaushik, SDas,MGupta,and A Basu: To elucidate therole of Kruppel like factor 4,a novel transcription factor inneuroinflammation.XXVIIAnnualconferenceofIndianAcademyofNeuroscience. NIMSUniversity,Jaipur,18-20December,2009.

7. S Das, and A Basu: Infectiono f n eu ra l s t em c e l l s b yJapanese Encephalitis Virus:Implications in long-term viralneuropathogenesis.XXVIIAnnualconferenceofIndianAcademyofNeuroscience, NIMSUniversity,Jaipur,18-20December,2009.

8. ABasu: JapaneseEncephalitis:fromneuropathologytotherapeuticintervention.WestBengal StateUniversity, Barasat, North 24Paraganas,23rdOctober,2009.

9. ABasu: JapaneseEncephalitisVirus infectsNeural StemCellsanddecreasestheirproliferation.Biology and Pathogenesis ofViruses:MolecularInsights,IISC,Bangalore,4-5thMay,2009.

10. A Basu: The brain’s responseto Japanese Encephalitis virusinfection:Do neural stem cellsplayarole?15thSNIPConference,Wuhan,China,21st-24thApril,2009.

11. ABasu:Hostpathogeninteractionin JapaneseEncephalitis Virus


infection:frombenchtobedside;Department of Physiology,UniversityofCalcutta,6thApril,2009.

Fundings:

1. To e luc ida t e the r o l e o finflammasomeandothermoleculareventsleadingtoHypoxiainducedneuro inflammation [FundedbyLifescienceResearchBoard,DRDO(NoLSRB-213/EPB/2010)]

2. Dissectingmolecular circuitriesthat regulate Progenitors CellResponsetoJapaneseEncephalitisVirus. (Funded byDepartmentof Biotechnology, BT/PR8682/Med/14/1275/2007)

3. Evaluation of Minocycline asa neuroprotective and/or anti-inflammatoryand/orantiviraldruginJapaneseEncephalitis [FundedbyCSIR,(27(0173)/07/EMR-II)]

Degrees Awarded (Ph.D.):

ManojKumarMishra.



dr. Ranjit Kumar Giri

Research Fellows

Pankaj Ghate

Technical Assistant

Sanjay Kumar

Lab Attendant

Lalit Bidla

Alzheimer’sdisease(AD)isaprogressiveand irreversible neurodegenerativedisorder.Itisthemostcommoncauseof dementia worldwide. AD can beclassifiedeitherassporadicAlzheimer’disease (SAD) or familial Alzheimer’sdisease (FAD). Genetic studies ofearlyonsetFADhaveidentifiedthreecausative genes: amyloid precursorprotein (APP), Presenilin 1 (PSEN1)andpresenilin2(PSEN2).Mutation/sin these genes affect the stability orincrease formation of Aβ peptides,specificallythemorefibrillogenicAβ1–42peptides that forms the backbone oftheamyloid (Aβ)cascadehypothesis.

Development of a novel in vitro Model of Alzheimer’s Disease employing neurosphere Culture from tgAPPswePS1ΔE9 mice

However, very little is known aboutexact role of beta amyloid peptidestowardsneurotoxicity.Inordertostudythe mechanisms in AD associatedneurodegeneration in humans,transgenic lines expressing humanFAD geneswere developed. Thoughthese transgenic mice show betaamyloiddeposits,astrogliosis,impairedlearningprocessesandmildcognitiveimpairement,exactroleofbetaamyloidpeptidestowardsneurotoxicityremainspuzzled.Moreover, the effect of betaamyloidonvariousmaturebraincellsisnotknown.Therefore,analternativemodel that retains the capacity togenerate major cell types of brainand generates human beta amyloidpeptides endogenously isneeded.Nosuchmodelisavailabletodate.

Extensive researches have pointedoutthepresenceofneuralstemcellsinadultandembryonicbrainbothinanimals and in humans. TheseCNSstem cells posses the potential todifferentiatetowardsmajorcell typesofbrainexceptmicroglia in vitroandin vivo.ItisnotclearwhythesecellsfailtoreplenishtheneuronalcelllossseeninAD,especiallyinhippocampuswhereCNS stem cells are enriched.Thus,wehypothesizethatbetaamyloidpeptidesmightbeaffectingthenormal


functioningofCNSstemcells.So, torecapitulatemost of the pathologicalfeaturesofAD,suchas,denovobetaamyloid production and to study itseffectonmajorcelltypesofbrain,mylabisworkingtowardsdevelopinganalternative in vitromodel employingCNSstemcells.AccordingtoAβcascadehypothesis,Aβpeptide is thecentralandkeymoleculeinthedevelopmentofAD.Therefore,endogenousproductionandmultimerization of human Aβpeptides are essential features indevelopingADmodelin vitro.

Asshowninpreviousannualreport,wehavedeveloped4separateneurospherelines. Two of thesewere positive for

HuAPPswe andHuPS1ΔE9 gene (Tg+ve)andtwoarenegative(Tg–ve)whichservedascontrol.WehaveshownthatTg +ve lines expressHuAPPswe andHuPS1ΔE9transgenesatmRNAlevel(byRT-PCR)whichisnotpresentinTg-veneurospherelines.

Previously, we have also shown theexpression of human APP proteinand its fragments in all transgenicpositiveneurospherelinesbutnot intransgenic negative lines bywesternblot analysis of neurosphere lysatesandby immunohistochemistry (IHC).However, presence of beta amyloidpeptides was not detected in anytransgenicpositiveline.Wespeculated

Figure1Westernblot analysis of Aβpeptidesfrom culture supernatants (A). 60µg of totalprotein from Tg -ve and Tg +ve neurosphereculture supernatantwas size fractionated in16% Tris-tricine gel alongwithmouse brainhomogenates (MBH) from Tg -ve and Tg +veanimalsand25ngofbetaamyloidpeptideaspositivecontrol.Proteinsweretransferredontoanitrocellulosemembraneandimmunoblottedwith6E10antibodyspecificforhumanAPPanditsproteolyticpeptides includingAβpeptides.TheresultindicatesthepresenceofAβpeptides

onlyinTg+vebutnotinTg-veneurosphereculturesupemantants.Thedensitometricanalysisalsoconfirmed the increasedpresenceofAβpeptideonly inTg+veneurosphereculturessignificantoverTg-veneurospherecultures(B)


that, intracellular beta amyloid poolmightnotbewithindetectablerangebywesternblottingorAβpeptidesmighthave been released to extracellularspace,theculturemedia.Therefore,wewantedtodetecthumanAβpeptidesfromculturesupernatantsofbothTg–ve and Tg +ve active neurospherecultures.Interestingly,thewesternblotanalysisofmediaconcentrateindicatedthe presence of humanAβ peptidesin all Tg +ve neurosphere lines butnotatallinTg-velinesasshowninFigure01.Moreover,theseAβpeptidesare seen both asmonomers aswellasoligomers(seenashighmolecularweightsmear).

It is also known extensively that inAD brain, Aβ peptides accumulateextracellularlyassenileplaques.SinceneurospheresgrowasthreedimensionalspheresandareactivelysecretingAβ

peptides, wewanted to explore thisadditionalpathologicalfeatureinourproposedin vitromodelofAD.DetectionofAβ1-42isthemajorstepinaddressingthisissueasextracellularsenileplaquesinADbrainconsistsmostlyofAβ1-42.InphysiologicalconditionAβ1-42hasatendencytoformbetasheetstructurethere by hindering its interactionwith antibodies specific for Aβ1-42.However, we utilized conformationdependent immunocytochemistryto unfold beta sheet structure ofAβ1-42. Formic acid (FA) has beenutilized previously to unfold Aβ1-42betasheetstructures.Therefore,itisspeculatedthatneurosphereexpressingAβ peptide upon FA treatment willhave more immunoreactions overuntreated counterparts. As to ourexpectation, the intensity of Tg +veneurosphere section is significantlyhigher in FA treated neurosphere

Figure 2 Immunohisto-chemicalanalysisofAβ1-42inneurospheresections.10µmsectionswereobtainedfromTg–veandTg+veneurospheres.Sectionswere treatedwithFA to unford β-sheet richAβ1-42.Immunostainingwasperformed using antibodyspecific for Aβ1-42. Resultindicated vere high levelof expression in Tg +veneurospheres than inTg –ve neurospheres (A,20X). Moreover, Tg +veneurospheres treatedwithFAhave significantlymoreimmunoreactionthanwithoutFAtreatedneurospheres(B,63X;C).FA:FormicAcid,Ab:Antibody


sectionsthanuntreatedcounterparts.Furthermore,Tg+veneurospherehasfarmore immunoreactions towardsantibodyspecificforAβ1-42thanTg–veneurosphere sections as depicted inFigure02.Thus, theresultsstronglyindicate the expression, proteinmisfoldingandaccumulationofhumanAβ1-42 peptides in Tg+veneurospherecultures in parallel with transgenicmicebrain.Collectively,itindicatesthegenesisofanewerin vitromodelforAD

thathasthepotentialtoaddressotherpathological effect of Aβ peptides onvariousadultbraincellslikeneurons,astrocytes,oligodendrocytesandCNSstemcells.

Funding:

Th i s w o r k i s s u pp o r t e d b yRamalingaswami fellowship fromDBT,NBRCcorefundtoPIandCSIRfellowshiptoRF.



dr. Ranjit Kumar Giri

Research Fellows

Himakshi

Technical Assistant

Sanjay Kumar

Lab Attendant

Lalit Bidla

Prion Diseases are a group of rareneurodegenerative disorders thatinclude Kuru, Cruetzfeldt-JakobDisease(CJD),Gerstmann-Straussler-Scheinker syndrome (GSS) and fatalfamilial insomnia (FFI) in humans;scrapieinsheepandgoat,andbovinespongiform encephalopathy (BSE) incattle.Themaincausativeagentisaninfectiousproteinwhichreplicatesbyusingcellularisoformofamembraneanchoredglycoprotein(PrPC)assubstrateandconvertingitintodiseasecausingisoform(PrPSc).ThoughthemechanismofconversionofPrPCtoPrPScisyettobeunveiledbut ithasbeenreported

Understanding the Cellular and Molecular Pathology of Prion Disease using Cns stem Cell Cultures Replicating Mouse Prions

that replication and subsequentaggregation and accumulation ofPrPSc in brain parenchyma causesthe neuropathological changescharacteristic of prion diseases. Theneuropathological features of priondiseases include amyloid plaqueformation,spongiformdegenerationofbrainparenchyma,reactiveastrogliosisand neurodegeneration. Various in vivo and in vitromodels have beendeveloped to have better insight toprion propagation but nomodel sofarhavebeenabletoaddresseffectofprion replication on variousmaturebrain cell types includingCNS stemcells.NeurosphereculturescontainingCNS stem cells canbe isolated fromembryonicandadultmousebrainandcanbeculturedoverseveralpassages.Moreover, theyaremulti-potent,andcanbedifferentiatedtovariousbraincell types like neurons, astrocytesandoligodendrocytes. Therefore, thisculturemodelprovidesopportunitytostudy thepathological effectofprionreplication on different brain celltypes separately or in combination.Furthermore, using thismodel, wealso aim to address the effect ofprion replication onCNS stem cells.Therefore,theimmediategoalsoftheprojectare


1. Replicationofmouseprionproteinin CD1 and C57BL/6J miceneurosphereculture.

2. To study cellular pathology ofpriondiseaseusingneurospherecultures support ing pr ionreplication.

3. To study the effect of prionreplicationonCNSstemcellsfatedeterminants.

Last year, we had establ ishedneurosphereculturesfromCD1mouseembryosandshownthereplicationofprion protein in those neurospherecultures. To validate the findings, inthe current year we have extendedthe replication of prion protein inneurosphere cultures establishedfromC57BL/6Jmice.BothCD1andC57BL/6JmiceexpresswildtypelevelofPrPCandarehomozygousforPrnPa/aallele.Atpresent,wehaveestablished

CNS stem cell lines fromC57BL/6Jmouseembryos.TwoCNSstemcelllineshavebeenisolatedfromC57BL/6JE15embryos(Figure1,A).SimilartoCD1mouseneurospherecultures,thesecelllines express PrPC protein as showninwesternblotanalysis(Figure1,B)andImmunohistochemistry(Figure1,C).Since thesecell linesexpress thePrPC, substrate for PrPSc replication,weanticipate,theymaysupportmouseprionreplication.Oncetheneurospherecellculturemodelforpriondiseaseisestablished,wewouldliketoaddressthe 2nd and 3rd objectives usingimmunocytochemistry,proteinbiologyandhigh-through-putgeneexpressionandregulationsystems.

Funding:

ThisworkissupportedbyagrantfromDBT(No.BT/PR10721/Med/30/105/2008)andNBRCcorefund.

Figure 1: Expression of PrPc inCNS stem cell cultures. A) Twoindependentneurospherecultureswere established fromC57BL/6Jmouse embryos. B) Westernblot analysis demonstrating theexpressiononPrPcinthesecultures.Mouseliverhomogenate(LH)andbrainhomogenate(BH)arenegativeandpositivecontrolsrespectively.C)Immunohistochemicalanalysisindicates PrPc expression inneurosphere sectionsofboth thecell lines.However, exposure toGdnSCNhaslittleeffectonepitoperetrievalofPrPc.Un:unglycosylated;Mono : monog l y c o s y l a t ed ;Di:Diglycosylated.

Systems & Cognitive Neuroscience

Dr. aditya Murthy

Dr. Rema Velayudhan

prof. Neeraj Jain

Dr. soumya Iyengar

Dr. Narender K. Dhingra

Dr. Yoganarasimha Doreswamy

55Systems & Cognitive Neuroscience


dr. Aditya Murthy

Research Fellows

Arjun Ramakrishnan, Sharika K.M., Neha Bhutani, Atul Gopal P.A.

Technical Assistant

Ramakrishnan

Our visual sensitivity is not uniformbut rapidly declines centrifugallyfromthecentreofgazeasaresultofwhichobjectsintheperipherycannotbe identified clearly. To counter thisproblem our brain has evolved amechanismwherebythevisualsceneisexploredindiscretesteps,eachofthemcorresponding to an eyemovementcalledasaccade,followedbyafixation.By carefully observing the patternof fixations, a number of behavioralstudies have shown that saccadesare not random but direct gaze toobjects of interest. Therefore, beforeeachgazeshift,perceptualprocessingmustidentifypotentialtargetsforthe

Probing the control of action using saccadic eye movements

eyemovement andmotor processingmustprepareandexecute themotorcommand. The role of cognition alsoprovidesanaddedlevelofcomplexitysincebehaviorisnotstrictlydictatedbyperceptualprocesses:internalgoalsareimportant.Thechallengethereforeistounderstandtherepresentationsoftheimagethatguidesorientingresponsesand the computations that subserveandlinkvisualandcognitiveprocessingwitheyemovementprogramming.

OBJECTIVES

Spatial programming of double-step saccades.

Saccadesaregoaldirectedmovementsthat direct the fovea to points ofinterestinavisualscene.Beingeasilyaccessible and simple, with well-definedneuralsubstrates,thesaccadicsystem is a popularmodel to studysequentialmovementsingoaldirectedbehavior. A longstanding questionin understanding the planning ofsequentialsaccadesishowthebrainprepares a saccade to the secondstimuluswhentheretinalvectortothesecondtargetbecomesdifferent fromthesaccadicvectorneededtocaptureitfollowingthefirsteyemovement.


Figure 1

In a typical double-step task (Fig.1), there are two possible solutions.The allocentric solution is to storeinmemory the spatial relationshipbetweenAandB,whichcanprovidethevector A→B. The egocentric solutionis to sum the retinal coordinates ofstimulus B (retinal vector 2) withthe coordinates of the effected eyedisplacementtoA(saccade1)toprovidethecoordinatesofstimulusBinspace.Thereisgoodpsychophysicalevidencefortheexistenceofaninternalsignalofeyepositionoreyedisplacementinthebrainthatcouldhelpincomputingthe latter. However, how exactlythe computation that involves aneye-position signal is implementedis unclear. We have examined thenature of this process at play in thecomputation and preparation of thesecondsaccademotorvector.

Figure 2

1. Planning of the second saccade before the end of first saccade

We used the Target-Shift (see Fig.2) trials to determine if themotorpreparation of the second saccadecanoccurbefore the endof thefirstsaccade.Thelogicusedwasasfollows:ifthesecondsaccademotorpreparationcannotoccurbeforetheendofthefirstsaccadeandcommencesonlyafterthefirst saccade, they should always bedirectedtothenew,shiftedpositionofthefinaltarget.However,ifthesecondsaccademotorpreparationcanbeginbefore the end of the first saccade,oneshouldfindinstanceswhenthesesaccades endup at the old positionofthefinaltarget.Acrosssubjectswefound that while in some trials the

Systems & Cognitive Neuroscience 57

secondsaccadeslandedupinthenewpositionofthefinaltarget,inothers,theyweredirectedattheoldlocationofthefinaltarget,consistentwiththesecond alternative proposed abovethatmotorpreparationofthesecondsaccademaybeginbefore theendofthefirstsaccadeitself.

2. Preparation of the second saccade motor command – Feedback or Feedforward?

Weexaminedifthepreparationofthesecond saccade’s motor commandinvolves continuous updating of theretinal error of the final targetwithinformation about the ongoing firstsaccade(dynamicfeedback)orreliesontheefferencecopyoftheplannedfirstsaccadebeforeitsinitiation(predictiveremapping). For this,we shifted theinitial target ina fractionof trials toa new location (about 60ms beforethe fixation spot disappears), whilemaintaining the retinal error of thefinaltarget.Inhalfofsuchtrials,thefinaltargetisthenshiftedduringthe

executionofthefirstsaccade, likeinanormalTarget-shifttrial,toexaminetheeffectof the initial targetshift inthe frequency of second saccades totheold.Ifthepreparationofthesecondsaccade’smotorcommandoccursviadynamicfeedback,shiftingtheinitialtarget shouldn’t affect the frequencyof saccades to theold in these trials(whencomparedtotheirfrequencyinnormal Target-shift trials) since theretinalerrorofthefinaltargetremainsthe same.On the other hand, if thepreparation of the second saccade’smotorcommandreliesonthepredictiveremapping of the first saccade, thenshiftingtheinitialtarget,andthereby,changingthefirstsaccadevector,wouldmakethepredictivesignalineffectualandhence,decreasethepercentageofsecondsaccadestotheold.Nineoutof tensubjects show the latter effect(overall, P < 0.025) suggesting therole of predictively remapped visualsignalinthepreparationofthesecondsaccademotorcommand.

Annual Report 2009-1058


dr. Aditya Murthy

Because eyemovements canprovideabehavioralmeasureofsensorimotorprocessing and cognitive functionsof thebrain, their studycanprovidean elegant and simple system tounderstanding the neural basis ofvoluntarycontrol.Fromanimal,humanlesionandneuroimagingstudies,themajorbrainareasunderlyingsaccadiceyemovementshave been identified.Theseincludetheparietalcortex,thedorsolateral prefrontal cortex, thefrontaleyefields,thesupplementaryeyefields,theanteriorcingulatecortex,thebasalganglia, thesuperiorcolliculusandthebrainstem.Sincegoaldirectedeyemovements involve participationofanumberofdifferentbrainareasaconceptually challenging question istounderstandhowcomputationsdonelocallyinoneareaintegrateoraffectthecomputationsperformedelsewhereandhowthesecomputationscontributetogoal directed behaviors. Last yearwehaveusedanewapproachcalledTranscranialmagneticstimulation tostudy the role of themedial frontalcortex (supplementary eye fields) in

Brain Mechanisms of Action Control in Humans

collaboration with Dr. S. Neggers,UtrechtUniversity,Netherlands.

OBJECIVES

TMS on the supplementary eye fields during a delayed saccade double-step task

Neuronsinthesupplementaryeyefields(SEF) are known to be active duringassociativelearningofsaccades,duringashiftofthecurrentplantoanovelonebasedonvisuo-motorassociations,performancemonitoring as well asforexecutivecontrol.Basedonthesestudies,weexaminedtheroleofSEFbyreversiblydisturbingitsfunctionwhilenormal,healthyvolunteersperformedthe delayed saccade task (with 40%Target-shift trials). As a control, thevertexwas stimulated on a differentsession.PerturbingSEFfunctionwashypothesizedtocompromisetheabilityforcontrolledbehaviouri.e.theabilitytoswitchtonewplanswhenrequired,thereby facilitating the programmingof saccades to the old final targetposition.

Disruption of ‘controlled’ behaviour by TMS on the supplementary eye fields

Thepercentageoftrials inwhichthe


secondsaccadewenttotheoldpositionof the final target was significantlyhigher(P<0.05)incaseofTMSonSEFascomparedtothatonthevertexforsevenoutoftensubjects(Fig.3).Wealso examined the second saccadesthatlandedinalocationmid-waytotheoldandnewpositionofthefinaltarget(referred to as ‘mid-way’ trials fromhereafter).Sincetheshiftinthefinaltargetpositionisessentiallyaverticalone,Iplottedthey-coordinatesoftheend-points of all second saccades inmid-waytrialstofindthatthemedianof eye-positions showed a significantshift (P < 0.025) towards the old

targetformidwaysinTMSonSEFascomparedtothatonVertex.

The above results show that TMSonSEF facilitated not only the totaloutcome of the decision process byincreasing the frequency of secondsaccades to the old, but influencedthe process itself on the whole byweighingthemid-waysmoretowardsthe old. This is consistent with therole of SEF in proactive executivecontrolofactionandsuggeststhatitsdisruptioncanfacilitateuncontrolled,almost‘automatic’behaviorborneoutofpractice.

Figure 3

Effect of TMS on SEF



dr. Aditya Murthy

Tounderstandhowneural networksinstantiatesaccadecontrolweusethenon-human primatemodel to studyhow the pattern of electrical activityinsingleneuronscanberelatedtothecomputationalmodels thatwe haveproposed to account for behavior. Inthese series of experimentswe trainmonkeysonsimilartasksthathumansubjectshaveperformedandrecord/stimulate/microinject drugs ontosingle/groups of neurons in frontalcortexandbasalgangliatounderstandinformationprocessingintheso-calledoculomotorloopinwhichinformationfrom the frontal eye fields (FEF), isrelayedtothebasalganglia,processedandsent to themediodorsalnucleusofthethalamusandsentbacktotheFEF. Here we propose to study thesensorimotor transformations in thisloopinthecontextofhowbasalgangliathalamocortical circuitry initiatesactions,howactionsmaybecancelledand reprogrammed by this circuitandhowthiscircuitmayhelpinthecorrection of erroneous actions. Thelong term goal of this project is to

neural control of action by frontal /basal ganglia networks

understandtheneuralrepresentationsthat control our actions in basalganglia/frontalcortex.

OBJECIVES

Control of decision-making by frontal cortex

Actionsaretypicallymadeindynamicenvironments,whichoccasionallyforceareconsiderationofplannedactions.Instantiatingsuchonlinecontrolraisesan interesting problem for the brainsinceinterruptionofthecurrentmotorprogrammust occur by a competingmotorprogram thatbegins laterandisweakerinstrength.Tounderstandhowchangesofmindgetexpressedatthebehaviorallevelweusedaredirecttaskthatentailedmonkeystochangea planned saccade after suddenlypresenting a second stimulus.Usingintracortical microstimulation inmacaque frontal eye field we haveshownhowwecan trackachangingaction bymeasuring the systematicdeviations from the evoked saccadeduring redirect behavior.We testedthepredictionsfromthreeracemodels(GO-GOmodel;GO-STOP-GOandGO-GO+STOP)ofredirectbehavior.TheGO-GO+STOPmodelthatincorporatedanactiveandspatiallyspecificinhibitorymechanism to suppress the first


saccadecouldbestpredictthepatternofthedeviation.Thetimetoinhibit,asestimatedfromthedeviationprofiles,alsomatchedthatpredictedfromsucha racemodel. Thus it appears thatchangesofmindrequireacovertshort-acting but potent inhibitory processto inhibit the current inappropriateaction,allowingtheexpressionofthenewaction.

Publications:

1. Murthy, A.,Shorter-Jacobi,S.M.,Thompson,K.G.andJ.D.Schall(2009) Neural control of visualsearchbyfrontaleyefield:Effectsoftargetdisplacementonvisualselectionandsaccadepreparation.Journal of Neurophysiology,101:2485-2507.

2. K.M. Sharika, SupriyaRay andA. Murthy (2009) Attention forAction duringErrorCorrection.Progress in Brain Research.176:227-244.

3. Ramakrishnan,A.,Chokandre,S.andA. Murthy(2010)Voluntarycontrolofmulti-saccadegazeshiftsduringmovement preparationand execution. Journal of Neurophysiology 103:2400-16.

Presentations:

1. Ramakrishanan,RamakrishnanS. andA.Murthy.Tracking thedecision as it changes: Supra-thresholdmicrostimulation inmacaquefrontaleyefieldrevealshowdecisionsarecontrolled.Soc.forNeuroscienceAbstract (USA)2009.

2. Gopal, P. Vishwanathan, A.Murthy.TheControlofEyeHandCoordinationinaRedirectTask.IndianAcademyofNeuroscience,Jaipur,India.2009.

3. N. Bhutani, Ramakrishnan S.,A.Murthy. Basal Ganglia andthe Control of Sequential EyeMovements. Indian Academyof Neuroscience, Jaipur, India.2009.

Funding:

ThisworkissupportedbyNBRCCoreandDBTfunds.

Collaborator:

Sebast ian Neggers and Chris .Djeikermann,University ofUterecht,Netherlends

Prof.MadhuriBehariandProf.VinayGoyal,Dept.ofNeurologyAIIMS,NewDelhi.



dr. Rema Velayudhan

Research Fellows

Zia Ud din, Manisha Chugh, Rahul Chaudhary

Project Assistants

Ethiraj Ravindran, Sakthikumar. M

Technical Assistant

Ankit Sharma

We are interested in the neuronalplasticity of the cerebral cortex inresponsetoinjuries.Braininjurieshavemany ramifications,which could beduetoalterationsinneuronalactivity,metabolismandbloodflowatthesiteofinjury.Apartfromchangesatthesite of lesion, distant areas that areanatomicallyconnectedtotheinjuredregionfallintotherealmofsecondaryreactionsintheaftermathofaninjury.All these changes could transformbehaviour.Theamountandnatureofthe ensuing behavioural impairment

Injury induced plasticity in the cerebral cortex

isdeterminedbythesizeandlocationinjury and also could influencepost-injury recovery of behaviouralfunctions.Themultifacetedreactionsthatresultfromcorticalinjuriescouldbe attributed to the ineffectivenessofmostinterventions.Lossoftissuecould limit the extent of recovery atthe site of impact. However, an indepth understanding of the ongoingcellular reactionsbecomesnecessaryfor identifying effective therapy topreventorreducetheseverityofdeficitsat distant regions connected to theinjuredsite.Ourresearchattemptstounderstandtheneuronalchangesthatoccurataregionofcerebralcortexthatisreciprocallyconnectedtoaninjuredarea. We are examining the effectof stroke-like injuries of themotorcortex on neuronal functions of thereciprocallyconnectedsomatosensorycortexinadultrats.

Rats acquire somatic sensation byrhythmicmovementofthelargefacialwhiskers(~25-30whiskers)overobjectsin the environment. Eachwhiskerprimarilyprojectstoagroupofneuronsin the cortex and is the “principalwhisker”forthoseneurons.Stimulationoftheprincipalwhiskergeneratesthe“centrereceptivefield”.Theseneuronsalso receive tactile information from


other whiskers which contribute toestablishing“surroundreceptivefield”.Thuscomputingthenatureofanobjectnecessitates integrationof thecentreand the surround receptive fields.In the rat somatosensory cortex thevariousfeaturesoftactilesensationaretransducedandprocessedintwomainfunctionaldomains:thebarrelcolumnandtheseptalcolumn.Variouslinesof evidence suggest that the barrelanditsrelatedcircuitsareinvolvedinprocessingthespatiotemporalaspectof sensory information,whereas thesepta and their related circuits areinvolvedintheprocessingoftemporallyencoded information. In addition,thereisalsolayer-specificprocessingofsensory informationsuch that thelayer4receivessensoryinputfromthethalamuswhichisthentransferredtooutputlayers2/3(supragranular)andlayer5 (infragranular). We thereforeexamined the layer-specfic changesfollowingstroke-likelesionsofmotorinneuronswithinthebarrelcolumnandthe septal column of somatosensorycortex.

Photothromboticlesionswereproducedin the whisker motor cortex ofadult rats tomimic stroke. At postlesion day 7, the effects of lesion onneurophyisological and behaviouralfunctions of whisker representationareaofipsilateralsomatosensorycortex(barrel cortex)were determined. Werecordedthespontaneousactivityandstimulusevokedresponsesofneuronsfrom layers 2/3, layer 4 and layer 5fromthebarrelcolumnandfromtheseptal column. The centre receptivefieldfortheneuronswasdeterminedbyestimatingtheresponsemagnitudetostimulationoftheprincipalwhisker.

The responses to stimulation of thewhiskers adjacent to the principalwhisker generated the surroundreceptivefield.Themajorfindingsofthese experiments show that lesionin thewhiskermotor cortexproducedifferential effect on centre receptivefield of neurons in barrel and septalcolumnsofthesomatosensorycortex.In lesioned animals, neuronswithinthe barrel column showed higherspontaneousandevokedactivities incomparisontocontrols. Whereas, inthe septal columns the spontaneousactivity of neurons did not differsignificantly,buttherewasareductionin the evoked responses of lesionanimalsincomparisontocontrols.Mostsignificant changes in spontaneousand evoked activities of barrel andseptalcolumnneuronswereobservedin supra and infragranular layers.Lesions in thewhiskermotor cortexmodifiedthesurroundreceptivefieldofneuronsinthesomatosensorycortex.There is increase intheresponsesofneurons to stimulation of surroundwhiskersinalllayersofbothseptalandbarrelcolumns,suggestingthatthereisachangeinexcitationandinhibitionoftheseneurons.Theseresultsimplythatlesionsinthemotorcortexcouldresult in interference with spatio-temporal aspects of somatosensationand hence affect the somatosensorybehavioural functions. We thereforeexamined somatosensory behaviourinratswithmotorcortexlesions.Thelesioned animals showed sensorydeficits inperformanceofawhisker-dependent tactile task called “Gap-crossingtask”.Thisstudyshowsthatfocallesionsinapartofcortexdoesnotproducegeneralizedeffectonneuronalactivity of all functional columns in


anatomicallyconnectedintactregions.Rather,thelesionhadspecificeffectson neurons belonging to differentlayersanddifferentcolumnswithinthecortex.Theatypicalneuronalactivitycouldbethereasonforthedeficitsseeninthebehaviouralfunctionsfollowingstroke-likeinjuriesinthecortex.

Presentations:

1. Rahul Chaudhary, PraseedaVenugopa lan & V . Rema.Unilateral barrel cortex lesionresultsinlong-lastingdeficitsinsomatosensorybehaviorofadultrats. Society for NeuroscienceAnnualMeeting.Chicago,Illinois,October,2009.

2. S ak th i kuma r M , E th i r a jRavindran,RahulChaudharyandV.Rema.Effectoffocalinjuryondistant, anatomically connectedbrainregions.IndianAcademyofNeuroscience.JaipurDec.2009.

Funding:

Thisworkissupportedby:

InternationalSeniorResearchFellowshipfromtheWellcomeTrust,UK;

GrantfromDBT.“Recoveryofneuronaland behavioural functions withembryonicstemcelltherapyfollowingbraininjury”.DBTIndia;

NBRCCorefunds.



Prof. Neeraj Jain

Research Fellows

Niranjan Kambi, Leslee Lazar, Radhika Rajan, Mohammed Hisham

Project Assistants

Vishalini Sivarajan, Kanchan Bisht

Theinformation-processingnetworksof the somatosensory areas of thebraininvolvebothserialandparallelpathways. Any perturbation resultsin widespread effects throughoutthe system. Research interest inmy laboratory centres aroundunderstanding the organizationand information processing in thesomatosensory andmotor systems,anddetermininghowthesesystemsareaffectedbyspinalcord injuries.Wearealsointerestedindevelopingtechnologies for recoveries fromspinalcordinjuries.

To understand the effects of spinalcordinjuriesonthebrain,weperformunilateral lesions of the dorsal

Brain Reorganization following spinal Cord Injuries

columns of the spinal cord, leavingspinothalamic and other ascendingand descending pathways intact. Asa result of these lesions theanimalsloose their fine tactile discriminationabilities. Usingmultiunit mappingand intracortical microstimulationtechniqueswedeterminetheeffectsofthese injuries on the somatosensoryandmotorareasofthebrain.Weusebothprimateaswellasrodentmodelsfor our studies, because eachmodelsystemoffersspecificadvantages.Theworkdoneduringtheyearisdescribedbelow.

Brain reorganization following dorsal spinal cord injuries in primates.Wehave previously shown that theprimary somatosensory area 3band the somatosensory areas of thelateralsulcus(areaS2,thesecondarysomatosensoryarea,andareaPV,theparietal ventral area) undergo large–scale reorganization after unilaterallesions of the dorsal columns atcervicallevels.Inthesesomatosensoryareastheintactfaceinputsexpandintothedeafferentedhand regions. Sincemotorsystemdependsonthesensoryfeedback for control ofmovements,wedeterminedif long-termabnormalinputsfromthesomatosensorycortexaffect the functional organization


of the motor cortex. Last year wereportedourfirstresultsaftermappingthemotor cortex inmonkeys withchroniclesionsofthedorsalcolumns.We had reported thatmanymonthsafter unilateral lesions of the dorsalcolumns, the overall organization ofthemotor cortex remained normal,withfacetohindlimbrepresentationsin a lateral tomedial sequence. Thethreshold currents required to evokemovementswerelargelysameasinthenormalanimals.

Figure1(A)Adorsolateralviewofthemacaquemonkeybrain.Thestippledregioncorrespondstotheprimarymotorcortexandtherostrallyadjacentmotorareas;thehatchedregionshowsthelocationoftheprimarysomatosensoryarea.Thecentralsulcushasbeenshownopenedtoillustratetheseareasinthepre-centralandpost-centralcortex.ArC,arcuatesulcus;CS,centralsulcus;SuPC,superiorpre-centraldimple.(B)Relativeareaofrepresentationofthedigits,wristandshoulderasapercentageoftotalareaoftheserepresentationsinanormalmonkeyNM56,andtwomonkeyswithlesionsofthedorsalcolumns-LM98andLM78.Thedifferencesbetweenthenormalmonkeyandthelesionedmonkeyswerenotsignificant.(C)ThepercentageofD1movementsitesfromwhichflexion-extension,andadduction-abductionmovementsofthedigit1(thumb)wereevokedintheprimarymotorcortexofanormalmonkeyNM56,andtwomonkeyswithlesionsofthedorsalcolumns-LM98andLM78.Thedifferencesbetweenthenormalmonkeyandthelesionedmonkeyswerehighlysignificant(P<0.001).

Ourfurtherexperimentsdoneduringtheyear,andanalysisofthedatashowthattherelativeareaofrepresentationsofdifferentbodypartsintheprimarymotorcortexofmonkeyswiththelesionsdoes not change (Fig. 1). However,we found a significant differencein the nature of themovements ofdigit 1 (D1) or the thumb that areevoked from themotor cortex of thelesionedanimals.Innormalanimals,at nearly all the stimulation sitesthe evokedD1movement is flexion-


Figure 2.Activationofneuronsindifferentpartsofthehandrepresentationinarea3bwhendifferentlocationsontheskinofthehandarestimulatedat1Hz.Eachrowinthepanelsshowsnormalizedfiringrate(seescaleontheright)ofasingleneuronwhenstimulatedatlocationsmarkedalongthex-axis.TheleftpanelshowsactivityofneuronswhosereceptivefieldwasonthedistalpartofD1(digit1orthumb),andtherightpanelshowsactivityofneuronswhosereceptivefieldwasontheproximalpartofD5(digit5orlittlefinger).RedlinesseparateD1andthethenarpad(pTH)fromrestofthedigitsforeaseofvisualization.NotethatneuronsintheD1representationgenerallydonotgetactivatedwhenthehandisstimulatedelsewhere.TheneuronsinD5representationshowactivationwhendigitsD2toD5arestimulated,butverylittleactivitywhenD1orpTHisstimulated.d,distal;m,middle;p,proximal.

extension. In the lesioned animals,theadduction-abductionmovementisevokedatsignificantlylargernumberofsites,whilethereisareductioninthe percentage of sites fromwhichextension-flexion is evoked (Fig. 1).Thesedifferences reflect the inabilityof the lesionedmonkeys touse theirdeafferentedhand for precision grip,which requires flexion of D1. Thusabnormal sensory feedback, whichleads to altered behavioural use ofthehandresults in reorganizationoftheprimarymotorcortexofmacaquemonkeys.

Information processing in the hand area of the primary somatosensory cortex of monkeys.Weareinterestedindetermininghowinjuriestothespinalcordaffectinformationprocessingand

connectivity in the somatosensorycortex. We determined responseproperties of neurons in differentparts of the hand representation inarea 3b (the primary somatosensorycortex),whenaparticularlocationontheskinofthehandisstimulated.Thedata show that in normal animals,nearly all of the neurons in theD1representation of area 3b primarilyrespondtothestimulationoftheskinonD1;whereas,neurons inD2,D3,D4 andD5 representations respondto stimulation on any of these fourdigits, but rarely to the stimulationofD1 (Fig.2).The results show thatevolutionaryadvancedbehaviouraluseof the increasingly opposable thumbinMacaca,anOldWorldmonkey,haslead to concomitant changes in theintrinsicconnectionsinthecortex.


Normal organization of the motor cortex in rats. In our previously publishedreport(Tandonetal.,EurJNeurosci.27:228, 2008), based on differencesinthemovementsevokedbyelectricalstimulation of neurons in themotorcortex of ratsunder different depthsof anesthesia, we have argued thattheratmotorcortexhastwoseparaterepresentations of thewhiskers.Wesuggestedthattherostralwhiskerarea(RWA),alongwithpreviouslydescribedrostral forelimb area (RFA)might bepartofasecondmotorarea.Basedontheseobservations,wesoughtfurther

experimental proof for the existenceof twomotor areas in rats.Weusedneuroanatomicaltracerstodeterminecortico-cortical connections of thetwowhiskers areas, RWA andCWA(caudalwhiskerarea),andcomparedthe pattern of these connections tothat of the two forelimb areas, RFAandCFA (caudal forelimb area). TheresultsshowthatthesourcesofinputstoRWAandCWAaredifferent(Fig.3).Moreover, the connection pattern ofRWAissimilartothatofRFA,andtheconnectionpatternofCWAissimilarto that forCFA.The results stronglysuggestthatas forhighermammals,

Figure 3.Ipsilateralcorticalinputstothecaudalwhiskerarea(CWA)andtherostralwhiskerarea(RWA)oftheratmotorcortex(showningrey).Injectionsoffluoroemerald(green)andfluororuby(red)weremadeinthesetwoareas,andtheretrogradelylabeledcellswereplotted.Notethatinputstothesetwoareasaredifferent,supportingthepropositionthatthesearetwo distinct areas. Themajor sources of inputs to theCWAarea are thewhisker barrelsomatosensorycortex(WB)andtheretrosplenialcortex(RS),whereastheRWAdoesnotgetmanyinputsfromWBcortex.TheinputstoRWAarefromRS,orbitalcortex(OC),andtheCWA.Visualcortex(VIS)isshownforreference.ULupperlip;LJ,lowerjaw;FB,forepawbarrels;Tr,trunk;HL,hindlimb;RFA,rostralforelimbarea;SII,secondsomatosensoryarea,M,medial;R,rostral.Therepresentationsshowninitalicsareintheprimarysomatosensorycortex.


theratmotorcortexalsohasmultiplemotorareas.

Publications:

1. Shashank Tandon, NiranjanKambi,LesleeLazar,MohammedHishamandNeeraj Jain(2009)Large-scaleexpansionofthefacerepresentationinsomatosensoryareasofthelateralsulcusfollowingspinalcordinjuriesinmonkeys.Journal of Neuroscience, 29:12009-12019.

2. AatiraGNedungadi,GRangarajan,Neeraj Jain and MingzhouDing (2009) AnalyzingmultiplespiketrainswithnonparametricGranger causality.Journal of Computational Neuroscience,27:57-64.

3. Hui-XinQi,Neeraj Jain,ChristineECollins,David Lyon and JonH Kaas (2010). FunctionalOrganization of motor cortexof adult macaquemonkeys isalteredbysensorylossoccurringininfancy.Proc. Natl. Acad. Sci., USA,107:3192-3197.

Presentations:

Abstracts:

1. Niranjan A Kambi, ShashankTandon, HishamMohammed,Leslee Lazar, Radhika Rajanand Neeraj Jain: Topographyof primary motor cortex inmonkeys with dorsal spinalinjuries. Neuroscience 2009,AnnualMeetingoftheSocietyforNeuroscience,Chicago,USA.Oct17-21,2009.

2. LesleeLazar,RadhikaRajanandNeeraj Jain: Focal stimulationontheskinofthehandactivatedneuronsoverlargeregionsofthehandrepresentationinarea3bofmacaquemonkeys.Neuroscience2009, Annual Meeting of theSocietyforNeuroscience,Chicago,USA.Oct17-21,2009.

Invited Presentations:

1. ‘AdvancesinBiologicalSciences’,aNationalConferenceorganizedbyDepartmentofZoology,PanjabUniversity, Chandigarh, India.March29-30,2010.

2. ‘ChallengesinSpinalCordInjuryRepair’ a seminar organized byDr ALMPG Institute,UniversityofMadras.March5,2010.

Funding:

Defense Research andDevelopmentOrganization.

DepartmentofBiotechnology.

Collaborators:

Prof. G. Ranagaran, IIScBangalore,ProfAshitavaGhoshal,IIScBangalore,DrMSrinivasan,MITBoston,andCAIRBangalore.



dr. Soumya Iyengar

Project Assistants

M. Sakthikumar, L. Shahul Hameed


OP Sharma, Arvind Singh Pundir

Earlierstudieshadshownthataxonalconnectivity in the human auditorycortex develops over a protractedperiodcomparedtootherregionsofthebrain. Using immunohistochemistryfor phosphorylated neurofilaments(SMI-312andSMI-31), these studiesdemonstrated that neither cortico-cortical nor thalamocortical axonsappearedtobepresentinthetemporallobe(futureauditorycortex)untilthefirst postnatal year. Their studiesrevealed that the marginal layer(futureLayerI)appearedat22GWandcontinuedtoincreaseinsizeuntil4.5monthsafterbirth.However,nootheraxonsappeartobepresentinLayersII-VIofthecortexuntil4.5monthsafterbirth. They also demonstrated thattherewasanincreaseinthenumber

emergence of Connectivity in the Developing Auditory Cortex in Humans

of axons in Layers IV-VI starting at1 year after birth. Axons could beseen in supragranular layers (LayersII and III) 3 years after birth andincreased to resembleadultpatternsonlyby12years.Theseearlierresultssuggestedthattheauditorycortexhada prolonged period of developmentcompared to other human primarysensorycortices,whichmatureduringthefirstpostnatalyear.

Ouraimwastoconfirmtheaboveresultsnot only by immunohistochemistrybut also by using RT-PCR (reversetranscriptionpolymerasechainreaction)to detect neurofilamentmRNA andwesternblotstodetectneurofilamentprotein.Tooursurprise,wefoundthatmRNAforneurofilamentH(heavychain)was present in the human temporallobe (presumptive auditory cortex)in the second trimester (at 15GW,19GW,21GWand26GW)andduringthepostnatalperiod(1year-4years).Further,western blotsusing specificantibodiesagainstSMI-312andSMI-31confirmedthepresenceofmediumaswellasheavychainneurofilamentsinthetemporallobeattheseages.Finally,immunohistochemistry was used todetectthepresenceoffiberslabeledwithSMI-312andSMI-31asearlyas15GWin the temporal lobe. Interestingly,


we foundthata fairlywell-developedplexus of axons immunoreactive forbothantibodieswaspresentinLayerIandinpresumptivelayersVandVIat15GW.Additionally,wefoundaxonsinLayerIIandIII,runningperpendiculartothepialsurface,withwell-developedvaricositiesalongtheirlengthsatthisage.Thecomplexityofaxonsincreasedfrom25GWuntilbirth(40GW)whereinnumerousfibers,couldbeseeninalllayersoftheauditorycortex(Figure1).Further, we found that the densityof axons in almost all layers of theauditorycortexappearedtobeadult-like at 9months after birth whenvisualized using immunoreactivity

to SMI-312 and SMI-31. The onlyexceptionwasLayerIIwhereat9months(postnatal), the immunoreactivity forneurofilamentswasslightlylessthanthat seen in adults. Taken together,our results suggest that the timelinefordevelopmentofthehumanauditorycortexmayinfact,besimilartothatofothersensorycorticesinthebrain,suchasthatofthevisualcortex.Ourresultsalsosuggestthatauditoryinputfromauditorybrainstemregionsandthemedial geniculate nucleusmayreach the auditory cortexduring thesecond trimester itself rather thanafterbirth.

Figure1 (Left)VeryfinefibersandaxonterminalsaswellasasmallnumberofaxonsorientedtowardsthepialsurfacecanbeseeninthedeeperpartofLayerIjustbelowthedensebandoffibers(arrowheads).Largevaricositiesarealsoseenalongsomeofthefibers.LayerIIconsistsofdenselypackedcells,someofwhicharelabelledforSMI-31.(Layer IV-V)SMI-31-positiveaxons(arrowheads)arealsopresentatthejunctionofLayersIVandV,interspersedbetweencells.(Layer VI)AdenseplexusofSMI-31immunoreactivefibersispresentinpresumptiveLayerVIofHG.Scalebar=20µm.


Funding:

ThisstudyissupportedbyNBRCcorefunds.

Collaboraters:

Dr.PCDikshit,MAMC,Delhi

Dr.SKShankar,NIMHANS,Bangalore

Dr.AnitaMahadevan,NIMHANS,Bangalore

Dr.KJoshi,PGIMER,Chandigarh

Dr.BRadotra,PGIMER,Chandigarh

Dr.S.Bishnoi,GurgaonCivilHospital,Gurgaon

Dr.N.Thapar,GurgaonCivilHospital,Gurgaon

Dr.S.Sharma,GurgaonCivilHospital,Gurgaon

Col.P.Kumar,ArmyBaseHospital,NewDelhi



dr. Soumya Iyengar

Research Fellow

Nazia Khurshid

Project Assistants

L. Shahul Hameed, Sivaraj Mohanasundaram


Arvind Singh Pundir

An interesting research question istoattemptincreasingorupregulatingendogenouslyoccurringneurogenesisinadultbrainstorepairdamagecausedbydifferentlesionsorneurodegenerativediseases.Thesongbirdbrainprovidesanexcellentmodelsystemtostudyadultneurogenesis.Inthesespeciesofbirds(awell-studied example being zebrafinches),newneuronsarecontinuouslyproducedinadultlifebytheventricularzone and are then incorporated intodiscrete neural circuits, some ofwhich are important for singing and

neurogenesis in the song Control system of Zebra Finches

song learning.We are interested instudyingwhether the opioid system(consisting of endogenous opioidsand their receptors)modulates adultneurogenesisinzebrafinches,sinceitisknowntoaffectneuronalandglialproliferation.Our objectiveswere tolocalizetheopioidreceptorsindifferentbrainregionsincludingtheventricularandsubventricularzone(VZandSVZ)ofadultmalezebrafinches.Further,we would like to examine whetherincreasingthelevelsofneurogenesisinadultmalezebrafincheswouldchangetheirsongs,whicharenormallyhighlystereotyped.OurimmediateaimistoincreasethelevelsofneurogenesisinthesebirdsbyblockingopioidreceptorsexpressedbytheVZwhich isknownto increase cell proliferation in otherspecies.

WeusedquantitativeRT-PCRand insituhybridizationtodemonstratethatµand-opioidreceptorsareexpressedbytheVZofadultmalezebrafinches,aswellasothercellsinthesurroundingbrainparenchyma.Inordertoconfirmthatcellproliferationisaffectedbytheopioidsystem,primaryculturesofadultzebrafinchVZcellsweremaintainedandtreatedwiththeopioidantagonistnaloxone aswell asmet-enkephalin(an endogenous opioid), followed by


treatmentwith the S-phasemarkerBrdU (5-bromo-2-deoxyuridine) orEdU (ethynyldeoxyuridine).Whereasnaloxonetreatmentledtoasignificantincreaseincellproliferationinculture,treatment with met-enkephalindecreasedcellproliferation.Systemicadministration of naloxone (2.5mg/kgbodyweight)forfourdaysinadultbirds (bothmale and female) alsoled to a significant increase in cellproliferationintheVZ,comparedwithsaline-treated controls. Interestingly,wealsofoundthatthehighestincreasein cell proliferation occurred in theventral subdivision of the VZ at thelevel of the anterior commissure inzebra finches. Since this subdivisionof the VZ is known to give rise toGABAergic interneurons throughoutthe telencephalon including songcontrol regions, our results suggestthattheendogenousopioidsystemmaymodulate the production of differentcell typesmainly from the ventralproliferative areas of the zebra finch

brain by inhibiting cell proliferation.Ourresultsalsosuggestthatnaturalvariationsintheendogenousopioidsinsomeofthesongcontrolnucleiduringsingingmaymodulatethenumberofcells (both neurons and glia) beingproducedbytheVZ,whichwouldlikelyinfluencethecompositionofthesongcontrolnucleiinzebrafinches.

Further,preliminarydatafromourlabsuggeststhatzebrafinchVZculturestreated with the δ-OR agonist SNC80 are slightlymore differentiatedthansalinetreatedcontrols(Figure1).Thatis,individualneuronsinculture(whicharelabelledwiththeneuronalmarkerTuj1)havea greaternumberof neurites compared to those fromcontrols.ThereisalsoasmallincreaseincellproliferationfollowingtreatmentwithSNC-80,suggesting thatµ-andδ-ORsmay have opposite effects oncellproliferation,sincemet-enkephalin(whichisaµ-ORagonist)decreasescellproliferation.

Figure1TreatmentofzebrafinchVZcultureswiththeδ-ORagonistSNC80leadstoanincreaseintheoutgrowthofneurites(arrowheads)indifferentiatingneuronslabelledwithTuj1(red),comparedtoasaline-treatedcontrolculture.NucleiinbothcasesarelabelledwithDAPI(blue)andsomeofthenucleiarealsolabelledwiththeS-phasemarkerEdU(green)showingthattheyareundergoingproliferation.Scalebar=20µm.


Publications:

1. Khurshid N, Jayaprakash, N,Hameed,LS,Mohanasundaram,S and Iyengar S (2010)Opioidmodulation of singing inmalezebra f inches (Taenopygia guttata).Behav. Brain Res.208;359–370.

Presentations:

1. Soumya Iyengar: Developmentof theHuman Auditory Cortex– Neuroanatomical Studies.Psychology Dept., VanderbiltUniversity, Nashville, TN,USA.October,2009.

2. Soumya Iyengar: The humanauditorycortex–adevelopmentaltimeline.NationalProgrammeonPerceptionEngineering(TechnicalWorkshop). NBRC, Manesar,December,2009.

3. Arv ind S Pundi r , Senth i lKrishnasamy,SouvikKar,BishanS Radotra, Praveen Kumar,PC Dikshit, Soumya Iyengar:The human auditory cortexduring the third trimester andatterm.PosterpresentedattheAnnualMeeting of Society forNeuroscience,Chicago,IL,USA.October,2009.

4. ArvindSPundir,BishanSRadotra,Praveen Kumar, PC Dikshit,Soumya Iyengar: Developmentof the perinatal and postnatalhumanauditorycortex.PosterpresentedattheAnnualmeetingof the Indian Association ofNeurology, Jaipur, December2009.

5. ParthivHaldipur,UpasanaBharti,Chitra Sarkar, Corinne Alberti,SoumyaIyengar,PierreGressens,ShyamalaMani:Pretermdeliveryaltersthedevelopmentalprogramofthecerebellum.Posterpresentedat“FrontiersinOrganogenesis”,ameetingorganizedbytheCentreforDevelopmentalBiology,Kobe,Japan,March2010.

Funding:

1. Effects of altering the levels ofneuronal proliferation on thelearningandproductionofsongbehavior inmale zebra finchesawarded in 2007. Thiswork issupported by NBRC Core andDBTfunds.

2. OpioidModulationofsonginMalezebrafinches awarded in 2010.ThisworkissupportedbyNBRCCoreandDSTfunds.`



dr. Narender K. dhingra

Research Fellow

Varsha Jain, Saumya Nagar, deepak Poria, Manvi Goel

Project Assistants

Santhosh Sethuramanujam, Varun Venkatesh, Ethiraj Ravindran


Sumit Mahapatra

RetinaldegenerativediseasessuchasRetinitisPigmentosaandAge-RelatedMacularDegenerationarecharacterizedbyphotoreceptordegeneration,andareamongtheleadingcausesofblindness.While photoreceptors progressivelydegenerate,theinnerretinalneurons,especiallyretinalganglioncells(RGCs),whichsendvisualsignalstothebrain,arerelativelypreserved,atleastinitially.Basedprimarilyonthis,severalnoveltherapeuticstrategies,suchasstemcelltransplantationandimplantationofa

Replacement of Degenerating Retinal neurons by Retinal Prostheses or stem Cells - A study on Retinal Circuitry and Information Processing

prostheticdevicehavebeendesigned.A retinal prosthesis is an electronicdevice designed to transform visualinformationintoaspatiotemporalsetofelectricalstimuliwhichareappliedtothesurvivingretinalneuronsviaanarrayofmicroelectrodes.Theunderlyingassumption is that the informationaboutthespecificcomponentsofthevisualscenewouldbecorrectlyencodedintheformofelectricalstimuliwhichwill be transferred to specific retinalneurons. Similarly, the transplantedstemcellsareexpectedtodifferentiateinto photoreceptors which wouldsynaptically connect to the survivingretinal neurons. These treatmentapproacheshaveshowngreatpromiseinrecentyears,buttheclinicaloutcomehas so far been limited. Our lab isinterested in understanding normalretinalcircuitry,howitisalteredafterphotoreceptordegeneration,andhowthesetreatmentstrategiescanleadtobetterfunctionalrecovery.

We have been studying a specificgroup of RGCswhich express brn3transcriptionfactors,intermsoftheirsize, spatial distribution, dendriticarbor, projections and co-expressionof other ganglion cellmarkers.Wehave found evidence that the brn3-expressing RGCs exclusively carry


image-forming visual information.We have also found that a specificsubtypeofintrinsically-photosensitiveganglion cells, theM1 cells do notexpressbrn3(Fig.1).Consideringthatbrn3-expressingRGCsconstituteonlyabout35%ofallcellsintheganglioncell layer, they offer amore specifictargetforelectricalstimulationforthetreatmentofretinaldegeneration.

Figure1:Thetranscriptionfactorbrn3isexpressedbyabout35%ofcells(red)outofallcellsintheganglioncelllayer(blue).Aspecifictypeofintrinsically-photosensitivecells,theM2cells(lightgreen,arrows),butnottheM1cells(brightgreen,arrowheads)expressbrn3.

Wehavealsobeenstudyingstructuraland functional alterations in retinalcircuitry following photoreceptordegeneration.Wehaverecentlyfoundthat loss of photoreceptors leadsto upregulation of synaptic activityselectively in amacrine cells. Theseresultshaveimplications,notonlyinunderstanding the disease processand in improving the therapeuticstrategiesforretinaldegeneration,butalso in unraveling how adult retinalcircuitryismaintainedandfunctionsnormally.Forexample,wearetesting

thehypothesisthatGABAcreceptorson thebipolarcellaxonterminalarecritically required for the RGCs tobeabletopreciselyencodeandsendvisualsignalstothebrain.

In another project, we have foundevidencethatMuellerglialcellsundergodedifferentiation after photoreceptordegenerationandmayactlikestemcells.Among other cell-based therapeuticapproaches we are evaluating howMueller cells can be promoted todifferentiateintorodsandconesafterphotoreceptordegeneration.

Publications

1. Smith RG,Dhingra NK (2009)Idealobserveranalysisofsignalquality in retinal circuits.Prog Retin Eye Res, 28:263-288.

Presentations

1. NK Dhingra: Remodeling inThird-Order Retinal NeuronsAfterPhotoreceptorDegeneration.InvitedtalkatIIT,Delhi,July15,2009.

2. NKDhingra: Invited to chair asymposiumonNeurophysiologicalBasisofComplexBehaviors,andpresentonRetinalDegenerationin an Inducible AnimalModel– Biochemical, Morphological,Physiological and BehavioralCorrelates in InternationalConference on NeuroscienceUpdates& ISN, APSN, IBRO&SNCISchool,Cochin,December7-14,2009.

3. S.Nagar,S.Sethuramanujam,V.Jain,P.Cherukuri,NKDhingra:RemodelingofThird-OrderRetinalNeuronsFollowingPhotoreceptor


Degeneration. 27th AnnualConferenceoftheIndianAcademyofNeurosciences,Jaipur, India;December18-20,2009.

4. V.Jain,NKDhingra:ExpressionofMelanopsin byBrn3-PositiveRetinalGanglionCellsinMouse.27th Annual Conference of theIndianAcademyofNeurosciences.Jaipur,December18-20,2009.

5. NKDhingra: Invited to presentat a brainstormingmeeting bySocietyforBiomedicalTechnology,DEBEL,DRDOregardingBionicEyeinIndia,Bangalore,January16,2010.

Funding

ThisworkissupportedbygrantsfromDepartmentofBiotechnology,GovtofIndia,andNBRCcorefunds.



dr. Yoganarasimha doreswamy

Research Fellows

Apoorv Sharma, Guncha Bhasin

One of the fundamental challengesof neuroscience is to understandhow the brain constructs higher-order representations of experienceand how those representations arestored and recalled as consciousmemor i es . P lace ce l l s o f thehippocampus are an outstandingmodel system for deciphering theneuralnetworkmechanismsbywhichthe brain constructs these cognitiverepresentationsfrommultimodalinput.The discovery of hippocampal “Placecells”whichselectivelyfiresataspecificlocationinanenvironment,leadtothesuggestionthatthehippocampusmayform the locus of a “cognitivemap”ofthesurroundingenvironment.Thehippocampus is critically involvedin certain forms of spatial learning,context-dependent learning, anddeclarativememory.Despite yearsofresearch, elucidation of the precisecomputations performed by the

neural network Mechanisms Underlying spatial Learning And navigation

hippocampushasbeenhamperedbyalimitedknowledgeofrepresentationsfromitsinputbrainareas.Themedialentorhinalcortexreceivesmajorinputfrom the dorsal presubiculum andretrosplenial cortex, which containdirectionally and spatially tunedneurons,andfrompostrhinalcortex,which is connectedwithvisuospatialregionsoftheneocortexandhasbeenlinked to contextual processing. Thelateralentorhinalcortexreceivesmajorinputfromtheperirhinalcortex,whichis connectedwith unimodal sensoryareasandappearstobeinvolvedintheprocessingofconfigurationsofobjects.Bothmedial and lateral entorhinalcortex provide inputs to differentsub-regions of the hippocampus forcreating conjunctive representationof the external environment.While,the role of perirhinal cortex innonspatial information processinghasbeendocumented,thepostrhinalcorticalneuronsareweakly spatiallymodulated,indicatingthatotherbrainareasmay be involved in transfer ofspatial information to the entorhinalcortex.Subicularcomplex(comprisingof subiculum proper, presubiculumandparasubiculum), receive sensoryinputs from different cortical areasand connects to the hippocampusand entorhinal cortex, two major


brain areas involved in processingof spatial information. Based onanatomical connectivity, subiculumhasbeenregardedasbothanafferentandefferentareaofthehippocampus.Subiculum receives projections fromthe hippocampus; also it connectstosuperficiallayersoftheentorhinalcortex, which are the input layersto different hippocampal subfields.Dorsalpresubiculum (alsonamedaspostsubiculum), is also connectedto anterodorsal thalamic nuclei(containingheaddirectioncells),whichencode the current head directionandserveasinternalcompassfortheanimal.Thus,thesubiculummayactas an interface between these brainareasintheintegrationofspatialanddirectionalinformation.

Subicular neurons show directionaland locational correlates, althoughthespatial tuninghasbeen reportedto be less specific than that of thehippocampalplacecells.Further,thetamodulated place by direction cellshavebeenreportedinpostsubiculum,which may act as internal unitsallowing updating of position fromone location to another based onthe current directional heading. Thesubiculumneuronsalsoencodeheadangular velocity and running speed,two properties that are necessaryto allow self-motion informationto update representation of headdirection and location. Consideringtheanatomicalconnectionswithother

brain regions involved inspatialanddirectionalinformationprocessing,itisessentialtounderstandthefunctionalproperties of subicular neuronalfiringinordertoidentifytheamountof processing performed by differentbrainareas.Our studywill result incomprehensive characterization ofdifferent types of subicular complexneuronal response during spatialnavigationandlearning,whichinturnhelpindeterminingthepreciseroleofhippocampusininformationprocessing.Recording of large population ofneurons in vivo usingmultitetrodee lec trophys io log ica l record ingtechnique in different sub-areas ofsubicularcomplexsimultaneously,willresultindissociatingthedynamicsofrepresentationswithin this area andalsoleadtobetterunderstandingoftherelativecontributionofdifferentbrainregionsininformationprocessing.

Presentations:

D. Yoganarasimha: Representationof external environment in place celland head direction cell networks.SymposiumonNeurophysiologicalBasisof ComplexBehaviors. InternationalConferenceonNeuroscienceUpdates& ISN, APSN, IBRO&SNCI School.Centre for Neuroscience, CUSAT,Cochin,December7-142009.

Funding:

ThisworkissupportedbyNBRCCorefunds.

Computational Neuroscience and Neuroimaging

Dr. Nandini chatterjee singh

prof. prasun Kumar Roy

Dr. pravat Kumar Mandal

Computational Neuroscience & Neuroimaging 83


dr. Nandini Chatterjee Singh

Research Fellow

Tanusree das

Project Assistants

T. Sumathi

Background:Theadventof functionalneuroimaginghasprovided auniqueopportunitytostudytherepresentationof different languages in the humanbrain.Unlike spoken language,whichisacquiredthroughimmersion,readingis acquired only through instruction.Readingprovidesauniqueexampleofneuroplasticity,inthatbrainnetworksmeant for visualizing and hearingdevelopnewconnectionsinordertomapunitsofsoundontounitsofawritingsystem.Our laboratory is currentlyinterestedinfocusedonunderstandinghowthisremarkableprocessisachievedinadultsandchildren.

Earlier,functionalneuroimagingstudieshaveestablishedcorticalnetworksforreadingalphabetic,scriptslikeEnglish

Cortical network for reading words in Devanagari

and French, syllabic scripts likeJapaneseandlogographicscriptslikeChinese.ThewritingsystemofHindi,calledDevanagari,isdifferentfromalloftheseinthatitisanalphasyllabary,with anunusual blend of alphabeticand syllabic properties. The basicwrittenunitinthescriptisanAkshara,whichiseitheravowelinfullformoraconsonantwithanembeddedvowel/voweldiacritic.Hence,everyaksharaisasyllable,whichcanbebrokendownintoconstituentphonemes.Devanagariis a largely transparent script, withalmostone-to-onemappingofsoundsonto these units. It has a distinctorthographiclayourandisnon-linearinnature,with consonantsarrangedin left-to-right order, but vowelsplaced on the sides, above or belowthe consonant. Although about 33%oftheIndianpopulationspeaksHindiofwhicharound200millionuse theDevanagariscript(Singh,SolankiandBhatnagar,2008,UNDPreport,2004),very few studies have ventured toinvestigatetheneuralreadingnetworksinDevanagari(T.Dasetal,2009).Thereiscurrentlynoinformationaboutthedifferentcorticalareasthatparticipateinreadinganalphasyllabary.WeusefunctionalbrainimagingtostudythereadingnetworkforDevanagari,


In this study we used functionalneuroimagingtoascertainthecorticalreading network when 10 nativespeakers of Hindi, read only linearwords in Devanagari. As shown inFig.1 we found that reading linearwordsinDevanagariexhibitactivationsin superior temporal gyr i andoccipitotemporal areasas seen inanalphabeticscriptlikeEnglish;andleftinferiorparietallobuleasobservedinasyllabicscriptlikeJapaneseKana.Akintootherwordreadingstudies,wefoundactivation in themid-fusiform gyrus(visualwordformarea,BA37).Regionofinterestanalysisshowedinvolvementof left superior temporal gyrus (BA41),similartothatseenforalphabetic

scriptsandinferior(BA40)andsuperiorparietal(BA7)lobules,similartothoseseenforsyllabicscripts.Ourfindingssuggestthatthereadingnetworkforanalphasyllabaryincludescorticalareasinvolvedinreadingbothalphabeticandsyllabicwritingsystems.

Publications:

1. T. Das, U. Kumar, R. S. Bapi,P.PadakannayaandN. C. Singh(2009) Neural representationofanalphasyllabary–thestoryofDevanagari.Current Science,97,1033.

Funding:

ThisworkissupportedbyNBRCcore.

Figure1:CorticalreadingnetworkforDevanagarishowsalphabeticandsyllabicfeatures.



dr. Nandini Chatterjee Singh

Research Fellow

Tanusree das

Background: The mult i l ingualenvironmentofIndianotonlypromoteslearning to speakmultiple languagesbut the educational system ensureslearningtoreadinatleasttwoscripts,namelyoneIndiclanguageandEnglish.Little is known about how the brainaccommodates the learningofdistinctscriptsandourasecondareaofinterestin our laboratory has been to studybiscriptals,namelybilingualindividualsreadingtwoscripts,inparticularEnglishandHindi and the effects of age ofacquisitionandproficiencyintheneuralpathwaysrecruitedduringreading.

HindiandEnglisharenotonlywrittenindifferentscriptsbutarealsodistinctorthographies.Orthography is sound-lettermapping.WhileHindiwritten inDevanagari script has a transparentorthographywithalmostuniqueletter-to-soundmapping;Englishwritten in

Distinct cortical pathways for reading distinct scripts (the case for Hindi and english)

Romanscripthasanopaqueorthographywithoneletterrepresentingmanysounds(eg,c/ough/,b/ough/).Theacquisitionofreadinginpopulationslearningtoreadtwolanguagescanoccurintwopossibleways,namelyinasimultaneousmanneror a sequentialmanner.We studiedboth groups of bilinguals, thosewholearn to readbothHindi andEnglishsimultaneouslyaround5yearsarecalledsimultaneous readers as opposed tosequentialreaders,wholearntoreadthenativeHindiat5yearsofageandEnglishafterage7yearsofage.AsshowninFig.2,ourfunctionalneuroimagingresultsshowedthatearlysimultaneousreadersshow distinct cortical pathways forreadingdistinctorthographies(namelyEnglish andHindi)whereas the latesequential readers show a commonpathway for readingbothEnglishandHindi.

Long term goals Two new projectshavebeenintroducedinthelaboratorynamely

a) IdentificationoftheneuralcorrelatesfordyslexiainDevanagari.

b) Comparing speech andmusicnetworksinchildrenwithautismspectrumdisorder,


Publications:

1. T.Das,R.S.Bapi,P.Padakannaya,andNandini C Singh (2010)Cortical network for readinglinearwordsinanalphasyllabary.Reading and Writing(InPress)

2. U.Kumar,T.Das,R.S.Bapi,P.Padakannaya, R.M. Joshi andNandini C Singh(2010)Readingdifferentorthographies:AnfMRIstudyofphrasereadinginHindi-Englishbilinguals.Reading and Writing,23,239-255.

Presentations:

1. N.C.Singh:DistinctReadingroutesfordeepandshalloworthographiesin simultaneous biliterates – afunctionalimagingstudy,Abstract,Human Brain Mapping, SanFrancisco,USA,June2009.

2. N.C. Singh: Influence of nativelanguage reading networks onthe second language – a fMRI

study,Abstract,ScientificStudiesforReading,Boston,USA,June2009.

3. N.C.Singh: Fourier transforms,NovelapplicationsinNeuroscience,DelhiUniversity,March2010.

Funding:

Research grant fromDepartment ofScienceandTechnology.

Collaborators:

1) D. Prakash Padakannaya,Professor & Coordinator forUGC Innovative Program onlearningdisabilityanddyslexia,Department of Psychology,UniversityofMysore.

2) Dr.RSBapi,DeptofComputerandInformationSciences,UniversityofHyderabad.

3) Dr. Kenneth Pugh, HaskinsLaboratories, New Have, CT,USA.



Prof. Prasun Kumar Roy

Research Fellow

Suhela Kapoor

Project Assistant

Vinay Shukla

Aseminal challenge inbrain researchandneuroscience is to decipherhowflowprocessesoccur,whether that ofinformation, electrical current, drugs,cells or tissue displacement, acrossthe layered brain extent.One needsquantitativematrix (tensor) approachthatcanaccountfor,andcanfurnishaquantitativedescription,offlowprocessesanditsneuromodulationacrossbrain.Wehavedevelopedthemethodologyofdynamicfunctionaltensorneuroimagingand obtained accuratemeasurementofmatrix-tensormapstodescribeflowanddeformationprocesses,informationfluxor connectivity in thebrain. Theresearchhas considerablepotentialityof applications to clinicalmedicineaswell as to biological engineering,especially for diagnosis, therapy and

spatiotemporal Processing and Information transmission in Brain

neurophysiological investigations.Forinstance, theMRI tensorial imagingtechniquetodeterminethestress-straindisturbanceandinobstructivebloodorCSFflowhasbeendeveloped,alongsidepatenting the procedure jointlywithDelhiUniversity.Themethodologyhaspotential applications in predictingearly thrombogenesisand intracranialtensionindysfuntionalflowofbloodorCSF respectively.Theoverall objectiveof thisprogram is to comprehend thephysiologicalorpathologicaldynamicsoftransportorflowprocessesinthebrain,whetherthatoffluids,tissue,energyorinformation.

Energy Flow Mapping and Heat Tensor Imaging:

The spatiotemporalmapping of thedistribution of energy transmissionacrossthebrain,isrequiredforsomeessential inputs in diagnostic andtherapeuticmanagementinneurology,oncology and radiology. Using theMRI scanner platform,we have alsodevelopedthenoveltechniqueofthesetensor imagingprocedures, includingdetermination of other transport ormobilityindices(matrices)ofthebrain,such as the conduction/ convectiontensor,deformationtensor,aswellasthermal conductivity tensor imaging,


a multimodal imaging approach.Conventionally,tissueheatenergyflowconductivityisassumedasscalar,whichinduceserrorsinobtainingproperheatflowdistribution.Usingthermodynamicsprinciples, we evolve amethod forconstructingheat conductivity tensorimage of a spatiotemporally extendedtissueoranorgan,usinganMRIscanner(fig. 1 a,b).Ournoninvasive imagingmethodologyisquantitativelyvalidatedwithover90%accuracy,tothevaluesofthetransportparametersofthetissuemeasureddirectlyby invasiveprobes.Wedelineatethepossibleapplicationsofthisnovelimagingmodalitytoclinicalproblems involving biological heattransferequations,suchasplanningofhyperthermic treatment forpaediatrichypoxia-ischemiaandbraintumours,orforelectrodelocalizationindeepbrainstimulationduringParkinson’sdisease(Fig.1c).

Imaging-enabled Regenerative Intervention in Stroke

Utilizing MRI-based finite elementanalysisofbrainparenchyma,thestudyofspatiotemporalmobilityofendogenousreparativeneuroblastsacrossthebrainis a potential area for regenerativetherapyinstrokeandvasculardementia.We develop a quantitative analysisof neurogenesis and progenitor cellmigration from subventricular zone(SVZ)underinfluenceoferythropoietin/IGF2-baseddrugsthatcanbeenabledtocrossblood-brainbarrier(Fig.2a,b).BymeansoftheconsequentNFĸBpathwaymodulation,wedevelopthecellularflowdynamicsusingthenonlineardifferentialequationsforneuralstemcellformationintheSVZ.ThereafterweformulatetheNPCmigrationprocessthatisknowntobethermodynamicallycoupledtotheCSFflowdynamics,themigrationoccurring

Figure1(a)Heatconductivitytensorimage(traceplot)ofbrain;(b)HeatTractographyacrossbraintissueshowingpathwaysofenergyflux:saggitalview;(c)EnergyFlowMapping(EFM)ofbrainusedtodeterminethetemperaturecontourandthermaldoserateofagliomatumourduetointerstitialheatingbyanelectrode(yellowcross).Thevoxel-wiseheatconductiontensorismeasuredbytheMRItechniquedeveloped,andthenthetensorialBioheatequationissolvedonafiniteelementmeshworkacrossthebraintissue.Asthemeshresolutionandgradientorientationsincrease,thebluecurve(thetemperaturecontourpredictedfromtheEFMmethod)approximatestheredcurve(thetemperaturecontourobtainedbydirectthermometricprobes),thusshowingtheapplicabilityoftheMRImethod.


across the lateral ventricular rostralextension (MRI/CSFflow image), andthenacrosstheorthogonalfibretracts(MRI/DTIimage).Weobserveastrongpeakofmaximalproductionofmaturedneurons at specific dose rate andparticulartimeduration(Fig.2c).Theseareoptimaldosageandtherapyduration,any other combination reduces theneurogenesis.Theprocedureisvalidatedbyempiricaldataonanimalstudiesinacollaboratinglaboratorywherestrokeisinducedbyocclusionofmiddlecerebralartery(Fig.2d).Additionalconfirmationof theaccuracyof themethodology isfurnishedbyitspredictionofthespeedof neuroblastmigration at 34 µm/hour,whichprecisely corresponds toexperimentalvalueswithin8%error.Theclinicalapplicabilityoftheproceduretooptimizeregenerativetherapyinstrokepenumbraisbeingnowexplored.

Funding:

1. MinistryofEducation&Research,ItalianGovt.underaprogramoftheEuropeanCommission.

2. Dept.ofBiotechnology,Govt.ofIndia (collaborative projectwithAIIMS).

Collaborators:

1. Dr A lan Evans , Montrea lNeurological Institute, McGillUniversity

2. Dr T R Seshadri, University ofDelhi.

3. DrPatriziaBaraldi,UniversityofModena/CNRS-Rome.

4. DrManjari Tripathi &DrMVPadma, All-India Institute ofMedicalSciences,NewDelhi.

Figure 2(a)MRI structural image; (b) Perfusion image, both after stroke, the subtractivemismatchimageobtainedfromthetwoimagesdenotesthepenumbraregionthatisattemptedtobesalvagedbyregenerativeintervention;(c)Dose-Time-ResponsesurfaceofErythropoetin-inducedneuroblastpopulationreachingthepenumbra;verticalaxesdenotesneurogenesisintermsofcellnumber,thetwohorizontalaxesstandforerythropoetinconcentrationandtimedurationsinceadministration, respectively.Note the inverted-Ushapedperformancecurveimplyingoptimizationofneurogenesisoutputatspecificvaluesofdoseandduration,thecurvecanbewidenedornarroweddependingofthedrugdosingandsystemparameters;(d)Validationbyexperimentaldata,x-axisistimedurationindays,andy-axisimpliesthecellformation.ObservetheinvertedU-shapedoptimalitycurvecloselycorrespondingtotheoptimalcurvepredictedinthequantitativemodelshownin(c).

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Time (weeks) (a) (b) (c) (d)

Figure 2.

(a) (b) (c) (d)

Figure 3

(a) (b) (c) Figure 4

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Neural Population (increase over control, 106

Neural population (normalized)

Diffusion Tensor of neural fibres: Three fibres Two fibres One fibre P



Prof. Prasun Kumar Roy

Research Fellow

Subhadip Paul

R&d engineer

VPS Rallabandi, Sripad Kondra

A fundamental quest in appliedneuroscience is the enhancement oftheefficiencyofclinicaloutput,suchasneuroradiological processes,whetherdiagnosticortherapeutic.Apromisingapproach is offeredby theprocess ofperturbation-induced activation, anemergingresearchfieldincomputationalneuroscienceandbioengineering.Thisprocedure of stochastic activation,noise-aided resonance orfluctuation-inducedtransition,isageneralprincipleof nonlinear behaviour applicable tovarious systems,whetherphysical orbiological,andtakesplacebasicallydueto the statisticalkineticnatureof thecomponents thatexhibitsprobabilisticfluctuationsofparameters.Thepracticalapplicationoftheprincipleofstochasticactivationasanoveltechniqueforsignal

Application of stochastic Activation and stability Analysis for Brain Imaging and therapy

enhancement,whether in diagnosticortherapeuticradiology,hasnotbeensystematically investigated.Exploringthe feasibility of such applicationstowards clinicalmedicine is the aimofourprogram.To illustrate,wehaveformalized the techniqueofStochasticResonance Imaging as a generalradiologicalmethodologywhichcanbeappliedinFourierspaceforupgradationofthesignal,thetissue-adaptivetechniqueof how to administer the stochasticperturbationintheMRIimagetransformhas been rigorously delineated,withthe image upgradation performanceincreasingby45%-85%.Theprocedureaffords increasing characterization oftissue or lesion architecture acrossvariouspathologies,rangingfrombenigntomalignantfociandfromdevelopmentallesionstocerebrovascularincidents.

Higher Order Tensor Imaging of Brain Tumour Invasion:

Diffusivebehaviourisamostimportantmanifestationoftheprocessofstochastickinetic fluctuation seen in variousbiologicalsystems,whethermolecularorcellular,innormalityordisease.However,conflictingresultsarefoundinclinicalutility of theusually available lower-orderMRIdiffusiontensorimaging(DTI)forcharacterizationofthearchitecture


ofmalignanttumourtissueorcerebralstrokepenumbra.Asperconventionalpractice,theDTIbasedstudyofbrainlesionsuse loworder (2nd rank)DTIbased formulation. Actually, higher-order (4th rank)DTI can furnish thearchitectureofmultiplecrossingneuraltracts,whichthelower-orderDTIcannotprovide (Fig. 3 a,b). Indeed, the errorbetweentheactualdiffusionsignalandtheestimateddiffusionsignalappreciablylessensinthehigherranktensorimage.Such imagingmodehasnotbeenyetexplored to study brain tumours oranypathologicallesion.Utilizingrapid-switchingmotion-probing gradients

across15ormoredirections,weshowforthefirsttimethathigherorderdiffusiontensorimagingsignificantlyrepresentsaccuratelythediffusionprocessinhigh-gradeandlow-gradegliomatissuewhencomparedtoconventional2ndorderDTI(Fig.3 c,d). Therebywe candelineatethebrain regionwhere themalignantcellshavecovertlyinvaded(thoughthiscannotbefoundbyotherMRIprotocols),therebyonecanplantheradiotherapybeamtoaffect the invadedtissue,butminimize thenormal tissue exposure.We are applying higher order tensorimagingtodelineatebrainlesionsthatcanregenerate,asstrokepenumbra.

Figure 3(a)Structuralimageoftheglioma;(b)Crossingnervefibres:2ndordertensorimagingshowsonlytheonemajorfibre(rightdiagram),forotherfibres,oneneedshigherordertensorimaging;boththetwoandthreefibrearchitecture(leftandmiddlediagrams)canbeobservedusing4thranktensormapping;(c)Errormapof2ndranktensorimage,thepixelvalueorwhitenessintensityofeachpixeldenotestheerrorinthatpixel,observethehighhyperintensityinthetumourregionindicatinghigherrorbehaviortherein(pointP);(d)Errormapof4thrank tensor image.Note that the image ishypointensewith lessergraeyvalues, implyingconsiderableerrorreduction.Thepeak-errorpointsPareabsent.

Window to the Ageing process in Normality and Neurodegenerative disease.

Ageing gracefully is a coveted desireofpeopleastheyjourneythroughlife.Howeverabnormalageinggiverisetomildcognitive impairment (MCI) heraldingAlzheimer’sdiseaseorvasculardementia,amajorupcomingpublichealthproblem

worldwide.Oneideallyneedsasimplequantitative formulation of normalbrain ageing thatwould differentiatenormal from very early dementicbrains,whentherapeuticinterventionshas better efficiency.Moreover, theformulation shouldbe implementableasasimpletechnician-basedautomatedtechnique for readyMRI screening inthepublichealthsetting.Wedevelopa

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Figure 2.

(a) (b) (c) (d)

Figure 3


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conceptualbiophysics-basedmodel ofbrainageing,treatingthenormalbrainas a elastoplastic two-phase porousmediumwith stochastically generatedmorphometricpatterning.As□-amyloiddeposition increasesduringdementiaprogression, there is rising elasticshearstressduetoneurodegeneration-inducedreactiveoxygenspecieswhichis associatedwithmisaligned stress-straininthecross-□-sheet,alongwith

change of elasticmodulus in brainparenchyma.Based on elastoporouscharacterization of MRI scans andirreversiblethermodynamicanalysis,wederiveaquantitativelinearprincipleofnormalbrainageing.ByaccessingthetexturalstrainintheMRIimage,thepre-MCIstage,namelytheearliestdeviationfromnormalageing,canbedetectedatanespeciallyinitialstage.

Figure4.(a)MRI image for accessing the 2-phase tissue-fluidmedium; (b) The texturalcharacterizationofporousmediumfurnishesestimationofelastometricindices;(c)Elastoporousstress-strainanalysisoftheMRIbrainimageprovidesanwindowtotheageingprocess,asgradualtemporalrelaxationbehaviouroccursintheelastometricindices.

Publications:

1. Kh.BudhachandraSingh,VinayShukla andPrasun Roy (2010)Thermal Conductivity TensorImagingandEnergyFlowMappingof Brain: An MRI FeasibilityStudy,Annals of Biomedical Engineering (in press), (DOI:10.1007/s10439-010-9974-9).

2. SripadKondraandPrasun Roy(2010).AMathematicalApproachto Brain and Cognition. InS.Doraiswamy(ed).Mathematics

of Biological Processes, CRCPress,(inpress).

3. ParthaRaghunathanandPrasun Roy(2010),TheNeuroimagingofCognitiveprocesses,inVKSingh(ed).Advances in Neuroscience, Springer-Narosa,(accepted).

Patent:

1. A non-invasive technique toproducethestressimageoffluidflow(stresstensor)withmedical

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Figure 2.

(a) (b) (c) (d)

Figure 3


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applications (Assignee: NBRC,DelhiUniversityandDBT).

Presentations:

1. SubhadipPaul:TensorimagingoftheBraintooutlinehiddentumourinvasion,B.H.U.,Varanasi,July2009.

2. Suhela Kapoor: Image-guidedapp roach t o t h e r apeu t i cneurogenesis in stroke andvascular dementia, IndianAcademyofNeuroscience,Jaipur,Dec.2009.

3. VinayShukla:Pulseperturbativechemotherapytoincreasecytotoxicefficiency, Indian Academy ofNeuroscience,Jaipur,Dec2009.

4. VPS Rallabandi, Prasun Roy:GlimpsestotheLandscapeoftheAgeingBrain:ANeuroimagingPerspective, NationalDementiaSummit: Alzheimer’s&RelatedDisorders Society of India,NewDelhi,Sept2009.

5. Budhachandra Singh, VinayShukla, Prasun Roy: EnergyFlowTensorImagingasaClinicalModality:AConceptualExtensionofDiffusionandPerfusionTensorImaging, Nuclear MagneticResonance-10, Sanjay GandhiMedicalInstitute,Lucknow,Dec2010.

6. VPSRallabandiandPrasunRoy:Imaging in NeurodegenerativeDisease: New Horizons forAlzheimerDisease,InternationalConference on Alzheimer’s &Related Disorders Society ofIndia,Calcutta,Dec2009.

7. SuhelaKapoor,VPSRallabandi,Prasun Roy: A ComputationalNeuroimaging Approach ForO p t im i z i n g T h e r a p e u t i cNeurogenesisandSynaptogenesisin Stroke, DST Workshop &Symposium on MathematicalBiology,IISER,Pune,Aug2009.

8. Subhadip Paul, Prasun Roy:Higher order Tensor Imaging:NewHorizons of TranslationalMolecular Radiology, DST-NWO Indo-DutchWorkshop onMedicalImaging&TranslationalMedicine,SCTIMST,Trivandrum,Jan2010.

9. PrasunRoy:Cross-scaleIntegrationof Information Transmissionacross Neuronal, Cortical andCognitive Modes: A SystemsBiologyApproach,ComputationalNeuroscience & NeuroimagingWorkshop,SCTIMST,Trivandrum,Oct2009.

10. PrasunRoy:MultiscaleSystemsApproach to Brain Disorders:Towards Rad i ogenomicsand Programmed Therapy,International Neuro-informaticsWorkshoponMultiscaleModelling,NCBS,Bangalore,Nov2009.

11. PrasunRoy:ANeuroregenerativeApproachtoIschaemicCerebralPalsyusingMolecularRadiology,National Institute of MentallyHandicapped, Hyderabad, Feb2010.

12. Prasun Roy: The Self and itsBrain: The Newest Frontier ofComputing, IIIT, Allahabad,March2010.


Fundings:

1. Defense Ministry (DefenseResearch & Deve l opmentOrganization).

2. NBRCCorefund.

Collaborators:

1. Dr Peter Luijten,DutchCentrefor Translational MolecularMedicine

2. DrR.K.Padhi,IndianInstituteofScience,Bangalore.

3. DrPaulThompson,UniversityofCalifornia–LosAngeles.

4. Dr P. Sarat Chandra, All-IndiaInstituteofMedicalSciences,NewDelhi.

Awards:

1. Subhadip Paul, SERC StudentFellowshipaward,WorkshoponFiniteElementModellingofFluidFlow,BHU,Varanasi,Aug2009.

2. SuhelaKapoor,NeuroinformaticsTravelAward,NCBS,Bangalore,Oct2009.

3. VinayShukla,Traineefellowshipaward, AdvancedWorkshop onControlSystemsAnalysis,I.I.Sc,Bangalore,May2009.

4. Prasun Roy, Asia PartnershipProfessor Award in MedicalImaging, Utrecht UniversityMedical Centre, Utrecht, TheNetherlands,Nov2009.



dr. Pravat Kumar Mandal

Project Assistant

Manisha Ahuja

R&d engineer

Sebathi Ghosh, deepak Kamboj and Rohit Jadav

Alzheimer’s disease (AD) is amajorneurodegenerative disorder and aworldwide serioushealth concern fortheelderly.Thecauseofthisdiseaseisstillnotknown.However,itisindicatedthat oxidative stress, energetic stress,and irregularmembranephospholipidmetabolismplayan important role inADpathology.Amongthesemolecularprocesses,whichcomefirstandcausallyrelatedtothediseaseisacrucialareaofADresearch. InvivoMRIandMRStechniquecanprovidevitalinformationfor identifying the causalmolecularprocessinAD.

Biomarker for Alzheimer and other neurodegenerative disorders using in vivo Magnetic Resonance imaging (MRI) and spectroscopic (MRs) techniques.

Using 3T MRI scanner, we areinvestigatingvolumetric(using3DMRI)aswellasneurochemicalanalysisusing1H and 31PMRS onmild cognitiveimpairment(MCI),AD,Parkinsondisease(PD)andage/gender/educationmatchedhealthycontrolsubjectsforlongitudinalanalysis.Weareconductingsinglevoxelandmultivoxel(1HMRS,31PMRSMRS),MEGA-PRESSexperiments.AchangeofN-acetylaspartate (NAA) concentrationandan increment ofmyoinositol (mI)fromnormaltoMCIandADpatientsisfound.Dataareprocessedusingdifferentdata processing software packages(LCModel,3DiCSIandjMRUI).

Figure1showsthe1HsinglevoxelMRSspectra of three categories of subject(healthycontrol,MCIandADpatients).Figure2showsthe31PMRSspectraofsame regionandonsamecategoryofsubject.

Funding:

DepartmentofBiotechnology,Govt.ofIndia


Collaboration:

1. Dr.Manjari Tripathi,MD,DM,Department o f Neurology,(AIIMS)

2. Dr. Subbulakshmy Natarajan,MBBS,Ph.D

3. Dr. SadaNandDwivedi, Ph.D,Dept.ofBiostatistics,(AIIMS)

4. Dr.ParthaRaghunathan,Ph.D

Figure1Singlevoxel(25mmx25mmx25mm)1HMRSspectraforhealthcontrol(1A),MCI(1B)andAD(1C)subjectson3TPhilipsscanneratNBRC.Totalexperimenttime7minutesineachcase.

Figure2:Singlevoxel(25mmx25mmx25mm)31PMRSspectraforhealthcontrol(2A),MCI(2B)andAD(2C)subjectson3TPhilipsscanneratNBRC.Totalexperimenttime26minutesineachcase.



dr. Pravat Kumar Mandal

Project Assistant

Manisha Ahuja

R&d engineer

Sebathi Ghosh

Alzhe imer ’s d isease (AD) is aneurodegenerative disorder affectingmillions of people worldwide andhas become amajor global concern.Uncon t r o l l ed o l i g omer i z a t i on(aggregation) of Aβ peptide is thehallmarkofADanditisbelievedtobecausallyrelatedtoADpathomechanism.Intensiveresearch(biophysical,animalmodel and clinical) is underway toinvestigatethecauseofthisunexplainedAβ peptide oligomerization,which isprobably triggered by some agent orprocess in predisposed individuals,and subsequently to trace themolecular pathways involved in thephenomenon.

smaller sized Anesthetics Induce Amyloid beta peptide oligomerization

Recently,itisreportedusingbiophysicalstudies that several commonlyused inhaled anesthetics induce A□aggregation (oligomerization). Similarobservations have also been foundfromanimalmodelstudiesthatsmallersizedanesthetics,inducemoreplaqueload in transgenicmice compared tonon-transgenicmice (control group).ButthemolecularmechanismfortheseanestheticsinducedAβoligimerizationisunknown.

Ourlaboratory,usingNMRspectroscopictechniquesonseveralanesthetics,havearrivedattheconclusionthatsmallersizedanesthetics(Figure1)areabletoaccessandinteractwiththehelix-loop-helix regionofAβpeptidecontainingthree specific amino acid residues(G29,A30 and I31); thereby causingAβoligomerization.The“sizefactor”oftheseanestheticsandtheirprofoundroleinAβoligomerizationisanovelandthought-provokingconcept.

Themolecularpathwayforthesmallersized inhaled anesthetic inducedhalothaneisshowninFigure2


Figure2:AschematicdiagramforAβinteractionswithisofluraneand/ordesfluraneataclinicallyrelevantconcentrationthatleadstooligomericAβformation.Aβpeptideisgeneratedbytheamyloidprecursorprotein(APP),bytheactionofβandγsecretasebynaturalprocess,andtheinhaledanestheticinteractswiththreespecificresidues(G29,A30andI31)andinitiatestheformationofneurotoxicoligomericAβformation.ThisoligomermayberesponsibleforplaqueformationasseeninADpatientsonbiopsy

Figure1Molecularstructureofanestheticsbasedonmolecularvolume(Å3).Themolecularvolumeofpropofolisintheintermediaterangebetweensmaller(inhaled)andlargersized(intravenous)anesthetics.


Publications:

1. Pravat K Mandal *, VirgilSimplaceanuandVincenzoFodale(2010) Intravenous AnestheticDiazepamdoesnotinduceAmyloidbeta-peptideOligomerizationbutDiazepamCo-administeredwithHalothaneOligomerizesAmyloidBeta-peptide: An NMR study.Journal of Alzheimer Disease,Vol20(1),127-134.

2. V. Fodale, L.B. Santamaria,D. Schifilliti andP. K. Mandal(2010) Anaesthetics and post-operative cognitive dysfunction:a pathological mechanismmimicking Alzheimer’sDisease.Anesthesia,Vol65(4)388-395.

3. Pravat K. Mandal*andVincenzoFodale(2009)Smallermolecular-sized anaesthetics oligomerizeAbeta pept ide s imula t ingAlzheimer’s disease: a relevantissue. European Journal of Anesthesiology,Vol26(10)805-806.Editorial (last year it was indicated as in press )

Funding:

ItalianMinistry for University andResearch Program (Multi-centerGrant)

Collaboration:

1. Dr . V incenzo Foda le , MD(UniversityofMesina,Italy)

2. Prof. Virender S. Chauhan(ICGEB),NewDelhi

puBlIcatIoNs & pateNts


Publications:

1. S.Mulherkar andN. R. Jana(2010). Loss of dopaminergicn e u r o n s a n d r e s u l t i n gbehavioural deficit in mousemodel of Angelman syndrome.Neurobiology of Diseases. (InPress)

2. N. R. Jana (2010). Role ofubiquitin-proteasome systemandautophagyinpolyglutamineneurodegenerative diseases.Future Neurology,5,105-112.

3. R.Maity, J Sharma andN. R. Jana (2010).Capsaicin inducesapoptosis through ubiquitin-proteasomesystemdysfunction.Journal of Cellular Biochemistry,109,933-942.

4. S.Mulherkar,J.SharmaandN. R. Jana(2009).TheubiquitinligaseE6-AP promotes degradationof α-synuclein. Journal of Neurochemistry, 110, 1955-1964.

5. Mishra, S. K. Godavarthi andN. R. Jana (2009).UBE3A/E6-AP regulates cell proliferationby promoting proteasomaldegradationofp27.Neurobiology of Diseases,36,26-34.

Publications & Patents

6. RaoS.N.,SharmaJ.,MaityR.andJana N. R.(2010).Co-chaperoneCHIP stabilizes aggregate pronemalin,anubiquitinligasemutatedin Lafora disease. Journal of Biological Chemistry, 285,1404-1413.

7. ShaileshKumarGupta, KarinaMeiri2,KashifMahfooz1,UpasnaBharti1 andShyamala Mani.(2010) Coordination betweenextrinsicextracellularmatrixcuesandintrinsicresponsestoorientthe centrosome in polarizingcerebellar granule neurons.Journal of Neuroscience,30(7):2755–2766.

8. Angela M. Kaindl, SandrinePassemard Pavan Kumar ,BenedicteGerard,AlainVerloes,Shyamala Mani and PierreGressens(2010).Manyroadsleadto primary autosomal recessiveprimarymicrocephaly.Progess in Neurobiology,90(3):363-83.

9. JenniferL.Moran,EmilyT.Shifley,John M. Levorse, Shyamala Mani,KristinOstmann,AriadnaPerez,DawnM.Walker,ThomasF.Vogt,andSusanE.Cole(2009).Expressionanddeletionanalysesof Manic fringe indicates that


it isnot required for embryonicdevelopment, and that FRINGEproteins are not functionallyredundant. DevelopmentalDynamics, Developmental Dynamics,238(7):1803-1812.

10. Kim-DaDestot-Wong,KunLiang,ShaileshKumarGupta,GéraldineFavrais, Leslie Schwendimann,MichaelSpedding,VincentLelièvre,Shyamala ManiandPierreGressens(2009).TheAMPAreceptorpositiveallostericmodulator, S18986, isneuroprotectiveagainstneonatalexcitotoxic and inflammatorybrain damage through BDNFsynthesis.Neuropharmacology,57:277-286.

11. Saeed, U., Ray, A., Valli, R.K.andRavindranath, V (2010)DJ-1 loss by glutaredoxin butnotglutathionedepletiontriggersDaxxtranslocationandcelldeath.Antioxidants & Redox Signaling,13(2):127-144.

12. K a r u n a k a r a n , S . a n d Rav ind r ana th , V ( 2009 )Activation of p38MAP kinasein substantia nigra leads tonucleartranslocationofNF-kBinMPTPtreatedmice:Implication in Parkinson’s disease. J.Neurochem,109:1791-9.

13. Ghosh S, Tewari R, Dixit D,Sen E (2010) TNF inducedoxidative stress dependent Aktsignalingaffectsactincytoskeletalorganization in glioma cells.Neurochemistry International56(1):194-201.

14. SharmaV,KoulN,JosephC,DixitD, SGhosh andSen E (2009)HDACinhibitorScriptaidinduces

glioma cell apoptosis throughJNK activation and inhibitionof telomerase activity.Journal of Cellular and Molecular Medicine.

15. Dixit D, Sharma V, Ghosh S,Koul N, Mishra PK and Sen E (2009) Manumycin inhibitsSTAT3, telomerase activity andgrowthofgliomacellsbyelevatingintracellular reactive oxygenspecies generation.Free Radic Biol Med.47(4):364-74.

16. Sharma V and Sen E (2009)Tumormicroenvironment andinflammation:roleinglioblastomaprogression.Editors:GPTalwarandOPSood(NarosaPublishinghouse).

17. Bain JM, Ziegler A, Yang Z,LevisonSW#,SenE*(2010)TGFβ1stimulates over-production ofwhitematterastrocytesfromglialprecursorsofthe“brainmarrow”in a rodentmodel of neonatalencephalopathy. PLoSOne, 5;5(3):e9567.

18. MaharanaC,SharmaKP,Sharma SK(2010).DepolarizationinducesacetylationofhistoneH2Binthehippocampus.Neuroscience,167:354-360.

19. Sharma SK (2010). Proteinacetylationinsynapticplasticityandmemory.Neurosci Biobehav Rev.,34:1234-40.

20. Sharma S (2010) HepatocytegrowthfactorinsynapticplasticityandAlzheimer’sdisease.Scientific World Journal,10:457-61.

21. KDutta,MKMishra,ANazmi,K L Kumawat and A Basu


(2010)MinocyclineDifferentiallyModulatesMacrophageMediatedPeripheral Immune ResponseFollowingJapaneseEncephalitisVirusInfection.Immunobiology.(InPress)

22. KDutta,DGhosh, ANazmi, KLKumawat,andA Basu (2010)ACommonCarcinogenBenzo[a]pyreneCausesNeuronalDeathinMouseviaMicroglialActivationPLoS One,5(4):e9984.

23. DNandi,MKMishra,A Basu,andBBishayi (2010)Protectiveef fects of Interleukin-6 inLipopolysaccharide(LPS)inducedexperimental endo-toxemia arelinkedtoalterationinhepaticanti-oxidantenzymesandendogenouscytokines.Immunobiology,215:443-451.

24. RMukhopadhyay,MKMishra,A Basu,andBBishayi(2010)Effectofparticularantigenicstimulationor in vivo administration ofInterleukin-6 on the level ofsteroidogenicenzymesinadrenalglands and lymphoid tissues ofmicewith parallel alteration inendogenousinflammatorycytokinelevel.Cellular Immunology,261(2010)23–28.

25. S Das, D Ghosh, andA Basu(2009) Japanese encephalitisvirusinduceimmuno-competencyinneuralstem/progenitorcells.PLoS One,4(12):e8134.

26. *MKMishra,KDatta,SKSaheb,andA Basu(2009)Understandingthe molecular mechanism ofbloodbrainbarrierdamageinanexperimentalmodel of JapaneseEncephalitis: Correlation with

minocycline administrationas atherapeuticagent.Neurochemsitry International,55(8):717-233.

27. *KDatta,DGhosh,andA Basu(2009)CurcuminprotectsneuronalcellsfromJapaneseEncephalitisvirusmediatedcelldeathandalsoinhibits infective viral particleformation by dysregulation ofUbiquitinproteasomesystem.J Neuroimmuno Pharmacology,4(3):328.

28. KDutta, ANazmi, andA Basu(2010)ChemotherapyInJapaneseEncephalitis:AreWeThereYet?Infectious Disorders - Drug Targets.(InPress)

29. S Chakraborty, D K Kaushik,M Gupta, andA Basu (2010)InflammasomeSignalingAtTheHeartofCentralNervousSystemPathology. J Neurosci Res.,88:1651-1631.

30. SChakraborty,ANazmi,KDutta,andA Basu (2010) “NeuronsUnder Viral Attack: VictimsOrWarriors?” Neurochemsitry International,56:727-735.

31. KDutta,PNRangarajan,SVrati,andA Basu (2010) JapaneseEncephalitis: Pathogenesis,Prophylactis and Therapetucis.Current Science, 98 (3): 22-30. (Special section: Biology and pathogenesis of Virus)

32. *D Ghosh andA Basu (2009)Japanese Encephalit is - APatho log ica l and C l in ica lPerspective PloS Neglected Tropical Diseases,3(9)e437.

33. Murthy, A.,Shorter-Jacobi,S.M.,Thompson,K.G.andJ.D.Schall


(2009) Neural control of visualsearchbyfrontaleyefield:Effectsoftargetdisplacementonvisualselectionandsaccadepreparation.Journal of Neurophysiology,101:2485-2507.

34. K.M. Sharika, SupriyaRay andA. Murthy (2009) Attention forAction duringErrorCorrection.Progress in Brain Research.176:227-244.

35. Ramakrishnan,A.,Chokandre,S.andA. Murthy(2010)Voluntarycontrolofmulti-saccadegazeshiftsduringmovementpreparationandexecution.J. Neurophysiology

36. Shashank Tandon, NiranjanKambi,LesleeLazar,MohammedHishamandNeeraj Jain(2009)Large-scaleexpansionofthefacerepresentationinsomatosensoryareasofthelateralsulcusfollowingspinalcordinjuriesinmonkeys.Journal of Neuroscience, 29:12009-12019.

37. AatiraGNedungadi,GRangarajan,Neeraj Jain and MingzhouDing (2009) AnalyzingmultiplespiketrainswithnonparametricGranger causality.Journal of Computational Neuroscience,27:57-64.

38. Hui-XinQi,Neeraj Jain,ChristineECollins,David Lyon and JonH Kaas (2010). FunctionalOrganization of motor cortexof adult macaquemonkeys isalteredbysensorylossoccurringininfancy.Proc. Natl. Acad. Sci., USA,107:3192-3197.

39. Khurshid N, Jayaprakash, N,Hameed,LS,Mohanasundaram,

S and Iyengar S (2010)Opioidmodulation of singing inmalezebra f inches (Taenopygiaguttata).Behav. Brain Res.208;359–370.

40. Smith RG,Dhingra NK (2009)Ideal observer analysis ofs i gna l qua l i t y i n r e t ina lcircuits.Prog Retin Eye Res, 28:263-288.

41. T.Das,U.Kumar,R.S.Bapi,P.Padakannaya andN. C. Singh(2009)Neuralrepresentationofanalphasyllabary–thestoryofDevanagari.Current Science,97,1033.

42. U.Kumar,T.Das,R.S.Bapi,P.Padakannaya, R.M. Joshi andNandini C Singh(2010)Readingdifferentorthographies:AnfMRIstudyofphrasereadinginHindi-Englishbilinguals.Reading and Writing,23,239-255.

43. Kh.BudhachandraSingh,VinayShukla andPrasun Roy (2010)Thermal Conductivity TensorImagingandEnergyFlowMappingof Brain: An MRI FeasibilityStudy,Annals of Biomedical Engineering (in press), (DOI:10.1007/s10439-010-9974-9).

44. SripadKondraandPrasun Roy(2010).AMathematicalApproachto Brain and Cognition. In S.Doraiswamy (ed).Mathematics of Biological Processes, CRCPress.(inpress).

45. ParthaRaghunathanandPrasun Roy(2010)TheNeuroimagingofCognitiveprocesses,inVKSingh(ed).Advances in Neuroscience, Springer-Narosa,(accepted).


46. Pravat K Mandal* , Virg i lSimplaceanuandVincenzoFodale(2010) Intravenous AnestheticDiazepamdoesnotinduceAmyloidbeta-peptideOligomerizationbutDiazepamCo-administeredwithHalothaneOligomerizesAmyloidBeta-peptide: An NMR study.Journal of Alzheimer Disease,Vol20(1),127-134.

47. V. Fodale, L.B. Santamaria,D. Schifilliti andP. K. Mandal(2010) Anaesthetics and post-operative cognitive dysfunction:a pathological mechanismmimicking Alzheimer’sDisease.Anesthesia,Vol65(4)388-395.

48. Pravat K. Mandal*andVincenzoFodale(2009)Smallermolecular-sized anaesthetics oligomerizeAbeta pept ide s imula t ingAlzheimer’s disease: a relevantissue. European Journal of Anesthesiology,Vol26(10)805-806.Editorial (last year it was indicated as in press )

Patents

P.K. Roy: A non-invasive techniqueto produce the stress image of fluidflow (stress tensor) with medicalapplications (Assignee: NBRC,DelhiUniversityandDBT).

Ellora Sen: “Bicyclic triterpenoidIripallidalasanovelanti-gliomaandanti-neoplastictherapyinvitro”.FiledforIndianpatentthroughDepartmentofBiotechnology (#2915/DEL/2008)and International patent (PCT/IN09/000336).

V. Ravindranath:Withania somniferaplantextractandmethodofpreparationthereof.JointpatentwithUniversityofDelhiandIndianInstituteofScience-Bangalore.

pReseNtatIoNs

Presentations 111

1. S.Godavarthi andN. R. Jana:AngelmanSyndromeCandidateProtein-E6AP,isaCoactivatorofGlucocorticoidHormoneReceptor,IAN,Jaipur,2009.

2. N. R. Jana: Toxic prote inaggregationinneurodegenerativediseases. National Institute ofAdvancedResearch,Ahmedabad,2010.

3. N. R. Jana:Understanding thefunctional role of E6-AP – anubiquitin protein ligase andsteroid receptor coactivatorimplicated in Angelmanmentalretardation syndrome. AOSCE,JNU,NewDelhi,2010.

4. N. R. Jana: Toxic prote inaggregation in polyglutamineneurodegenerative diseases.DRDO,NewDelhi,2009.

5. N. R. Jana: Suppression ofpolyglutamineneurodegenerationbyubiquitinproteinligases.IGIB,NewDelhi,2009.

6. S. Rao, J. Sharma, R. Maity.S.K.Shankar.P.SatishchandraandN.R. Jana. Lafora diseaseand ubiqui t in-proteasomedysfunction, PME Conference,Venice,Spain,2010.

Presentations

7. J.SharmaandN.R.Jana.Laforadisease associated ubiquitinligase,malin interactswithandpromotes proteasome-mediateddegradation of neuronatin. IAN,Jaipur,2009.

8. S. Rao, J. Sharma and N. R.Jana.CHIP stabilizes aggregatepronemalin,anubiquitinligasemutated inLaforadisease. IAN,Jaipur,2009.

9. ParthivHaldipur,UpasnaBharti,Chitra Sarkar, Corinne Alberti,SoumyaIyengar,PierreGressens,ShyamalaMani:Pretermdeliveryaltersthedevelopmentalprogramof the cerebellum. Frontiers inOrganogenesis, Kobe, Japan.23rd–25thMarch2010.

10. N. Sehgal , V. Agarwal , K.Valli, L. Antonovic, H. Strobel,V.Ravindranath.Neuroprotectiverole of cytochrome P4504f inresolution of inflammation inbrain.Presentedatthethe39thannualmeeting of the SocietyforNeuroscience,Chicago,USA.October17–21,2009.

11. RayA,SaeedU,ValliRK,KumarAMRK, Karunakaran S andRavindranathV:Perturbationofproteinthiolhomeostasisthrough


downregulationofglutaredoxin,aproteindisulfideoxidoreductase,results in loss ofDJ-1 throughproteolysis; Poster presented attheXVIIIWFNWorldCongressonParkinson’sDiseaseandRelatedDisorders,Miami Beach, USA.December13-16,2009.

12. P. Seth: Invited Speaker, BrainAwarenessWeek,BanarasHinduUniversity,Varanasi,India,March2010.

13. P.Seth:GuestSpeaker,NationalScienceDay,KendriyaVidyalaya,Manesar,India,February2010.

14. P.Seth:GuestFaculty,JawaharlalNehruUniversityAcademicStaffCollegeLectureseriesforcollegeteachers, New Delhi, India,January2010.

15. P. Seth: Invited Speaker &ConvenerInternationalSymposia,AnnualMeetingofIndianAcademyof Neurosciences, NIIMSUniv,Jaipur,India,Dec2009.

16. P.Seth:InvitedSpeaker,AnnualmeetingofInternationalSocietyofNeurovirology(USA),Miami,USA,June2009.

17. P . Seth: Inv i ted Speaker ,InternationalNeuroAIDSResearchMeeting organized by HIVNeurobehavioralResearchCenter(HNRC),Miami,USA,May2009.

18. P . Seth: Inv i ted Speaker ,Annual meeting of Society ofNeuroimmunopharmacology(USA)atWuhan,China,heldinApril2009.

19. Vivek Sharma *, Nitin Koul,Veer SinghMehta and Ellora

Sen: Interleukin-1β inducedHIF-1 transcriptional activityin glioma cells is regulated byRas via NF-ĸB. Frontiers inBasicCancerResearchMeeting.Boston,October2009.

20. Ellora Sen: Inflammation andCancer:Romancingdeath.WestBengalStateUniversity,Calcutta,August,2009

21. Deobrat Dixit*, Vivek SharmaandEllora Sen: Casein Kinase2 inhibition induces SOCS-1express ion and sensi t i zesglioblastoma cells to TumorNecrosis factor (TNF) inducedapoptosis. Indian Academy ofNeuroscience,JaipurDecember,2009.

22. Nitin Koul*, Vivek Sharma,Deob ra t D i x i t , S adash i bGhosh andEllora Sen:Bicyclictriterpenoid Iripallidal inducesapoptosis and inhibits Akt/mTORpathway in glioma cells.International Symposium onCancer Chemoprevention andTranslational Research, NewDelhi,December,2009.

23. VivekSharma,NitinKoul, VeerSinghMehta and Ellora Sen*:3rdInternationalSymposiumonTranslational CancerResearch,Bhubaneswar,December,2009

24. VivekSharma,NitinKoul, VeerSinghMehta and Ellora Sen*:Macbeth’sthreewitchesinglioma:IL-1β,RasandNFĸB.MolecularImmunology Forum. Calcutta,January,2010

25. Shiv K Sharma, Kiran Pandey,ChinmoyeeMaharanaandKaushik

Presentations 113

Sharma: Histone deacetylaseinhibitor- and activity-inducedacetylationofp55:relevanceforsynapticplasticityandmemory.PosterpresentationattheSocietyfor Neuroscience Conference,Chicago,USA,Oct.17-21,2009.

26. ChinmoyeeMaharana,KaushikP Sharma andShivK Sharma:D e p o l a r i z a t i o n i n d u c e shistoneH2B acetylation in thehippocampus.PosterpresentationattheXXVIIConferenceofIndianAcademy of Neurosciences,Jaipur,Dec.18-20,2009.

27. Kiran Pandey, ChinmoyeeMaharana, Kaushik Sharmaand Shiv K Sharma: Activity-dependent regulation of alphatubulin acetylation. Posterpresentat ion at the XXVIIConferenceofIndianAcademyofNeurosciences,Jaipur,Dec.18-20,2009.

28. S Das, and A Basu: JapaneseEncephalitisVirusarrestsNeuralstem cell proliferation andconfersthemwithimmunogenicpropert ies. 2nd BangaloreMicroscopy Course, NCBS,Bangalore, 21st-28th February,2010.

29. ABasu:Immuno-competencyofNeural stem cells: Neuro-tropicViralinfectionasamodelsystem.Molecular Immunology Forummeeting.FortRadisson,Raichak(NearKolkata),15-17thJanuary,2010.

30. ABasu: JapaneseEncephalitisViruscauses“doubletrouble”tobrain.GuhaResearchConference.Summer Sand Beach Resort,

Ullal, Mangalore. 19th -23rdDecember,2009.

31. K Dutta, K L Kumawat, M KMishra,andABasu:MinocyclinemodulatesJapaneseEncephalitisVirus entry in the centralnervous system. XXVII AnnualconferenceofIndianAcademyofNeuroscience. NIMSUniversity,Jaipur,18-20December,2009.

32. S Chakraborty, S Das, and ABasu: Lipid rafts play a criticalrole in Japanese EncephalitisVirus entry into neural stemcells.XXVIIAnnualconferenceofIndianAcademyofNeuroscience.NIMSUniversity, Jaipur, 18-20December,2009.

33. DKKaushik,SDas,MGupta,and A Basu: To elucidate therole of Kruppel like factor 4,a novel transcription factor inneuroinflammation.XXVIIAnnualconferenceofIndianAcademyofNeuroscience. NIMSUniversity,Jaipur,18-20December,2009.

34. S Das, and A Basu: Infectiono f n eu ra l s t em c e l l s b yJapanese Encephalitis Virus:Implications in long-term viralneuropathogenesis.XXVIIAnnualconferenceofIndianAcademyofNeuroscience,NIMSUniversity,Jaipur,18-20December,2009.

35. ABasu: JapaneseEncephalitis:fromneuropathologytotherapeuticintervention.WestBengal StateUniversity, Barasat, North 24Paraganas,23rdOctober,2009.

36. ABasu: JapaneseEncephalitisVirus infectsNeural StemCellsanddecreasestheirproliferation.


Biology and Pathogenesis ofViruses:MolecularInsights,IISC,Bangalore,4-5thMay,2009.

37. A Basu: The brain’s responseto Japanese Encephalitis virusinfection:Do neural stem cellsplayarole?15thSNIPConference,,Wuhan,China,21st-24thApril,2009.

38. ABasu:Hostpathogeninteractionin Japanese Encepha l i t i sVirus infection: from bench tobedside;DepartmentofPhysiology,UniversityofCalcutta,6thApril,2009.

39. Rahul Chaudhary, PraseedaVenugopa lan & V . Rema.Unilateral barrel cortex lesionresultsinlong-lastingdeficitsinsomatosensorybehaviorofadultrats. Society for NeuroscienceAnnualMeeting.Chicago,Illinois,October,2009.

40. Sakth i Kumar M, Eth i ra jRavindran,RahulChaudharyandV.Rema.Effectoffocalinjuryondistant, anatomically connectedbrainregions.IndianAcademyofNeuroscience.JaipurDec.2009.

41. Ramakrishanan,RamakrishnanS. andA.Murthy.Tracking thedecision as it changes: Supra-thresholdmicrostimulation inmacaquefrontaleyefieldrevealshowdecisionsarecontrolled.Soc.forNeuroscienceAbstract (USA)2009.

42. Gopal, P. Vishwanathan, A.Murthy.TheControlofEyeHandCoordinationinaRedirectTask.IndianAcademyofNeuroscience,Jaipur,India.2009.

43. N. Bhutani, Ramakrishnan S.,A.Murthy. Basal Ganglia andthe Control of Sequential EyeMovements. Indian Academyof Neuroscience, Jaipur, India.2009.

44. Niranjan A Kambi, ShashankTandon, HishamMohammed,Leslee Lazar, Radhika Rajanand Neeraj Jain: Topographyof primary motor cortex inmonkeys with dorsal spinalinjuries. Neuroscience 2009,AnnualMeetingoftheSocietyforNeuroscience,Chicago,USA.Oct17-21,2009.

45. LesleeLazar,RadhikaRajanandNeeraj Jain: Focal stimulationontheskinofthehandactivatedneuronsoverlargeregionsofthehandrepresentationinarea3bofmacaquemonkeys.Neuroscience2009, Annual Meeting of theSocietyforNeuroscience,Chicago,USA.Oct17-21,2009.

46. ‘AdvancesinBiologicalSciences’,aNationalConferenceorganizedbyDepartmentofZoology,PanjabUniversity, Chandigarh, India.March29-30,2010.

47. ‘ChallengesinSpinalCordInjuryRepair’ a seminar organized byDr ALMPG Institute,UniversityofMadras.March5,2010.

48. Soumya Iyengar: Developmentof theHuman Auditory Cortex– Neuroanatomical Studies.Psychology Dept., VanderbiltUniversity, Nashville, TN,USA.October,2009.

49. Soumya Iyengar: The humanauditorycortex–adevelopmental

Presentations 115

timeline.NationalProgrammeonPerceptionEngineering(TechnicalWorkshop). NBRC, Manesar,December,2009.

50. Arv ind S Pundi r , Senth i lKrishnasamy,SouvikKar,BishanSRadotra, PraveenKumar, PCDikshit, Soumya Iyengar: Thehumanauditorycortexduringthethirdtrimesterandatterm.PosterpresentedattheAnnualMeetingofSocietyforNeuroscience,Chicago,IL,USA.October,2009.

51. ArvindSPundir,BishanSRadotra,Praveen Kumar, PC Dikshit,Soumya Iyengar:Developmentoftheperinatalandpostnatalhumanauditorycortex.PosterpresentedattheAnnualmeetingoftheIndianAssociationofNeurology,Jaipur,December2009.

52. ParthivHaldipur,UpasanaBharti,Chitra Sarkar, Corinne Alberti,SoumyaIyengar,PierreGressens,ShyamalaMani:Pretermdeliveryaltersthedevelopmentalprogramofthecerebellum.Posterpresentedat“FrontiersinOrganogenesis”,ameetingorganizedbytheCentreforDevelopmentalBiology,Kobe,Japan,March2010.

53. NK Dhingra: Remodeling inThird-Order Retinal NeuronsAfterPhotoreceptorDegeneration.InvitedtalkatIIT,Delhi,July15,2009.

54. NKDhingra: Invited to chair asymposiumonNeurophysiologicalBasisofComplexBehaviors,andpresentonRetinalDegenerationin an Inducible AnimalModel– Biochemical, Morphological,Physiological and Behavioral

Correlates in InternationalConference on NeuroscienceUpdates& ISN, APSN, IBRO&SNCISchool,Cochin,December7-14,2009.

55. S.Nagar,S.Sethuramanujam,V.Jain,P.Cherukuri,NKDhingra:RemodelingofThird-OrderRetinalNeuronsFollowingPhotoreceptorDegeneration. 27th AnnualConferenceoftheIndianAcademyofNeurosciences,Jaipur, India;December18-20,2009.

56. V.Jain,NKDhingra:ExpressionofMelanopsin byBrn3-PositiveRetinalGanglionCellsinMouse.27th Annual Conference of theIndianAcademyofNeurosciences.Jaipur,December18-20,2009.

57. NKDhingra: Invited to presentat a brainstormingmeeting bySocietyforBiomedicalTechnology,DEBEL,DRDOregardingBionicEyeinIndia,Bangalore,January16,2010.

58. D.Yoganarasimha:Representationof external environment inplace cell and head directioncell networks. Symposium onNeurophysiological Basis ofComplexBehaviors.InternationalConference on NeuroscienceUpdates & ISN, APSN, IBRO& SNCI School. Centre forNeuroscience, CUSAT, Cochin,December7-142009.

59. N.C. Singh: Distinct Readingroutes for deep and shalloworthographies in simultaneousbiliterates–afunctionalimagingstudy, Abstract, HumanBrainMapping, San Francisco, USA,June2009.


60. N.C. Singh: Influence of nativelanguage reading networks onthe second language – a fMRIstudy,Abstract,ScientificStudiesforReading,Boston,USA,June2009.

61. N.C.Singh: Fourier transforms,NovelapplicationsinNeuroscience,DelhiUniversity,March2010.

62. SubhadipPaul:TensorimagingoftheBraintooutlinehiddentumourinvasion,B.H.U.,Varanasi,July2009.

63. Suhela Kapoor: Image-guidedapp roach t o t h e rapeu t i cneurogenesisinstrokeandvasculardementia, Indian Academy ofNeuroscience,Jaipur,Dec.2009.

64. VinayShukla:Pulseperturbativechemotherapytoincreasecytotoxicefficiency, Indian Academy ofNeuroscience,Jaipur,Dec2009.

65. VPS Rallabandi, Prasun Roy:GlimpsestotheLandscapeoftheAgeing Brain: A NeuroimagingPerspective, NationalDementiaSummit: Alzheimer’s&RelatedDisorders Society of India,NewDelhi,Sept2009.

66. Budhachandra Singh, VinayShukla, Prasun Roy: EnergyFlowTensorImagingasaClinicalModality:AConceptualExtensionofDiffusionandPerfusionTensorImaging, Nuclear MagneticResonance-10, Sanjay GandhiMedicalInstitute,Lucknow,Dec2010.

67. VPSRallabandiandPrasunRoy:Imaging in NeurodegenerativeDisease: New Horizons forAlzheimerDisease,International

Conference on Alzheimer’s &Related Disorders Society ofIndia,Calcutta,Dec2009.

68. SuhelaKapoor,VPSRallabandi,Prasun Roy: A ComputationalNeuroimaging Approach ForO p t im i z i n g T h e r a p e u t i cNeurogenesisandSynaptogenesisin Stroke, DST Workshop &Symposium on MathematicalBiology,IISER,Pune,Aug2009.

69. Subhadip Paul, Prasun Roy:HigherorderTensorImaging:NewHorizonsofTranslationalMolecularRadiology,DST-NWOIndo-DutchWorkshoponMedical Imaging&TranslationalMedicine,SCTIMST,Trivandrum,Jan2010.

70. PrasunRoy:Cross-scaleIntegrationof Information Transmissionacross Neuronal, Cortical andCognitive Modes: A SystemsBiologyApproach,ComputationalNeuroscience & NeuroimagingWorkshop,SCTIMST,Trivandrum,Oct2009.

71. PrasunRoy:MultiscaleSystemsApproach to Brain Disorders:T ow a r d s R a d i o g e n om i c sand Programmed Therapy,International Neuro-informaticsWorkshoponMultiscaleModelling,NCBS,Bangalore,Nov2009.

72. PrasunRoy:ANeuroregenerativeApproachtoIschaemicCerebralPalsyusingMolecularRadiology,National Institute of MentallyHandicapped, Hyderabad, Feb2010.

73. PrasunRoy:TheSelfanditsBrain:TheNewestFrontierofComputing,IIIT,Allahabad,March2010.

DIstINctIoNs, hoNouRs aND

aWaRDs

Distinctions, Honours and Awards 119

Dr. Ellora Sen

NASI–SCOPUSYoungScientistAwardconferredjointlybyNationalAcademyofScienceandElseviers2010.

Dr. Pankaj Seth

Dr.Seth’sresearchwashighligtedbyInternationalSocietyofNeurovirologyinnewsletterinJanaury2010.

“BestPaperAward”toDr.PankajSeth,fromAlumniAssociationofDepartmentofBiochemistry,LucknowUniversity,Lucknow,Dec2009.

Selected as Associate Editor forJournal ofNeurovirologyandAnnalsofNeurosciences.

Dr. Nandini C. Singh

Travel award from the Society ofScientific Research on Reading toattendtheannualmeetingfromJune25-272009atBoston,MA,USA

Dr. Prasun Roy

Asia Partnership Professor Award inMedical Imaging,UtrechtUniversityMedica l Centre , Utrecht , TheNetherlands,Nov.2009.

Distinctions, Honours and Awards

Ms. Shaily Malik

“Best Paper Award” to Ms. ShailyMalik, from the organizers at XXVIIAnnualConferenceofIndianAcademyofNeurosciencesatNIMSUniversity,Jaipur.

“Prof.R.NathMemorialTravelAward”toattendXXVIIAnnualConferenceofIndianAcademy ofNeurosciences atNIMSUniversity,Jaipur.

Ms. Mamata Mishra

“Prof.R.NathMemorialTravelAward”toattendXXVIIAnnualConferenceofIndianAcademy ofNeurosciences atNIMSUniversity,Jaipur.

Mr. Subhadip Paul

SERC Student Fellowship award toattendWorkshop on Finite ElementModelling of Fluid Flow at BanarasHinduUniversity, Varanasi, August2009.

Ms. Suhela Kapoor

NeuroinformaticsTravelAward,NCBS,Bangalore,Oct2009.


Mr. Vinay Shukla

Trainee fellowship award to attendAdvanced Workshop on ControlSystemsAnalysis at Indian InstituteofScience,Bangalore,May2009.

Mr. Parthiv Haldipur

Center for Developmental Biologytravelfellowshiptoattend“CDB2010-FrontiersonOrganogenesis”organizedbytheCenterforDevelopmentalBiology(CDB)-RIKEN,Kobe,Japan.

Mr. Niranjan Kambi

IBRO/SocietyforNeuroscienceTravelGrants2009-SocietyforNeuroscience-May2009

Ms. Pretty Garg

Ph.Dstudent,hasbeenawardedfirstrank certificate upon completion ofcourseworkduringtheyear2009.

Mr. Apoorv Shrama

Ph.Dstudent,hasbeenawardedsecondrank certificate upon completion ofcourseworkduringtheyear2009.

Ms. Ruchi Bansal

Integrated Ph.D student, has beenawarded first rank certificate uponcompletionofcourseworkduringtheyear2009.

Following students have been awarded Ph.D. degree from NBRC.

Name of the Student

Name of the Supervisor

Title of Ph.D. Thesis Date of Award

Mr.ManojKumar

Dr.ShyamalaMani

Neuronaldifferentiationandsubtypespecification in embryonic stemcells.

12.06.2009

Ms.LatikaSingh

Dr.NandiniC.Singh

Developmentofarticulatory featuresinchildren.

01.09.2009

Ms.MamataMishra

Dr.PankajSeth

UnderstandingMolecular Basis ofHIV-1 Tat-InducedComplications inHumanFetalBrainCells.

12.02.2010

Mr.ManojKumarMishra

Dr.AnirbanBasu

Tostudytheaberrantglialresponsein Japanese Enephalitits; frommolecularmechanismtotherapeuticintervention.

16.02.2010

exteRNallY FuNDeD ReseaRch pRoJects

Externally Funded Research Projects 123

Dr. Nihar Ranjan Jana

UnderstandingtheFunctionalroleofE6-AP: A putative ubiquitin proteinligaseimplicatedinAngelmanMentalretardationsyndrome.(DBT,India).Understanding the role of ubiquitin-proteasomesystemdysfunctioninthepathogenesisofHuntington’sdisease:Indo-Japan cooperative scienceprogram(DST,India).

Study of the neuroprotective roleof ubiquitin ligase, E6-AP in thetransgenicmicemodelofHuntington’sdisease:NationalBioscienceAwardee(DBT,India).

Dr Pankaj SethCharacrerizationofhumanfetalbrainderivedNeuralStemcellsasamodelforstudyingNeurodegenerativediseases:Basicbiologyofstemcellsgrant(DBT,India)

Role onCNSOpportunistic infectionin subsequent development of HIVDementia.(RO1,NIH,USA)

Dr. Anirban BasuDissectingmolecular circuitries thatregulate progenitors cell response toJapanese Encephalitis virus. (DBT,India)

Evaluat ion o f Monocyc l ine asa neuroprotect ive and/or ant iinflammatoryand/orantiviraldruginJapaneseencephalitis.(CSIR,India).

Externally Funded Research Projects

Dr. Shiv K Sharma

Effect of amyloid beta on Growthfactor signaling the hippocampus:ImplicationfortheAlzheimerDisease.(CSIR,India).

Prof. V RavindranathEvaluation of the Molecular basisof action of anherbal extract in thetreatment of Dementia IncludingAlzheimer’sDisease.(DBT,India).

CytochromeP-450dependedtmetabolismofdrugsinbrain.(RO1,NIH,USA).

Dr. Ellora SenModulation of oxidative stress andhypoxiabyinflammation:Implicationin the pathogenesis of glioblastoma.(DRDO,India).Studyofthesignalingcascadesinvolvedintheproliferationanddifferentiationofcancerstemcells inGlioblastoma.(DBT,India).OligodendrocyteDifferentiation fromNeuralStemCells-ImplicationinCNSrepair:Basicbiologyofstemcellsgrant.(DBT,India)Role of lipid rafts in Epigeneticlilencing and immune cell signaling:Implication in the aggressiveness ofGlioblastomemultiforme: InnovativeYoungBiotechnologistAwardee.(DBT,India)

Understanding signalling circuitariesinvolved in transcriptional regulation


of genesassociatedwith survival andimmune response inan inflammatoryenvironment:Implicationsinglioblastomaprogression.(DBT,India).

Dr. Ranjit K Giri

The Study ofMolecular and cellulareventsinmouseCNSstemcellculturesreplicatingmouseprions.(DBT,India).UnderstandingthecellularpathogenesisofAlzheimer’sdiseaseemployingCNSstem cells cultures:Development ofanovel in vitromodel ofAlzheimer’sdisease.(DBT,India).

Dr. Shyamala Mani

Neural differentiation of embryoniccells.(CEFIPRA,France).

FactorsGoverningHumanStem cellDifferentiationBasic biology of stemcellsgrant(DBT,India).

Dr. Narender K Dhingra

Replacement of degenerating retinalNeurons by electronic prosthesis :A Study on parameter optimizationof electrical stimulus and on signalprocessingindifferenttypesofretinalGanglioncells.(DBT,India).

Transplantation of stem cells inDegenerating retina - A study onformation of Functional synapsesbetween stem cells and host retinalNeurons in vivo and in vitro: Basicbiology of stem cells grant (DBT,India).

Prof. Neeraj Jain

AutonomousNavigationUsingBrain-machineInterface.(DRDO,India).

Theusesofstemcellsintreatingcasesofspinalinjury:Basicbiologyofstemcellsgrant.(DBT,India).

Dr. Soumya Iyengar

Effectsofalteringthelevelofneuronalproliferation on the learning andproductionofbehaviorinmaleZebrafinches: Basic biology of stem cellsgrant.(DBT,India).

Dr. Rema Velayudhan

Embryonic Stem Cells therapy forBrainInjury:Basicbiologyofstemcellsgrant.(DBT,India).

Dr. Sayali Ranade

IronDeficiencymemory dysfunctionhippocampaldevelopmentanddefects:WomenScientistAwardee.(DST,India).

Dr. Pravat K Mandal

Characterization of the molecularinteractions of anesthetics with thebeta-amyloid. (Italian Ministry forUniversity&Research).

Theunderstandingof earlyMoleculareventswhich initiate theAlzheimer’sDiseaseusinginvivomagneticresonanceSpectroscopystudy.(DBT,India).

Prof. Prasun Roy

StochasticResonanceEffectasanewtechnique for Image Processing inneuroscience.(DRDO,India).

EstablishmentoftranslationalresearchunitatNBRC.(DBT,India)

Dr. Nandini Chatterjee Singh

ParkinsonDisease: Development ofComputationalModelBasedonhandWritingandSpeechforpredictionandTreatment.(DST,India).

Language and brain organization innormative multilingualism. (DST,India).

coRe FacIlItIes

Distributed Information Centre (DIC)

Animal Facility

Digital Library

Core Facilities 127

TheDistributed Information Centre(DIC)of theNationalBrainResearchCentreisresponsibleformanagementofITservicesoftheinstitute.Itnotonlyprovidese-servicesbutalsoconstantlyupdatesthedigitalenvironmentwithnewandexistingresourceswhichareinsyncwiththegrowingrequirementsofthecentre.

IT Infrastructure:

Central IT infrastructure and services provided by DIC are listed as under:

• Campus wide LAN over gigabitfiber backbonewithwi-fi hotspotsfor students and faculty. The network is running on manageable Layer-3 Swithces for security andmanageability.

• 20Mbps(1:1)Internetbandwidth(10Mbpsonfibreopticand10MbpsonRF) for redundancy. The network is securedbydedicatedsecurefirewallclusters.

• Centralized data storage to thetuneof50TBwithmultiplelevelofredundancy. It is further protected by automated tape library based backup solution.

• State-of-the-art video-conferencingfacility for collaborating research and teaching.

Distributed Information Centre (DIC)

• In-househostingofcriticalserverswhichincludes webservers, mail servers, dns servers etc. (http://www.nbrc.ac.in, http://neuroscienceacademy.org.in, http://snci.nbrc.res.in, http://webmail.nbrc.ac.in) primarily running on unix/linux platforms.

• Application servers running onwindows and linux are also centrally maintained for providing services to thin client systems. The performance of the critical servers are monitored round the clock and up-gradation,server consolidation, virtualization are done as and when required.

DICalsoprovidestechnicalsupporttousersintheroutinerequirementandalsoundertakesin-housedevelopmentofsoftwares,web-toolsandwebserversforaidingintheresearchandteachingactivitiesofthecentre.

New Initiatives:

Highperformance-compute(HPC)clusterusingbladeserversbasedinfrastructurefor data analysis in functionalMRIexperiments has being initiated. Theinstitutewill alsobe connectedunderNational Knowledge Network (NKN)to various universities and nationalinstitutesonagigabitlinkwhichwillopennewpossibilitiesofcollaborations,aidingin research activities and knowledgesharingwithotherscientificinstitutions/laboratoriesinIndiaandabroad.


NBRChasamodernanimalfacilitytomeettherequirementsofthescientistsfor advancedneuroscience research.TheanimalfacilityofNBRCprocuresandbreedsawidevarietyofspeciesoflaboratoryanimalswhichareusedasanimalmodelsforunderstandingthehumanbrain in health and disease.The Animal Facility adheres to thehigheststandardsoflaboratoryanimalcare,andcomplieswithallthenationaland international regulations for thecareanduseofanimals inresearch.The animal facility staff ensureshumaneandappropriateanimalcare.A high degree of hygienic conditionsaremaintained in the animal houseby regular cleaning and sterilizationof the cages, water bottles, beddingand feed.Theanimal roomsarealsoregularlydisinfected.Heavy-dutysteamautoclaveshavebeeninstalledforthesepurposes.Ahotvapourjetmachineisusedforcleaningthelargerabbitandmonkeycages.Thestaffisrequiredtotakeshower,beforechangingtowork-overalls before entering the animalrooms,andagainintheeveningafterfinishing the work. All users wearfacemasksandglovesbeforehandlinganimals.

All theanimalspeciesarehoused inspecies appropriate cages,whichare

Animal Facility

designedaspertheCPCSEAguidelines.Theoutdoorplayareafornon-humanprimateshassixlargeinterconnectedenclosuresthatprovideaflexiblelayoutforoptimisingenrichmentandsocialinteractions. The transgenic, knockoutandmutantmicearehousedundergerm-freeconditionsinfiltertopcagesandindividuallyventilatedcages(IVC).Suchanimalsarehandledinlaminarhoods,andthemovedto freshcagesincage-changingstationunderhepa-filteredair.

The animals aremaintained undercontrolled environmental conditionsas specified in CPCSEA guidelines,withtemperaturemaintainedbetween22± 2ºC, relative humidity between45-55%,12:12hrlight-darkcycle,and12-15airchangesperhour.Theair-handlingsystemuses100%freshairforeachchange.

Qualified and trained veterinariansoverseealltheanimalhealthconcerns,and provide all necessary veterinarycare to ensure that healthy animalsareavailableforresearch.

Theanimal facilityhasa state-of-artsurgicalsuiteequippedwithintensitycontrolled surgical lights, advancedsurgicalmicroscopes, gas anesthesiamachines, equipment formonitoring

Core Facilities 129

thephysiologicalstateoftheanimals,including heart ratemoniter, pulseoximeter and rectal thermometer.For cleaning and sterilization of thesurgical instruments there is anultrasonic instrument cleaner, glassbeadsteriliserandethyleneoxidegassteriliser.

The animal facility has a necropsyroom,perfusionroomwithaperfusionhood,deepfreezerforcarcassstorage,and incinerator for disposal of theanimalcarcass.

Theanimalfacilityhasbeenequippedwith a card reader security system.Theaccessisrestrictedtotheanimalhousestaff,maintenancestaffandtheinvestigatorswhoarelistedintheIAECapprovedprotocols.Allthepersonnelwho handle animals are required tohaveacurrenttetanusvaccination,andthosewhohandlenon-humanprimates(NHP) are screened for tuberculosis.Everyone handling NHP’s is trainedin the procedures for the first-aid incaseofaninjuryfromaanimalbiteorscratch.

Closecircuitmonitoringcamerashavebeen installed at various locationsin the facility to help in effectivemonitoringoftheanimalfacility.

The animal facility is currentlymaintainingthefollowingspeciesandstrainsoflaboratoryanimals.

Mice Strains

SWISS,BALB/c,C57BL/6J,CD1

Transgenic Mice

B6C3-Tg(APP695)85DboTg(PSEN1)85Dbo(Alzheimerdiseasemodel)

UBC-GFP(Greenfluorescentprotein)

B6CBA-Tg (Hdexon1 )62Gpb/3J(Huntingtondiseasemodel)

B6.Cg–Mapttm1(EGFP)KltTg(MAPT)8cPdav/J(Alzheimerdiseasemodel)

B 6 . 1 2 9 P 2 - G s k 3 b tm 1D g e n / J(Alzheimerdiseasemodel)

Knock Out Mice

GAP-43knockoutmice,

UBE3Anullmice(Angelmansyndromemodel)

Mutant Mice

CBA/Jmice (Retinal degenerationmodel)

Rat Strains

LongEvans

SpragueDawley

Rabbits

NewZealandwhite

Guinea Pigs

DuncanHartley

Non-human primates

Macacamulata

Macacaradiata

Birds

Zebrafinches

All themice strains aremaintainedby inbreedingand the rat strainsbyout breeding.Guinea pig and zebrafinch colonies are maintained byout breeding. The transgenic andknockoutmicearemaintainedundera specialized breeding programaftertheinvestigatorsprovidethemoleculargenotypingof thesestrainsbasedonpresence or absence of the gene ofinterest.


TheNBRC Library plays a vital rolein the collection, development anddisseminationofscientificandtechnicalinformation tomeet the present andfutureneedsofthecentreandisalsoprovidingthefacilitiesandsupporttotheScientists,researchers,students,staffsanditsnetworkedcenters.

TheNBRClibraryhasgoodcollectionofJournals,booksandotherrelevantresearchmaterials onNeuroscience,Biochemistry, Genetics, MolecularBiology, Immunology&Microbiology,Pharmacology and Toxico logy,Psychology, Physics, Mathematics,Computer Science and GeneralSubjects. NBRC Library is currentlysubscribingto16Journalsandrestof917OnlineJournalscoveredthroughDBTe-LibraryConsortium(DeLCON).LibraryisalsosubscribingNewspapers,NewsLetters.TheCollectionofNBRCLibrary is growing day-by-day in theviewofresearchandknowledgeinthefieldofNeuroscienceandrelatedareas.These resources were kept to fullymeet the present day requirementsoftheuserssuchasfaculty,researchscholars,studentsandstaffs.

Toprovideoptimumservicetoalluserswearedigitizingthelistofcollectionsavailable at NBRC and giving full

Digital Library

accesstotheusers.WeareusingtheLSEASE software for the digitizationofcollections.TheNBRCLibraryhasinstalledabarcodetechnologythroughLSEASE software for accurate andspeedy circulation (Check-in andcheck-our)andhouseholdmanagementofthelibrarydocuments.Italsohelpin efficient library operations viz.administration,acquisition,circulation,serialcontrol,cataloguing,informationretrievaletc.

TheNBRCLibraryhassetup22IBMPC-Pentium-IVComputerswithISDNInternetfacilitytoprovideservicesforuse of researchers and students atNBRC in the NBRCCommon room.TheLibraryprovidesaccesstothemostcurrent reference sources availablein order to assure the accuracy ofinformation. The Library has beenproviding electronic access to thesubscribed journals within campusportal.Itismaintainingdigitalarchivesandclippingsoffthecentre.

Atotalof110registeredusersincludingScientist, Researchers, students andother staff used the NBRC libraryfacilities. The NBRC Library alsoprovidestheservicesof“InterLibraryLoan” to the 48 Networked Centresat all over India. The researchers,

Core Facilities 131

scientists and students send theirrequirement for researchmaterial orjournalarticlesthroughemailtoNBRCLibrary([email protected])andstaffoflibrarydownloadthearticles/papers/informationandsendsthesametotherequestorsfreeofcost.Thelibraryhasentertained approximately 340 PDFarticlesinthisfinancialyear,andtherequestsareincreasingday-by-day.

TheNBRCLibraryregularlyevaluatesitsinformationservicestoensurethattheInstitution’srequirementsaremet.TheNBRCLibrarypromotesresourcesharing and cooperation activitiesamonglibrariesbyprovidingefficientandreliablemeansofresourcesharingi.e. inter library loan formaximumusersofresources,providingthecopiesofthedocumentsthatisnotavailableintheirrespectivelibraries.

The Main Activities of NBRC Library

1. BookAcquisition

2. PeriodicalsAcquisition

3. S e l e c t i v e D i s s em i n a t i o nInformation(SDI),

4. Current Awareness Services(CAS)

5. InterLibraryLoan

6. ResourceSharing

7. Circulationservices

8. ReferenceServices,Bibliographicservices

9. IndexingandSpecialServices

10. Collects maintains, store andretrieves information and datakeeping in the view of evolvingneedsofitsresearchers

11. HelptoNetworkCentres.

ASeparatetwostoriedlibrarybuildingis already under construction,which will have the providing forreading room, reference room, videoconferencing, online journal accessfacility,booksection, Internetaccessfacility, reprographic facilities etc.Themain aim to the NBRC Librarystaffistoprovideexcellentservicestothe scientists, researchers, researchassociates,studentsofNBRCandallcentersassociatedwiththe institute.The NBRC library is presently, wellequippedwitheverytypeofresourcesrequired by the faculty, researchersandstudents.

DBt’s electRoNIc lIBRaRY coNsoRtIuM

(DelcoN)

DeLCON 135

About ‘DeLCON Consortium’

The DBT ’s E lec t ron ic L ibraryConsortiumcalledas“DeLCON”.The‘DeLCONConsortium’ has been setup by the DBT to promote the useof electronic databases and full textaccesstojournalsbytheResearchandacademiccommunityinthecountry.

The ‘DBT’s Electronic L ibraryConsortium(DeLCON)’ismajorinitiativeof the ‘Department of Biotechnology(DBT)’ to bring qualitative change intheir research Institutions. It waslaunched in January, 2009 withthe 10 DBT member Institutions(includingDBTH.Q.& ICGEB)withalargenumberofhighimpactonlinejournals.Itisanationalinitiativeforprovidingaccesstoscholarlyelectronicresources including full-text andbibliographicdatabasesinallthelifescience subject disciplines to DBTInstitutionalcommunity.Itfacilitatesaccess to high quality e-resourcestoDBT research Institutions in thecountrytoimproveteaching,learningandresearch.

The ‘DeLCONConsortium’ providescurrentaswell asarchivalaccess tomorethan917coreandpeer-reviewedjournalsandonebibliographicdatabase(SCOPUS Database) in different

DBt’s electronic Library Consortium (DeLCon)

disciplinesfrom20Foreignpublishersincluding some of aggregators. Theaccess to allmajor e-resourceswasgiven to 10DBT Institutions in thebeginningoftheyear2009.Ithasnowbeen extended to new17moreDBTInstitutionsin1stphaseofextensioninthisyear2010.

The Faculties, Scientists, ResearchScholars, Students and ProjectAssistantsofInstitutionscoveredunderDeLCONaretheprimarybeneficiaries.DBT sponsored the entire expensesfor DBT organizations for providinge-Journals access through ‘DeLCONConsortium’.

TheDeLCONcomprisesthefollowing27Member Institutions which aregivenbelow

DeLCON MEMBERS

1. NationalBrainResearchCentre(NBRC),Manesar

2. Department of Biotechnology(DBT),NewDelhi

3. National Institute of PlantGenomeResearch(NIPGR)-NewDelhi

4. NationalInstituteofImmunology(NII)-NewDelhi


5. NationalCentreforCellScience(NCCS)-Pune

6. Institute of LifeSciences (ILS) -Bhubaneshwar

7. Institute of Bioresources andSustainableDevelopment(ISBD)-Imphal

8. CentreforDNAFingerprintingandDiagnostics(CDFD)-Hyderabad

9. Ra j i v Gandh i Cen t r e f o rB i o t e c hn o l o g y ( RGCB ) -Thiruvananthapuram

10. InternationalCentreforGeneticsandEngineering Biotechnology(ICGEB),NewDelhi

NEW DeLCON MEMBERS

1. TheWellcome Trust-DBT IndiaAlliance,Hyderabad

2. DibrugarhUniversity,Assam

3. AssamUniversity,Silchar

4. NorthEasternRegionalInstituteofScience&Technology,ArunachalPradesh

5. NorthEastInstituteofScience&Technology,Assam

6. MizoramUniversity,Mizoram

7. D.M.CollegeofScience,Manipur

8. SikkimUniversity,Gangtok

9. College of Veterinary Science,AssamAgricultural University,Guwahati

10. St.Anthony’sCollege,Meghalaya

11. BiotechnologyIndustryResearchAssistanceProgram(BIRAP),NewDelhi

12. GauhatiUniversity,Assam

13. ManipurUniversity,Imphal

14. College of Veterinary Science& Animal Husbandry CentralAgriculturalUniversity,Mizoram

15. Ra j i v Gandh i Un ive rs i t y ,ArunachalPradesh

16. NagalandUniversity,Nagaland

17. North-Eastern Hill University,Shillong

In terms of number of users, theDBT’sElectronicLibraryConsortium(DeLCON) is the largest Consortiumin India in the term of Life Sciences&BiotechnologySubject areawith avisionandplantoreachouttoallDBTInstitutions departments, ResearchInstitutions, Universities, and theircolleges affiliated to theDBT, over aperiodoftime.

OBJECTIVES

The main objective of the DBT’se- Library Consortium (DeLCON)is to provide access to qualitativeelectronic resources including full-text and bibliographic databases toDBT institutions at a lower rates ofsubscription. Themajor aims andobjectives of the DBT’s e- LibraryConsortium(DeLCON)areasfollows:

• To provide access to a high-quality and scholarly electronicresources to a large numberof DBT institutions includingresearchInstitutions,universitiesand colleges at substantiallylower rates of subscription andatmost favourable terms andconditions;

• To promote rapid and efficientaccesstoscholarlycontenttotheusersandtocreateandpromoteuseofDeLCONinteachingand

DeLCON 137

learninginresearchorganizations,universities, and colleges inIndia;

• ToextendthebenefitofConsortiumtoitsassociatemembers

• To imparttrainingtotheusers,librarians, research scholarsand faculty members of theinstitutions inuse of electronicresourceswithanaimtooptimizetheirusage;

• To promote use of e-resourceswith gradual decrease in printsubscription;

• Topromoteinteractionandinter-librarycooperationamongsttheparticipatingDeLCONmembers;

• To evaluate the usage of thesubscribed resources and toidentify new resources that arerequiredtobesubscribedundertheDeLCONConsortium;

• To bring qualitative change inteaching, learningand researchwith an aim tomeet the evergrowingchallengesofglobalizationofhighereducation;and

• To increase the researchproductivity of the institutionsboth in terms of quality andquantityofpublications.

Benefits OF ‘DeLCON CONSORTIUM’

The consortia-based subscription toe-resources is a viable solution forincreasing the access to electronicresources acrossDBT institutions ata lower rate of subscription.Majorbenefits ofDeLCONConsortium areasfollows:

• The DeLCONConsortium actsasasingle-windowserviceforalargenumberofDBTInstitutionswith their diverse research andacademicinterest;

• TheDeLCONConsortium,withitscollectivestrengthofparticipatinginstitutions, attracts highlydiscountedratesofsubscriptionwithmost favourable terms ofagreement for a wider rangeof e-resources. Most of thee-publishers have respondedpositively to the call of theConsortium. The rates offeredto the consortium are lower by60%to99%dependinguponthecategoryofDBTinstitutions;

• Usershaveimmediateaccesstomaterialpreviouslynotsubscribedto, at no incremental cost foraccessingbackfiles;

• It improves the existing libraryserv ices and reduced thesubscriptioncost;

• The research productivity ofDBT institutions is expected toimprovewithincreasedaccesstointernational full-text resources(Journalsanddatabase);

• The DeLCON Consortium isexpected to trigger remarkableincreaseinsharingofelectronicresourcesamongstparticipatingDeLCONmembers

• The DeLCON Consortium hasbeen opened-up to add moreDBTinstitutionsthroughitsnextphase of extension and otherDBT institutions can also jointhe DeLCON Consortium and


getthebenefitofnotonlyhighlydiscountedratesofsubscriptionbutalsothefavourabletermsandconditions;

• The DeLCON Consortium isofferedbettertermsofagreementfor use, archival access andpreservation of subscribedelectronicresources,whichwouldnot have been possible for anysingleinstitutions;and

• Since the subscribed resourcesisaccessibleonlineinelectronicformat, the DBT institutionshave less pressure on spacerequirement for storing andmanaging print-based libraryresources.Moreover,allproblemsassociatedwithprintmediasuchastheirwearandtear,location,shelving,binding,organizing,etc.are not an issue for electronicresources.

DeLCON Electronic Resources

TheDeLCONConsortium subscribesto electronic resources covering allmajor Life Science& BiotechnologysubjectdisciplinebeingtaughtintheDBTresearchInstitutions,Universities&Colleges.Itincludeswidevarietyofmaterialse.g.e-journals,bibliographicdatabases, reviews published byscholar ly societ ies , univers i typresses,institutionalandcommercialpublishers.TheDeLCONConsortiumsubscribesto917full-texte-resourcesand01bibliographicdatabasefrom20renownedforeignpublishersincludingsocieties and some of aggregators.Thememberinstitutionsareprovideddifferentialaccess to these resourcesbased on their needs and activityprofile as per the recommendationof the National DeLCON SteeringCommittee.

Thecompletelistoffull-textresources(e-Journals) and bibl iographicdatabases subscribed under theDeLCON Consortium is given inAppendix I.

Appendix I

1 AmericanAssociationforAdvancementofScience

http://www.sciencemag.org (3Journal)

2 AmericanAssociationforCancerResearch(AACR)

http://www.aacr.org (8Journals)

3 AmericanChemicalSociety(ACS)

http://pubs.acs.org (37Journals)

4 AnnualReviews http://www.annualreviews.org

(23Journals)

5 AmericanSocietyforBiochemistryandMolecularBiology

http:///www.jbc.org (2Journal)

6 AmericanSocietyForMicrobiology

http://www.asm.org/ (12Journal)

7 ColdSpringHarborLaboratoryPressJournals

http://www.cshl.edu (4Journals)

DeLCON 139

8 InformaHealthcare/TaylorandFrancis

http://www.informaworld.com

(7Journals)

9 LippincottWilliamandWilkins(LWW)/WolterandKluwer/OVID

http://ovidsp.ovid.com (11Journals)

10 MarryANNLiebert http://www.liebertonline.com

(7Journals)

11 NaturePublications http://www.nature.com (40Journals)12 OxfordUniversityPress(OUP) http://www.oxfordjournals.

org(18Journals)

13 SpringerIndia http://www.springerlink.com

(237Journals)

14 SocietyforGeneralMicrobiology

http://mic.sgmjournals.org (3Journals)

15 SocietyforHematology http://bloodjournals.hematologylibrary.org

(1Journal)

16 Wiley-Blackwell http://www3.interscience.wiley.com/cgi-bin/home

(86Journals)

17 ElsevierScience(ScienceDirect)

http://www.sciencedirect.com

(415Journals)

18 AmericanSocietyofPlantBiologist

http://www.aspb.org/ (2Journals)

19 AmericanAssociationofImmunologist

http://www.aai.org/ (1Journals)

20 ScopusDatabase http://www.scopus.com (1Database)

Subject Coverage Under DeLCON Consortium

TheDeLCONConsortium covers allthe disciplines and subjects comingunderLifeSciencesi.e.Biotechnology,B io in format ics , B iochemist ry ,Biology, Chemical Biology, Sciences,Immunology, Neuroscience, PlantGenome,PlantBiology,Microbiology,Physiology,Psychology,Physiotherapy,Psychotherapy, Genome, Gene,Genetics, Mathematics, Physics,Chemistry, Radiology, Medicines,ComputationalBiology,Cell Biology,

Cell Sciences, Molecularbiology,Molecular and Cellular Biology,ComputationalNeuroscience,SystemNeuroscienceetc.

DBT’s E-LIBRARY CONSORTIUM(DeLCON)JOURNALSareAVAILABLEtoACCESS:http://www.nbrc.ac.in/delcon/

DDLalDeLCONAdministratorNationalBrainResearchCentre

NatIoNal NeuRoIMaGING

FacIlItY


National neuroimaging faci l i tywas established by Department ofBiotechnology,Govt. of India in theyear 2006. The facility is equippedwithfourstate-of-the-artneuroimagingequipmentssuchas,

1) 3TMagneticResonanceImaging(MRI)Scanner

2) Electroencephalography(EEG)

3) Evoked Response PotentialRecording(ERP)

4) TranscranialMagneticStimulation(TMS)

Magnetic Resonance Imaging (MRI)is yet another major and distinctmilestoneinthehistoryofneuroimaging.MRI providesmuch greater contrastbetween the different soft tissues ofthebodythancomputedtomography(CT),making it especially useful inneurological(brain),musculoskeletal,cardiovascular,andoncological(cancer)imaging. Today the scope of MRIextendsbeyondstructuralimagingtoinclude

(1) MR S p e c t r o s c o p y (MRS )which provides non-invasiveneurochemicallevelestimations,enablingclinicalcorrelationandearlydiagnosisofadisease.

national neuroimaging Facility

(2) FunctionalMRI (fMRI)which,asthe name suggests, correlatesfunctionalactivity(haemodynamics)withanatomicalimagesofbrain.

(3) Diffusionweightedtensorimaging(DTI) is yet another specializedimagingmodality.

The3TeslaPhillipswholebodyMRImachine,thefirstofitskindinIndia,is housed in theMRI unit of NBRCasanationalFacility.This3TPhilipsscanner is equipped with state-of-the-art data processing software,as well as hardware required foreachimagingmodality.Thefacilityisbeingusedforperformingstructural,metabolic (multinuclear, e.g. protonandphosphorous)andfunctionalMRI.In addition to understanding brainfunction and clinical research, thecenteralsoiscloselyinteractingwithleading imaging centers within thecountryandacrosstheglobe.

Electroencephalography (EEG) isused for measuring and recordingthe spontaneous electrical activityof the brain caused by neuronalconduction.Specialsensors/electrodesareattachedtothescalpandtheneuralactivity is recorded as oscillations ofvaryingfrequency.Variousconditionslikeepilepsy,dementia,consciousness


andnarcolepsy(sleepingdisorder)canbestudiedbyEEG.

Evoked Response Potential Recording (ERP)isanelectricalpotentialrecordedfromthenervoussystemofahumanorotheranimalfollowingpresentationofastimulus.Evokedpotentialamplitudestendtobelow,rangingfromlessthanamicrovolttoseveralmicrovolts.

Transcranial magnetic stimulation (TMS) is a non-invasivemethod toexcite neurons in the brain: weakelectric currents are induced in thetissue by rapidly changingmagneticfields(electromagneticinduction).Thisway,brainactivitycanbetriggeredwithminimaldiscomfort,andthefunctionalityof the circuitry and connectivity ofthebrain canbe studied. Its earliestapplicationwas in thedemonstrationof conductionofnerve impulses from

themotor cortex to the spinal cord.By stimulatingdifferentpoints of thecerebralcortexandrecordingresponses,e.g.,frommuscles,onemayobtainmapsoffunctionalbrainareas.Bymeasuringfunctional imaging (e.g.MRI) orEEG,informationmaybeobtainedaboutthecortex (itsreactiontoTMS)andaboutarea-to-areaconnections.

T h e N e u r o i m a g i n g a n d Neurospectroscopy laboratory atNBRCisworkingonmetabolicanalysisofdifferentneurodegenerativedisorders(e.g. Alzheimer, Parkinson etc) usingMRStechnique.Theclinicalresearchis focused to identify biomarkers ofdisease,and this isaccomplishedbythe understanding of specific andselectiveneurochemicalchangesforthedifferentneurodegenerativedisorders.Figure 1 shows 31PMRS spectra of

Figure131PMRSdatacollectedusing1Hdecoupleddual tunedheadcoil (TransmitandReceive).Thisexperimentwasspecificallydesignedtoobtainspectrafromhippocampusbothleftandrightmarkedbyyellowcolor.Thedimensionoftheeachvoxelwas13.3mmX13.3mmX25mmandnumberofscanswere24.DataAcquisitiontimewas~25minutes.MRSdatawasprocessedusingPhilipssoftware.


thehippocampusofanormalcontrolsubject for different neurochemicalscontainingphosphorousatom.

The Speech and Language Laboratory (SALLY) at NBRC is interested instudying the cortical pathwaysunderlyingreading.ResearchersfromSALLYlaboratoryarecurrentlyfocusedon studyingword reading inHindi-Englishbilinguals.Thefigure2showsthe different brain areas involved inreadingwordsaloudinHindi.

The Computational Neuroscience and Neuroimaging Laboratory

worksondiagnosticandtherapeuticapplicationsalongwithatranslationalmedicine perspective. The unitworksonimaging-baseddiagnosisofneurodegenerativediseaseandpulsedradiotherapy and chemotherapyplanning for brain tumour. Incollaboration with clinical centresandmedical institutes, the labalsopursuesdelineationofflowdynamicsof blood, CSF and progenitor cellsin the brain, aswell as localizationof electrogenic focus in refractoryepilepsyusingEEG,ERP,fMRI,MRSandDTI(diffusiontensorimaging).

Figure2.Theleftrenderingdepictsaventralviewwhiletherightrenderingdepictsadorsalviewofthebrain.Differentbrainareasinvolvedinreadinghavebeenshown

Figure3Diffusion tensor image of thebrainofepilepticpatientfromwhichtheconductivitytensorimageofthebrainisobtainedwhichenablesmoreaccuratelocalizationoftheelectricalfocibasedonEEGandpotentialfieldrecordings.

At the imaging facility, Prof. ParthaRaghunathan is the Consultant Professor whileMr.JitenderAhlawatistheMrI/eeg Operation staff.

tRaNslatIoNal & clINIcal

NeuRoscIeNce uNIt

Translational & Clinical Neuroscience Unit 149

Translationalresearchaimstoconnectbasic research to patient care: FromtheBenchtotheBedside.TheClinicalResearchUnitofNBRCcoversthefullspectrum of clinical neuroscience:n eu r o l o g y , n eu r op s y ch i a t r y ,neurosurgery, neuropsychology, andpsychometry. The unit has a tri-weekly,morning outpatient facility,at theGovernmentGeneralHospital,Gurgaon, one of NBRC’s consultantclinical faculty is available on adesignated day. TheNBRCUnit hasintegrated well with the Generalhospitalmedicalteamandthereisanincreasing number of referrals fromotherin-housedepartmentsandlocalhospitals. The out-patient facility isbusy,andonsomedaystheattendancecan be about forty patients. Around65% to 70% of the patients sufferfrom headache or seizure disorder,5%haveneuroses/psychosesandtheremainingbelongtoamiscellanygroupofperipheralneuropathies,Bell’spalsy,sciatica, trigeminal neuralgia, oldstroke,mental retardation and othercommonneurologicaldisorders.

The follow up by the patients isabout 90%.Male to female ratio isalmostequal.Paediatricgrouppatientattendanceismainlyformanagementof epileptic seizure and disorders of

thementally challenged. There arealso elderly patients attending, andmovement disorders is an importantreasonofattendance.PatientsattendingtheOPDattheGeneralHospitalcomefrom oldGurgaon township and thevillagesandtownsinthesurroundingdistricts of Haryana, while somecome from neighbouring states asRajasthan, Uttarkhand, Delhi andUttarPradesh.

Patientsrequiringadvancedspecialistneurologyin-patientcarearereferredtoAll-IndiaInstituteofMedicalSciences(AIIMS)orVardhamanMedicalCollege(SafdarjungHospital),NewDelhiortoothertertiaryhospitalasperthechoiceofthepatient,iftheydesire.

Outpatientcaserecordsinneurologyaremaintainedfromtheoutset,asidefromrelevantentryintothepatientOPcasesheets,whichthepatientskeepintheirpossession.AcomprehensiveNeurologycase sheet has been formulated andformattedbyDistributed InformationCentre of NBRC.We duly hope toprospectivelyenterallthemedicaldataof new patients, to create computerdatabasewith relevant patient dataalongwithanyplannedneuroimaging/molecular/physiological studies attheNBRClaboratories,thuscreating

translational & Clinical neuroscience Unit


awell documented “clinicalwindow”for our research institute. In thiseffort to narrow the gap betweenBasic Neuroscience and AppliedNeuroscience, an ethics committeeprotocolhasbeenformulated.

The associat ion of NBRC withAlzheimer’s&RelatedDisordersSocietyof India (ARDSI) which has beengoingonfrom2005,hasbeenfurtherfostered by the NBRC consultantfaculty. This interaction promises togrow to themutual benefit of bothinstitutionsconcernedprimarilywiththe common goal of ameliorationof neurodegenenerative diseases intheir varied aspects.Besides clinicalneuroscience, one is exposed to thepsychosocialandneuroepidemiologicalproblems of the ageing populace intheirenvironment.

F u r t h e r e x p a n s i o n o f t h eelectrophysiologicalfacilityisunderway,with procurement of 64-channelhigh density EEG/evoked potentialresponse analysis, electrical dipolesourcemapping, Electromyography(EMG)andNeurophysiologicalstudiesasNerveConduction velocity systemandneurometry.

For proper functioning and furtherclinical support, the Unit receivesfullcooperationoftheGovernmentofHaryana, and theCivil Surgeon andPrincipalMedicalOfficeroftheGeneralHospital.

Investigation facilities:

Thefollowingfacilitiesareavailabletothe patients of the unit through thehospital/clinicsatconcessionalrates:

MRI system: SiemensMagnetom1.5Teslascannerwithvariousinvestigationprotocols

CTsystem&Ultrasonography

Neurophysiology: EEG and Evokedresponse.

X-rayandContrastimaging.

Wetlab facil it ies: Biochemistry,Microbiology,Haematology,Pathology&Immunology.

Consultants:

ConsultantClinicalProfessor:Dr.V.S.Mehta

ConsultantNeurologist:DrSubbulakshmyNatarajan(tillDec.2009).

ConsultantClinicalAssistantProfessor:DrKapilAgarwal

ConsultantClinicalAssistantProfessor:DrRajnishKumar

Staff:

ResidentMedicalOfficer:DrShelly

ClinicalNeuropsychologist:KrishanKumar

ClinicAssistant:H.Singh

MeetINGs aND WoRKshop

Perception Engineering Workshop 2009

Meetings and Workshop 153

brain and the modelling of theseprocesses using computational toolsandmachines.Therewerepresentationsofresearchprojectsontargetedareasofrangingfromelectrophysiology,brainmachine interface and rehabilitationto neuroimaging, neuromorphictechnology and pattern recognition.Researchassociates,andstudentsfromNational BrainResearchCentre, IITDelhi,CEERIPilani,activelyparticipatedanditwasarewardingexperienceforthem,beingexposedtoawiderangeofinterdisciplinaryendeavours.PossibleareasofcollaborationbetweenNBRClaboratoriesandtheotherinstitutionswereexplored.

Thisisthefirstinitiativeinthecountryencompassing a versatile symbiosisofalltherelevantdisciplinescognateto the Perception Engineering fieldwhichiswellonthewaytotransformto the critical field of neuromorphictechnologyinnearfuture.

AworkshoponPerceptionEngineeringwasheldon4-5thDecember2009attheNational Brain ResearchCentrein coordination of the Ministry ofInformationTechnology,Govt.ofIndia.Theworkshopsessionswereconductedwithparticipationofactivegroupsacrossthecountryonneuroscience,cognitivescience,linguisticsalongwithcomputerengineers and robotics researchersandartificialintelligenceexperts.TheparticipantsintheworkshopwerefromIITDelhi,IITBombay,IIIT,Hyderabad,JadavpurUniversity,CentralElectronicEngineeringResearchInstitute(CEERI),Pilani,andCentreforDevelopmentofAdvancedComputing(CDAC),Kolkata,besides National Brain ResearchCentre.

The two dayworkshop, the first dayofwhichwasheld atNationalBrainResearch Centre,Manesar and thesecond day at Indian Institute ofDelhi,NewDelhi,mainly focused oninformationprocessesinginthehuman

Perception Engineering Workshop 2009

INteRNatIoNal collaBoRatIoNs aND NetWoRKING

International Collaborations

networking

International Collaborations and Networking 157

International collaborations aimedat promoting neuroscience enablingthe Centre to evolve cross borderrelationshipforIndianNeuroscientistswith the international neurosciencecommunity through such exchangeprograms. Towards this endeavourof excellence in a very short span oftime, NBRC hasmade great stridesin establishing such collaborationswithvariousprestigiousneuroscienceinstitutions in different countriesaroundtheworld.Followingareafewnotablecollaborativearrangements:

United States

NIH-RO1granthasbeenawarded toDr.PankajSethincollaborationwithProf. A.Nath of the Johns HopkinsUniversity. This NIH-RO1 grantproposes to study the “Role of CNSopportunisticinfectionsinsubsequentdevelopmentofHIVdementia”.

France

Dr.PierreGressensandDr.ShyamalaManihavebeenawardedanINSERM-ICMRcollaborativegranttostudytheeffectofmaternalmalnutritiononthedevelopingbrainofthefetusandalso

plan to use stem cells for neonatalneuroprotection.

Italy

The ItalianMinistry for Universityand Research funded a projectto Dr.Pravat K.Mandal, NBRC incollaborationwithProf.VincenzoFodaleofUniversityofMessina,Italytostudy“Characterization of themolecularinteractions of anesthetics with thebeta-amyloid”.

TheMinistryofEducation&Research,ItalianGovt.underprogramofEuropeanCommission,hasfundedaprojectforcollaborationbetweenProfPrasunRoyandProf.PatriziaBaraldi,UniversityofModena&ReggioEmilia,forfunctionalandtensorialneuroimagingapproachto cortical information transmission(studenttrainingproject).

The Netherlands

A project of high field neuroimagingmethodology deve lopment , forcollaborationbetweenProfPrasunRoyandProf.PeterLuijten,UtrechtMedicalCentre, has been sponsored by TheUtrechtUniversityFoundation.

International Collaborations


Amajor goal ofNBRC is to networkthe existing neuroscience groups/institutions in the country andpromotemultidisciplinaryresearchinneuroscience.Thisisaimedtopreventunnecessary duplication of theworkand facilitiesalreadyexisting. Italsofacilitates sharing of expertise andavailable infrastructure formutualbenefit.Networkingalsohelpstobringtogether researchers from varyingbackgrounds to pursue commonobjectives thatmay be beyond thecapacityofanindividualinvestigator,grouporinstitution.Thisisimportantbecause major achievements inneurosciencearebeingmadethroughamultidisciplinaryapproachbybringingtogetherscientistsworkingindifferentdisciplines into themain stream ofneuroscience and brain researchactivity.Thenetworkingispossiblebyinformationsharingthroughelectronicnetworkandidentifying“Collaborating”centres for mutual interaction.Currently48centresthroughoutIndiaarenetworkedtoNBRC.Thefollowinginstitutions/universities arememberofournetworkactivities

List of Network Centres

1. All India Institute of MedicalSciences(AIIMS),NewDelhi.

2. BanarasHinduUniversity(BHU),Varanasi.

3. Bangur Institute of Neurology,Kolkata.

4. CentreforBehaviouralandCognitiveSciences (CBCS), University ofAllahabad,Allahabad.

5. Centre forCellular&MolecularBiology(CCMB),Hyderabad.

6. CentralDrugResearchInstitute(CDRI),Lucknow.

7. Centre for DNA FingerprintingandDiagnostic,Hyderabad.

8. Central Food andTechnologicalResearch Institute (CFTRI),Mysore.

9. CochinUniversityofScienceandTechnology,Cochin.

10. Department of Biotechnology.NewDelhi.

11. DelhiUniversity,SouthCampus,Delhi.

12. Dr. A. L.NeurosurgicalCentre,Chennai.

13. IndoAmericanHospitalBrainandSpineCenter,Kerala.

14. InstituteofCybernetics,Systemsand Information Technology,Kolkata.

networking

International Collaborations and Networking 159

15. InternationalCentre forGeneticEngineering andBiotechnology(ICGEB),NewDelhi.

16. Institute of Genomics andIntegrativeBiology(IGIB),Delhi.

17. InstituteofHumanBehaviour&AlliedSciences(IHBAS),Delhi.

18. Indian Institute of InformationTechnology(IIIT),Allahabad.

19. Indian Institute of Technology(IIT),Mumbai.

20. Indian Institute of Technology(IIT),Delhi.

21. Indian Institute of Technology(IIT),Kanpur.

22. Indian InstituteofScience (IIS),Bangalore.

23. Indian Institute of ChemicalBiology(IICB),Kolkata.

24. InstituteofNuclearMedicineandAllied Sciences (INMAS), NewDelhi.

25. Industrial Toxicology ResearchCentre(ITRC),Lucknow.

26. Indian Statistical Institute,Kolkata.

27. InternationalSchoolofPhotomics,Cochin.

28. JagadguruSriShivarathreeshwaraMedicalCollege,Mysore

29. Jawaharlal Nehru University(JNU),NewDelhi.

30. Jawaharlal Nehru Centre forAdvance Scientific Research(JNCASR),Bangalore.

31. JiwajiUniversity,Gwalior.

32. M.S.UniversityofBaroda(Dept.ofMicrobiologyandBiotechnology

Centre),Baroda.

33. National Centre for BiologicalSciences(NCBS),Bangalore.

34. National Informatics Centre(Med ica l In fo rmat i cs andTelemedicineDivision),(NIC)NewDelhi.

35. NationalInstituteofMentalHealth& Neuroscience (NIMHANS),Bangalore.

36. Nizam’s Institute for MedicalSciences(NIMS),Hyderabad.

37. Ra j i v Gandh i Cen t r e f o rBiotechnology,Trivandrum.

38. National Neuroscience Centre(NNC),Kolkata.

39. Sanjay Gandhi Post-GraduateInstitute of Medical Sciences(SGPGIMS),Lucknow.

40. SchoolofInformationTechnology,WestBengalUniversity.

41. ShreeChitraTirunalInstituteforMedicalSciencesandTechnology,Thiruvanthapuram.

42. Sri Venkateswara Institute ofMedicalSciences,Tirupati.

43. Tata Institute of FundamentalResearch(TIFR),Mumbai.

44. University College of MedicalSciences(UCMS),Delhi.

45. Un ive rs i t y o f Hyderabad ,Hyderabad.

46. UniversityofCalcutta,Kolkata.

47. Vidyasagar Institute ofMentalHea l th and Neurosc i ence(VIMHANS),NewDelhi.

48. Vision Research Foundation,Chennai

INVIteD lectuRes


Sr. Name of the Speaker Title of the Lecture Date

1. Dr.RamaJayasundar,DepartmentofNMRAllIndiaInstitueofMedicalSciences(AIIMS)NewDelhi

Q u a n t u m l o g i c i nayurveda.

April6th09

2. Dr.ArpanBanerjee,NYU

‘Model Based approachesfor studying brain andbehavior.

April15th09

3. Dr.RomiNijhawanUniversityofSussex

Predicting the Present:Visual-MotorNeuralDelaysandCompensation.

April17th09

4. Dr.BeenaKhuranaUniversityofSussex

CuingofSaccadicOrienting:MovingEyesversusMovingArrows.

April17th09

5. Dr.AnandmohanGhoshCNRS,France

‘Noise during rest enablestheexplorationofthebrainsdynamicrepertoire

April24th09

6. Dr.DebabrataChakravartiAssociateProfessorNorthwesternUniversityFeinbergSchoolofMedicine

Chromatin remodeling andnuclearreceptorsignaling.

May13th09

7. Dr.TapasNag,AssociateProfessor,Dept.ofAnatomy,AIIMS,NewDelhi

Selective vulnerability ofcones in aging humanretina.

May25th09

8. Dr.AnilG.CashikarAssistantProfessorMedicalCollegeofGeorgia,USA

Molecular chaperonesand neurodegenerativedisorders.

June19th09

9. DrElizabethThomasUniversityofDijonBurgundy,France

The study of the neuralencoding of categorizationwithaKohonennetwork.

July6th09

Invited Lectures


10. Dr.DebRanjanBhattacharyaDeputyGeneralManager-Technical& Application Support LaboratoryProducts Group, ThermoFisherScientific,India

Recen t Spec t roscop i cDetection Techniques forBio-molecules & theirInteractions.

July30th09

11. Dr.SachinDeshmukhMindBrainInstituteJohnsHopkinsUniversityBaltimoreUSA

Representation of SpatialandNon-SpatialInformationin Lateral and MedialEntorhinalCortex.

August7th09

12 Dr.SamarjitBhattacharyya,Department of Psychiatry andBehavioral Sciences, StanfordUniversitySchoolofMedicine

The role of post-synapticdensity proteins in AMPAreceptortrafficking.

August11th09

13. Dr.SusanneReitererTheUniversityofTubingen,Germany

Aneuro-cognitiveapproachtospeechimitation&foreignlanguagelearningtalent.

August27th09

14. Dr.SankarVenkatachalam,DepartmentofAnatomy,Dr A.L.M. Postgraduate Institute ofBasicMedicalSciences,UniversityofMadrasTamilNadu

Role of bonemarrow andamnion derived stem cellsinspinalcordinjuryrepairresearch.

September3rd09

15. Dr.RashmiBansalAssociateProfessorDept.Neuroscience,MC-3401University of ConnecticutMedicalSchool 263 Farmington AvenueFarmingtonCT06030-3205USA

Role of Fibroblast GrowthFactors in Glial-NeuronSignaling.

September29th09

16. Dr.PoonamMalhotra,MDAssociateProfessorCardiacAnesthesiaAIIMS,NewDelhi

Inhaled Anesthetics andCognit ive performanceof patients undergoingCoronary artery bypasssurgery.

November3rd09

17. Dr.KennethR.PughAssociate Professor, Department ofPediatrics(Neurology),YaleUniversitySchoolofMedicineandPresident andDirector of Research,HaskinsLaboratories,NewHavenCT.06511

Neuroimaging studies ofReading and LanguageDevelopment:Anupdateonrecentfindings.

November17th09


18. Mr.SourojitBhowmickD e p t . o f M i c r o b i o l o g y a n dImmunologyUniv.ofConnecticutHealthCenter

The Sympathy behindimmune regulation: Anuniquerelationshipbetweenthe Sympathetic NervousSystem and regulatory Tcells.

November25th09

19. DrKavitaBabuDepartmentofMolecularBiologyMassachusettsGeneralHospital

An IgSF protein RIG-3p r e v e n t s s y n a p t i cpotentiationinC.elegans.

November25th09

20. DrHatimZariwalaAllenInstituteforBrainScience

Toward the genetic andcellularbasisofcognition.

November25th09

21. Prof.AdhipPNMajumdarDSc.,KarmanosCancerInst.,WayneStateUniversityDetroit

Cancer Stem Cel ls : ANew Paradigm in Agingand Gas t r o i n t e s t i na lCarcinogenesis.

December2nd09

22. DrPratikMuthaPennStateUniversityNMVAHealthcareSystem

Visua l modu la t i on o freflex responses duringmovement

December8th09

23. DrSujayKumarDharaResearchAssociateMorehouse School of Medicine,UniversityofGeorgiaAtlanta,GA

Human Embryonic StemCells inBasic andAppliedNeuralResearch.

December15th09

24. DrKrishSathianProfessorofNeurologyRehab i l i t a t i on Med ic ine andPsychologyEmoryUniversity,USA

Multisensory integration ofvisionandtouch.

December17th09

25. Dr.PuneetOpalAssistantProfessorDavee Department of Neurology,Northwestern University FeinbergSchoolofMedicine

Unravelingthepathogenesisof Spinocerebellar AtaxiaType1.

January6th10

26. Dr.CharanjitKaurAssociateProfessorNationalUniversityofSingapore

Hypoxia induced blood-brain, blood-retinal andblood-cerebrospinal fluidbarrierdysfunction

January21st10

27. Dr.MatthewBelmonteDepartmentofHumanDevelopmentCornellUniversity

Frontal Lobe Physiologyand Autistic Traits withinand beyond the AutismPhenotype

January18th10


28. Ms.SoniaBaloniGraduatestudentGermanPrimateCenter,Göttingen(Germany)

Spatial and feature Basedattention in area MST ofmacaquevisualcortex

February2nd10

29. KaveriRajaramanDept. of Molecular and CellularBiologyHarvardUniversity,USA

Intrinsicallyphotosensitive ganglioncellsofthetigersalamanderretina

February15th10

30. Mr.SouravBanerjeeNeuroscienceResearchInstituteUniversityofCaliforniaSantaBarbaraCA-93106,USA

MicroRNAs in SynapticPlasticity: Tiny RNAswithBigPotential

February19th10

acaDeMIc pRoGRaMMes

Ph.D. in neuroscience

Integrated Ph.D. in neuroscience

summer training and short-term Programmes

Academic Programmes 169

Deemed University Status

NBRCwasawardedDeemedUniversitystatus (de-novo category) in 2002under Section 3 of UGC Act, 1956(3 of 1956) vide notificationNo.F.9-52/2001-U.3 dated 20thMay, 2002issuedbyMinistryofHumanResourcesDevelopment, Government of India.NBRC is the first Institute amongthe Institutes of theDepartment ofBiotechnologytoattainthisstatus.

Oncompletionof5yearsperiodfromthetimeNBRChasbeengivende-novodeemedUniversitystatus,apanelof6MemberCommittee (dulyconstitutedbyUGC)visitedNBRCforreviewingthe‘DeemedtobeUniversity’statusandfor recommending further extension.Thereporthasbeenreceived.Howeverthedeemeduniversitystatushasbeenreviewedbyanindependentcommitteeconstituted byMinistry ofHRD. Thecommittee has given excellent reportand placed this university as “A”categoryInstitute.

UGC also desired to re-assess andreview the deemeduniversity statusandagainadulyconstitutedcommitteevisitedNBRC on 03rd, 04th& 05thFebruary,2010andgaveaverygoodreport.ThenotificationfromMinistryofHRDisawaited.

Academic Programmes

Courses Offered:

Ph.D. in neuroscience

NBRC has a Ph.D. Programme inNeuroscience to develop trainedmanpowerhavingabroadoverviewofdifferentaspectsofNeuroscience.

NBRC inducts students for its Ph.D.programmefromdiversebackgroundsincludingMastersdegreeinanybranchrelated toNeurosciences, PsychologyorM.B.B.S., B.E., or B.Tech. NBRCrecognizes that understanding brainfunctionsrequiresafusionofknowledgefrommultipledisciplines.

FellowshipforJuniorResearchFellowsisRs.12,000/-permonthandforSeniorResearch Fellows it is Rs.14,000/-(whichmaychangeasperextantrulesandaspercircularsissuedtimetotimeonthesubject).

Integrated-Ph.D. in neuroscience

NBRC has an Integrated Ph.D.Programme in Neuroscience todevelop trainedmanpower having abroadoverviewofdifferentaspectsofNeuroscience.

NBRC inducts students for itsIntegrated Ph.D. programme fromdiverse backgrounds including


Bachelor’sdegreeinanybranchrelatedto Neurosciences, M.B.B.S., B.E.,B.Tech.orPsychology.NBRCrecognizesthat understanding brain functionsrequires a fusion of knowledge frommultipledisciplines.

IntegratedPh.D.StudentsareprovidedafellowshipofRs.3000/-permonthforthefirsttwoyears.FromthirdyearonwardstheyarepaidfellowshiponparwithPh.D.students.AftercompletionoftheIntegratedPh.D.completionofthe IntegratedPh.D.programme, thestudents will be given dual degree(M.Sc. and Ph.D.). NBRC is one ofthe first Institutes in the country todevelopanintegratedmultidisciplinaryteachingprogrammeinLifeSciences.

NBRC offers certain benefits to itsstudents in the form of fellowships,hostelaccommodation,transportationfacility,medicalreimbursementtoitsstudents.

summer training and short-term Programmes

NBRC conducted Summer TrainingProgrammefortheStudentsthroughthree National Science Academiesviz: (1) Indian Academy of Science,Bangalore(2)IndianNationalScienceAcademy, New Delhi (3) NationalAcademyofSciences,Allahabad.Thesummertrainingwasforaperiodof8weeks.TheTraineeswereprovidedwithsharedaccommodation in theHostelofNBRCduringtheirtrainingperiod.Summertraineeswereencouragedtoattend seminars and journal clubsorganizedattheInstitute.

The summer training projects givestudentsanexposuretoNeuroscienceandencouragethemtoconsideritasafuturecareeroption.

AlsoScience Popularisation Lectureswere conducted at Faridabad andGurgaon located in Haryana andResearch Associates visited therespective places to deliver thelectures.

GeNeRal & acaDeMIc

aDMINIstRatIoN

Administration 173

General & Academic Administration – A Profile

The General Administration of theInstituteconsistsofthefollowingmajorwings:

1. General Administration, headedbytheChiefAdministrativeOfficerandheisresponsibleforoverallManagement of Establishment,Personnel&AdministrationWing,Stores&PurchaseWing,Import&ProjectCell,Finance&AccountsWing, Estate Management &EngineeringMaintenanceWing–Civil,Electrical&Mechanical.

2. Academic Administration isheaded by the Reg is t rar ,and he is responsible for thestudents’administration,projectco-ordination, new students’admissions,courseco-ordinationetc.

During the year under review, theAdministrationWing strived hard inproviding support services and incarryingoutthefollowingactivities.

• The cultural festival of NBRC,‘TANTRIKA2009’wasorganizedwithinthecampuswhichincludeda variety of cultural and sportsevents. Students, officers, andstaffofNBRCparticipatedintheevent.

• Making due di l igence andcompliance to the Right toInformationAct,2005includingcompilationandupdatingoftherequired disclosure data on thewebsite.

• Making major imports fromdifferent countries in termso f equ ipments and o therconsumableswith ameticulousplanningandpreciseschedule.

• The new hostel building forhousing staff and ResearchAssistantswas taken over fromDAE.

• ThestaffandResearchAssistantswere shifted in the new hostelbuilding at NBRC campus,Manesar.

Implementation of Official Language

NBRC, though a scientific researchorganization, is making effort toimplement usage ofHindi in all theadministrative jobs such as internalofficialmeetings, questioning in theinterviews,debate,generalapplicationsetc.AproposalforcreationofpostsforHindi Cell is under consideration oftheDepartmentofBiotechnology.Anappreciation letterhadbeenreceived


by NBRC from Ministry of HomeAffairs,RegionalImplementationOffice,GhaziabadtowardsimplementationofHindiindaytodayofficialwork.ThecorrespondenceinHindiis76%,whichis remarkable. The “Timahi Report”areusedtosenttoOfficialLanguageDepartment,Ghaziabad;DepartmentofBiotechnology,NewDelhiandNagarRajbhasha Vibhag, Gurgaon. Theofficial language committeewith itsmembers takingkeen interestand isactively looking intotheuseofHindiandisbeingreviewedeveryquarter.

RTI Act

The provisions of RTI Act are beingfollowedinNBRCinletterandinspirit.During2009-10,nineRTIapplicationswerereceivedseekinginformationonvariousmattersconcerningNBRC.Allapplicantswereprovidedtherequisiteinformationwithintheprescribedtimelimit.

Women Empowerment

NBRChasadistinctfeatureofgivingequalopportunitytowomenbywordsanddeed.TheCommittees,constitutedtodovariousworkofAdministration,Academicsandscientificactivities,havewomenmembers which ensure fair

participationandprotectionofwomen.There isacommittee forredressalofsexualharassmentofwomenatNBRCandgrievances,ifany,fromaggrievedgirl students/ women employees ofNBRC.Ifanylady/womanofNBRC,among the Students/ Employees,is subjected to sexual harassment,can approach any of the committeemembers. The person-in-charge forredressalof thegrievancealongwiththeDirectorwouldinitiateactionwiththehelpofthecommitteeconstitutedforthispurpose.

Reservations and concessions in Employment & Admissions of Students

NBRC fo l l ows reserva t i ons &concessionsasperrulesofGovernmentofIndiainEmploymentandinstudent’sadmissiontheprovisionofexemptionas provided in Gazette NotificationNo. 5 dated 4th January, 2007 isimplemented.

Vigilance

The Institute has a Chief VigilanceOfficer.AspertheguidelinesofDBT,oneoftheOfficer/ScientistsofNBRChasbeennominatedasChiefVigilanceOfficeroftheCentre.

INstItutIoNal GoVeRNaNce stRuctuRe

& people at NBRc

nBRC societyGoverning CouncilFinance CommitteeScientific Advisory CommitteeResearch Area PanelBuilding CommitteeAcademic Council

Board of studiesM.sc. neuroscience Co-ordination CommitteeScientific StaffOther Staff

Governance Structure 177

Members of the nBRC society

Prof.P.N.Tandon(President)No.1,JagritiEnclave,VikasMarg,NewDelhi

Dr.M.K.BhanSecretaryDepartmentofBiotechnology,NewDelhi

Dr.T.RamasamiSecretaryDepartmentofScience&Technology,NewDelhi

Dr.V.M.KatochDirector-GeneralIndianCouncilofMedicalResearch,NewDelhi

Dr.SandipK.BasuProfessorofEminence,NationalInstituteofImmunology,NewDelhi

Dr.K.VijayaraghavanDirectorNationalCentreforBiologicalSciences,Bangalore,Karnataka

Prof.SamirK.BrahmachariDirectorGeneralCSIRInstituteofGenomics&IntegrativeBiology,MallRoad,Delhi

ShriK.P.PandianJS&FADept.ofScience&TechnologyTechnologyBhavan,NewMehrauliRoad,NewDelhi-110016(Upto31January2010)

Ms.SheilaSangwan(IRS)AdditionalSecretary&FinancialAdvisorDepartmentofScience&Technology,NewDelhi(From01February2010)

Dr.GourieDeviDirector(Retd.),Flat–9,DoctorsApartments,VasundharaEnclave,Delhi

Dr.L.M.PatnaikVice-ChancellorDefenceInstituteofAdvanceTechnologyPune,Maharashtra

Prof.KalluriSubbaRaoHon.Professor.&INSA-SeniorScientistCentreforBiotechnology,(IST)JawaharlalNehruTechnologicalUniversityHyderabad,AndhraPradesh

Prof.GomathyGopinathFlat#001,KanchanjungaApartments,122/2,Nagavarapalaya,VarthurRoad,Bangalore,Karnataka

Dr.T.S.RaoAdvisor,DepartmentofBiotechnology,NewDelhiProf.V.Ravindranath(MemberSecretary)Director(Upto30April2009)NationalBrainResearchCentre,Manesar,Haryana

Prof.P.K.Roy(MemberSecretary)Director(I/C)(from01May2009)NationalBrainResearchCentre,Manesar,Haryana


Members of the Governing Council

Dr.M.K.Bhan(Chairperson)SecretaryDepartmentofBiotechnologyNewDelhi

Prof.P.N.TandonNo.1,JagritiEnclave,VikasMarg,NewDelhi

Dr.T.RamasamiSecretaryDepartment.ofScience&TechnologyNewDelhi

ShriK.P.PandianJS&FADept.ofScience&TechnologyTechnologyBhavan,NewMehrauliRoad,NewDelhi-110016(Upto31January2010)


Dr.K.VijayaraghavanDirectorNationalCentreforBiologicalSciences,Bangalore,Karnataka

Dr.AshokMishraChairmanIntellectualVenturesIndia,Bangalore,Karnataka

Dr.NimeshG.DesaiMedicalSuperintendent&HeadoftheDepartmentofPsychiatry,InstituteofHumanBehavior&

AlliedSciences,NewDelhi

Prof.P.BalaramDirectorIndianInstituteofScience,Bangalore,Karnataka

Prof.N.K.GangulyAdvisor,THSTINationalInstituteofImmunology,NewDelhi

Dr.A.K.AgarwalDeanMaulanaAzadMedicalCollege,NewDelhi

Dr.V.RajshekharNeuroSurgeonCMC,Vellore,TamilNadu

Dr.V.M.KatochDirector-General,IndianCouncilofMedicalResearch,NewDelhi

Dr.T.S.RaoAdvisorDepartmentofBiotechnology,NewDelhi

Prof.V.Ravindranath(MemberSecretary)Director(Upto30April2009)NationalBrainResearchCentre,Manesar,Haryana

Prof.P.K.Roy(MemberSecretary)Director(I/C)(From01May2009)NationalBrainResearchCentreManesar,Haryana


Members of the Finance Committee

Dr.M.K.Bhan(Chairperson)SecretaryDepartmentofBiotechnology,NewDelhi

ShriK.P.PandianJS&FADept.ofScience&TechnologyTechnologyBhavan,NewMehrauliRoadNewDelhi-110016(Upto31January2010)


Dr.K.VijayaraghavanDirectorNationalCentreforBiologicalScienceBangalore,Karnataka

Dr.V.RajshekharNeuroSurgenCMCVellore,TamilNadu

Dr.K.P.Singh(UGCNominee)JointSecretaryUniversityGrantsCommission,NewDelhi

Dr.T.S.RaoAdvisorDepartmentofBiotechnology,NewDelhi

Prof.V.RavindranathDirector(Upto30April2009)NationalBrainResearchCentre,Manesar,Haryana

Prof.P.K.RoyDirector(I/C)(From01May2009NationalBrainResearchCentre,Manesar,Haryana

Mr.SantoshKumar(MemberSecretary)Offg.Finance&AccountsOfficer,NationalBrainResearchCentre,Manesar,Haryana


Members of Scientific Advisory Committee

Prof.P.N.Tandon(Chairperson)No.1,JagritiEnclaveVikasMargExt.Delhi

Prof.N.K.GangulyAdvisor,THSTINationalInstituteofImmunologyNewDelhi

Dr.W.SelvamurthyOutstandingScientistChiefControllerR&D,(LS&HR)DRDOHeadquarters,NewDelhi

Dr.K.VijayraghavanDirectorNationalCentreforBiologicalSciencesBangalore,Karnataka

Prof.GomathyGopinathFlat#001,KanchanjungaApartments122/2,NagavarapalyaVarthurRoad,BangaloreKarnataka

Prof.BasabiBhaumikDepartmentofElectricalEngineeringIndianInstituteofTechnologyNewDelhi

Dr.V.MohanKumarEmeritusScientist&VisitingProfessor,SreeChitraTirunalInstituteforMedicalScience&TechnologyTrivandrum,Kerala

Prof.B.N.GangadharProfessorofPsychiatry,AdvancedCentreforYogaNationalInstituteofMentalHealthandNeurosciences(NIMHANS)Bangalore,Karnataka

Dr.RaviMehrotraScientist“F”NationalPhysicalLaboratoryNewDelhi

Dr.KanuriVenkataSubhaRaoScientistInternationalCentreforGeneticEngineeringandBiotechnology(ICGEB)NewDelhi

Dr.P.SatishchandraProfessor&HeadDepartmentofNeurologyNationalInstitueofMentalHealthAndNeurosciences(NIMHANS)Bangalore,Karnataka


Dr.SatyajitRathScientistNationalInstituteofImmunologyNewDelhi

Dr.ThomasD.AlbrightTheSalkInstituteforBiologicalStudiesSanDiego,USA

Dr.Jean-PierreJulienProfessor,LavalUniversityResearchCentreofCHULQuebec,Canada

Prof.SangramSisodiaThomasReynoldsSeniorFamilyProfessorofNeurosciencesDepartmentofNeurobiologyTheUniversityofChicagoChicago,USA

Dr.T.S.RaoAdvisorDepartmentofBiotechnologyCGOComplex,NewDelhi


Members of the Research Area Panel

Dr.R.K.GuptaProfessor&HeadDept.ofPathologySanjayGandhiPostgraduateInstituteofMedicalSciences(SGPGIMS)Lucknow,UttarPradesh

Dr.ShashiWadhwaProfessorDepartmentofAnatomyAllIndiaInstituteofMedicalSciencesNewDelhi

Dr.ShobhaSrinathProfessorDepartmentofPsychiatryNationalInstituteofMentalHealthandNeurosciences(NIMHANS)Bangalore,Karnataka

Dr.ChitraSarkarDepartmentofPathology,AllIndiaInstituteofMedicalSciences,NewDelhi

Dr.C.L.KhetrapalDirector,SanjayGandhiPostgraduateInstituteofMedicalSciences(SGPGIMS)Lucknow,UttarPradesh

Dr.SumitraPurkayasthaDepartmentofTheoraticalStatistical&MathematicsUnit,IndianStatisticalInstituteKolkatta,WestBengal

Dr.RajeshSagarAssociateProfessorPsychiatry&De-addictionCentreAllIndiaInstituteofMedicalSciencesNewDelhi

Prof.K.P.MohanKumarScientist“G”&Head,CellBiology&PhysiologyDivision,IndianInstituteofChemicalBiology(IICB),4RojaSCMullickRoad,JadavpurKolkata,WestBengal

Prof.V.RavindranathDirectorNationalBrainResearchCentreManesar,Haryana(HasrelocatedtoIISc,BangalorefromNBRCw.e.f.30thApril2009)

Dr.P.K.RoyDirector(I/C),NationalBrainResearchCentre,Manesar,Haryana


Members of the Building Committee

Dr.T.S.Rao(Chairperson)Advisor,DepartmentofBiotechnologyNewDelhi

Dr.SatishGuptaScientist,NationalInstituteofImmunologyNewDelhi

Prof.V.RavindranathDirector(Upto30April2009)NationalBrainResearchCentre,Manesar,Haryana

Prof.P.K.RoyDirector(I/C)(From01May2009)NationalBrainResearchCentreManesar,Haryana

ShriB.BoseSeniorConsultant,NationalInstituteofImmunology,NewDelhi

Mr.K.V.S.KameswaraRaoRegistrarNationalBrainResearchCentre,Manesar,Haryana

Mr.KannanKasturiN.S(MemberSecretary)Offg.ChiefAdministrativeOfficer,NationalBrainResearchCentre,Manesar,Haryana


Members of the Academic Council

Prof.V.Ravindranath(FormerDirector)hasrelocatedtoIISc,BangalorefromNBRCw.e.f.30thApril,2009.

Prof.P.K.Roy(Chairman)Director(I/C)NationalBrainResearchCentreManesar,Haryana

Prof.BasabiBhaumikDepartmentofElectricalEngineeringIndianInstituteofTechnologyNewDelhi

Dr.V.S.MehtaParasHospitalsGurgaon,Haryana

Prof.K.MuralidharHead,Dept.ofZoologyUniversityofDelhiDelhi

Prof.NeerajJainNationalBrainResearchCentreManesar,Haryana

Dr.PravatK.MandalNationalBrainResearchCentreManesar,Haryana

Dr.NiharRanjanJanaNationalBrainResearchCentreManesar,Haryana

Dr.PankajSethNationalBrainResearchCentreManesar,Haryana

Dr.NarenderK.DhingraNationalBrainResearchCentreManesar,Haryana

Dr.ShivKumarSharmaNationalBrainResearchCentreManesar,Haryana

Dr.RanjitK.GiriNationalBrainResearchCentreManesar,Haryana

Dr.YoganarasimhaDoreswamyNationalBrainResearchCentreManesar,Haryana

Dr.NandiniC.SinghNationalBrainResearchCentreManesar,Haryana

Dr.SoumyaIyengarNationalBrainResearchCentreManesar,Haryana

Dr.AnirbanBasuNationalBrainResearchCentreManesar,Haryana

Dr.ElloraSenNationalBrainResearchCentreManesar,Haryana


Mr.K.V.S.KameswaraRaoNationalBrainResearchCentreManesar,Haryana

Dr.AdityaMurthy(FormerFaculty)hasrelocatedtoIISc,BangalorefromNBRCw.e.f.19thMay,2009.

Dr.RemaVelayudhan(FormerFaculty)leftNBRCw.e.f.31stAugust,2009.

Dr.ShyamalaMani(FormerFaculty)hasrelocatedtoIISc,BangalorefromNBRCw.e.f.01stOctober,2009.


Members of the Board of studies


Prof.P.K.RoyDirector(I/C),NationalBrainResearchCentreManesar,Haryana

Prof.D.N.RaoIndianInstituteofSciencesBangalore,Karnataka

Prof.RohitManchandaIndianInstituteofTechnology,Mumbai,Maharashtra








Dr.YoganarasimhaNationalBrainResearchCentreManesar,Haryana







Dr.RemaVelayudhan(FormerFaculty)leftNBRCw.e.f.31stAugust,2009



Members of the M.sc. neuroscience Co-ordination Committee


Prof.P.K.RoyDirector(I/C)NationalBrainResearchCentreManesar,Haryana

Prof.K.MuralidharHeadDept.ofZoology,UniversityofDelhi,Delhi-110007

Dr.JayaTyagiDept.ofBiotechnology,AIIMSNewDelhi

Dr.ArjunSuryaChembiotechResearchInternationalBlockNo:BN-Plot-7,Sector-5,SaltLake,Kolkata

Dr.(Mrs.)SumanGovilAdvisorDepartmentofBiotechnologyC.G.O.Complex,NewDelhi








Dr.YoganarasimhaDoreswamyNationalBrainResearchCentreManesar,Haryana








Dr.RemaVelayudhan(FormerFaculty)leftNBRCw.e.f.31stAugust,2009.


189Governance Structure

Scientific Staff

Scientist

1 Prof.V.Ravindranath(Upto30April2009)

2 Prof.PrasunKumarRoy

3 Prof.NeerajJain

4 Dr.RemaVelayudhan(Upto31August2009)

5 Dr.PankajSeth

6 Dr.NarenderK.Dhingra

7 Dr.ShivKumarSharma

8 Dr.ShyamalaMani(Upto01October2009)

9 Dr.AdityaMurthy(Upto19May2009)

10 Dr.NiharRanjanJana

11 Dr.NandiniC.Singh

12 Dr.SoumyaIyengar

13 Dr.AnirbanBasu

14 Dr.ElloraSen

15 Dr.RanjitKumarGiri

16 Dr.PravatK.Mandal

17 Dr.YoganarasimhaDoreswamy

Consultants

1 Prof.ParthaRaghunathan

2 Dr.SubbulaxmiNatarajan(Till31.12.2009)

DST Women Scientist-A

1 Dr.KamaleshKumariGulia(Till6.12.2009)

2 Dr.SayaliC.Ranade

Clinical Psychologist

1 KrishanKumar

Research Associate

1 Dr.ArkadebDutta

2 Dr.KallolDutta

3 Dr.PratimaPandey

4 Dr.ShripadKondra

5 Dr.SanchariSinha

R & D Engineer

1 Mr.V.P.SubramanyamRallabandi

2 Mr.DeepakKamboj

Project Associate

1 Ms.AnyaChakraborty

Project Technician

1 Mr.UttamKumarSaini

2 Ms.T.A.Sumathi


Ph.D. Students

1 Mr.Ziauddin

2 Ms.NaziaKhurshid(Till19.02.2010)

3 Ms.UzmaSaeed(Till15.01.2010)

4 Mr.ShashankTandon(Till16.03.2010)

5 Ms.ManishaChugh

6 Ms.ChinmoyeeMaharana

7 Mr.LesleeLazar

8 Ms.ShalakaMulherkar

9 Mr.ArjunR

10 Mr.Kh.BudhachandraSingh(Till28.10.2009)

11 Mr.NiranjanA.Kambi

12 Mr.JaiprakashSharma

13 Ms.SulagnaDas

14 Ms.NehaSehgal

15 Mohd.HishamP.M

16 Ms.RichaTiwari

17 Ms.RupaliSrivastava

18 Ms.TanusreeDas

19 Ms.RadhikaRajan

20 Dr.NitinKoul

21 Ms.ShilpaMishra

22 Mr.SubhadipPaul

23 Mr.ParthivHaldipur

24 Mr.VivekSharma(Till26.02.2010)

25 Mr.KaushikPramodSharma

26 Ms.NehaBhutani

27 Ms.K.M.Sharika

28 Dr.SudheendraRao

29 Mr.RahulChaudhary

30 Mr.PankajSGhate

31 Mr.DeepakKrKaushik

32 Mr.KashifMahfooz(Till04.01.2010)

33 Mr.DeobratDixit

34 Ms.Kiran

35 Mr.ArshedNazmi

36 Mr.ApoorvSharma

37 Ms.PrettyGarg

38 Ms.ManjuPant

39 Mr.RaghavanVallur

40 Mr.IMohdAriff

41 Ms.RituSingh

42 Mr.Dharampal

43 Ms.IshimaBadhwar(Till09.10.2009)

Int. Ph.D. Students

1 Ms.SaumyaNagar

2 Ms.SwethaKameswari

3 Ms.VarshaJain

4 Mr.AjitRay

5 Ms.ShailyMalik

6 Mr.SadashibGhosh

7 Ms.MeghaMaheswari

8 Ms.PoojaVishwanathan(Till23.12.2009)

9 Mr.DeepakPoria

10 Mr.ManviGoel

11 Mr.PavanKumarR.

12 Mr.AtulGopalPA


13 Ms.MeghaSharda

14 Ms.SuhelaKapoor

15 Ms.GunchaBhasin

16 Ms.SarikaCherodath

17 Ms.RuchiBansal(Till02.12.2009)

18 Ms.Himakshi

19 Ms.RuchiGhildiyal

20 Ms.PiyushiGupta

21 Ms.AvantikaMathur

22 Ms.ShankhamalaSen

23 Ms.T.Geetanjali(Till17.08.2009)

24 Ms.SubhashikaG.

Project Assistant

1 Ms.T.PadmaSubhadra(Till12.03.2010)

2 Mr.Santoshsethuramanujam(Till17.07.2009)

3 Mr.S.Ramakrishnan(Till08.06.2009)

4 Mr.VinayKumarShukla

5 Mr.DebapriyaGhosh(Till23.04.2009)

6 Mr.PrakashKr.Mishra(Till15.03.2010)

7 Ms.UpasnaBharti(Till05.03.2010)

8 Ms.HenaKhalique(Till15.02.2010)

9 Mr.SenthilKrishnasamy(Till28.08.2009)

10 Md.SarfarazNawaz

11 Mr.N.Prakash(Till15.10.2009)

12 Ms.PraseedaK.Venugopalan(Till19.06.2009)

13 Mr.RanjanMaity(Till06.11.2009)

14 Mr.MadanRamKumar(Till25.01.2010)

15 Mr.ArnabMukherjee(Till09.10.2009)

16 Ms.SoumeeBhattacharya(Till26.05.2009)

17 Mr.L.ShahulHameed

18 Mr.AnupamGhosh(Till13.01.2010)

19 Mr.SabyasachiMaity(Till31.07.2009)

20 Ms.ManishaTaneja

21 Mr.P.VinodBabu(Till05.03.2010)

22 Mr.ChetanChandola

23 Ms.SwarupaChakraborty(Till15.01.2010)

24 Ms.PriyankaPatel(Till05.11.2009)

25 Mr.RajivKr.Mishra(Till03.11.2009)

26 Mr.R.Ethiraj

27 Mr.M.SakthiKumar

28 Mr.M.S.Sivaraj

29 Mr.ParthaNarayanDey

30 Mr.SauravRoyChoudhury

31 Ms.PreetiYadav(Till22.01.2010)

32 Mr.SushilKumar

33 Mr.S.K.SudiptaShaheen

34 Ms.KanchanBisht


35 Ms.MalvikaGupta

36 Ms.S.Vishalini

37 Ms.HemaBisht(Till10.07.2009)

38 Ms.JyotiChhibber

39 Mr.JonathanAllen(Till16.08.2009)

40 Mr.ShovanNaskar(Till4.12.2009)

42 Mr.B.VarunVenkatesh(Till04.12.2009)

43 Ms.ManishaAhuja

44 Ms.UpasanaSahu

45 Ms.AnanyaSamanta

46 Mr.DwaipayanAdhya

47 Ms.AnyaChakraborty

48 Mr.SouravGhosh

49 Ms.G.Revathy

193Governance Structure

Other Staff

Technical Staff

1. Mr.RajbirSingh

2. Dr.ShikhaYadav(Till07.12.09)

3. Mr.SanjeevK.Choudhary

4. Mr.DevDasLal

5. Dr.SureshKumar

6. Mr.R.KhaderValli

7. Mr.HariharakrihnanS.

8. Mr.JitenderAhlawat

9. MahenderKumarSingh

9. Mr.KedarSinghBajetha

10. Mr.VipinRawat(Till01.02.10)

11. Mr.SanjeevBhardwaj

12. Mr.ArvindSinghPundir

13. Mr.KanhaiyaLalKumawat

14. Mr.AnkitSharma

15. Mr.D.Narender

16. Mr.MithleshKumarSingh

17. Mr.SanjayKumar

18. Mr.SumitKumarSinhaMahapatra

19. Mr.DilBahadurKarki

20. Mr.DurgalalMeena

21. Mr.P.Manish

22. Mr.Rammehar

23. Mr.IrshadAlam

24. Mr.MahendraSingh

25. Mr.ManishKumar

26. Mr.ShankarDuttJoshi

27. Mr.HariShankar

28. Mr.SanjayKumarSingh

29. Mr.YunisKhan

Administrative Staff

1. Mr.K.V.S.KameswaraRao

2. Mr.KannanKasturiN.S.

3. Ms.NeenaKapoor(Till16.06.09)

4. Mr.SantoshKumarChoudhary

5. Mr.P.V.S.ShyamKumar

6. Mr.DebashishBhattacharjee

7. Mr.RavinderPal

8. Mr.AnujKumarGupta(Till14.01.10)

9. Ms.PoojaGosain

10. Mr.AnoopSingh(Till30.04.09)

11. Mr.SanjayKumarGupta

12. Mr.ShivKumar

13. Mr.RajbirSingh


14. Mr.SurenderKumar

15. Mr.BhupenderPalSharma

16. Mr.SatishKumar

DIC Staff

1. Mr.JibanandaChhotaray

2. Mr.AshishKumarUpadhyay(Till20.05.09)

3. Ms.ReemaSaxena

4. Mr.AmitKumar

5. Ms.Sunita

6. R.GaneshGurumoorthy

7. Mr.KamathamThiripal(Till17.09.09)

Dementia Project

1. Mr.Gajanand(Till11.11.09)

NBRC Construction Project Staff

1. Mr.ShailenderSingh

2. Mr.AnilKumarYadav

3. Mr.BhupenderSingh

4. Mr.SubhashjiRoy

final cover 240909 · dr. pankaj seth 22 dr. ellora sen 26 dr. shiv kumar sharma 32 dr. anirban...

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