Introduction to Neuroscience: The Basal Ganglia

Michal Rivlin

BasalGanglia– agroupofsubcorticalnuclei

• Striatum:caudate&putamen• Globuspallidus (external&

internalsegments)• Subthalamic nucleus• Substantia nigra (parscompacta

&parsreticulata)

Basal ganglia-thalamo-cortical loop

• BasalGangliareceivesrobustinputfromthecortex

• PrincipalprojectionoftheBG– viathethalamusbacktocorticaltargets

Overview of BG organization• Input:

– Caudateandputamen(together,thestriatum)

• Intrinsic:– Subthalamicnucleus(STN)– Externalsegmentofglobuspallidus

(GPe)

Output:Substantianigraparsreticulata(SNr)Internalsegmentofglobuspallidus(GPi)

Neuromodulator:Substantianigraparscompacta(SNc)

SNc

Striatum: Medium spiny neurons

• Caudateandputamen

• Mediumspinyneurons– 95%ofneurons;primaryprojectionneurons

– GABAergic;inhibitory

– Verylittlespontaneousactivity

Striatum: Intrinsic interneurons

2principletypes

– 3GABAergicinterneurons

– Tonicallyactiveneurons(TANs)• Cholinergic• Largecellbodies

Globus pallidus

Two segmentsInternal (GPi): Principle output nucleusExternal (GPe): intrinsic circuitry

GABAergic; inhibitory

high tonic firing rates

Globus pallidus

Elias et al. J. Neurosci. 2007

Subthalamic nucleus

Glutamatergic; excitatory

Substantia nigra

• Midbrain

• SNparsreticulata(SNr)– GABAergic– hightonicfiringrates– OutputofBG

• SNparscompacta (SNc)– Neuromelanin-containingcells

– Dopaminergic– Tonic/phasicfiring

SNc

Directandindirectpathways

Directpathwaypromotesaction

+

−

−

+

Indirectpathwaysuppressesaction

+

−

+

−

+−

Hyperdirect pathway

+

−

+

+

RoleofBasalGangliaBGdysfunctionhasbeenassociatedwithnumerousconditionsincludingParkinson'sdisease,Huntington'sdisease,Tourette'ssyndrome,schizophrenia,attention-deficitdisorder,obsessive-compulsivedisorder,andmanyoftheaddictions.

• Motorcontrol• Learning• Motivationandreward• Cognitivetasks

Reinforcementlearning

• Supervisedlearning–Allknowingteacher,detailedfeedback

• Reinforcementlearning–Learnandrelearnbasedonactionsandtheireffects(rewards)

• Unsupervisedlearning–Selforganization

Rescorla-Wagnerrule(1972)

• Theidea:error-drivenlearning• Changeinvalueisproportionaltothedifferencebetweenactualandpredictedoutcome

Outcome:Rewardvalue

RewardpredictedLearningrate

TDlearning

Vt =Estimatedvalueofcurrentstatebasedonpredictedfuturereward

η =Learningrate

rt =rewardgivenattimet

‘truer’valueofcurrentstate:Rewardatpresentstate+Estimatedvalueofnextstate

Estimatedvalueofcurrentstate

ThecomputationalmachineryoftheBasalGanglia

The basal ganglia networks are built as Actor-Critic network and employ temporal difference algorithms.

Dopamine provides the pleasure prediction error

EnvironmentSTATE

ACTION

REWARD

Ctx

SNc

Dop

amin

eST

N, S

tr

GP

Fron

tct

x

EnvironmentSTATE

ACTION

REWARD

ACTOR

CRITIC

TD

err

or

Dopaminematchsurprisesignal

Schultzetal.,1997

Dopaminematchsurprisesignal

Dopaminesignal=rewardoccurred– rewardpredicted

Dopamineneuronsencodethe(positive)mismatchbetweenpredictionsandreality

Cue Reward NoReward

Rwr

DA

Cue No-RwrCueD

AP=1.00P=0.75P=0.50P=0.25

Genela Morrisetal.,Neuron,2004

Effectsofdopamine

• Learning=plasticity• Teaching=modulatingsynapticplasticity• Cortico-striatalsynapsesareknowntoundergolong-termchangesinsynapticefficacy.– Long-termpotentiation(LTP)ismediatedbyactivationofdopamineD1receptors

– Long-termdepression(LTD)ismediatedbyactivationofdopamineD2receptors

D1D2

Thestriveforthedopaminergicreward

• Cocaineandamphetaminesincreaseamountofdopaminebyinhibitingitsreuptakeintothesynapticterminals.

• Opiatenarcoticsincreasedopaminereleasebydisinhibitingdopaminergicneurons.

• Nicotineincreasesstriataldopamine.• Aprolongedincreaseindopaminelevelsmayaffectsynapticplasticityand

providetheneuralbasisfordrugaddiction.

Electricalself-stimulationinneuronalpathwaysassociatedwithdopamine.OldsandMilner,1954

It’snotallaboutdopamine:balancebetweenneurotransmitters

Parkinson’sdisease(PD)

Clinicalsymptoms• Akinesia/bradykinesia,• Tremor,• Muscularrigidity,• Posturaldeficits• Emotionalandcognitivedeficits

Epidemiology• 3/1000oftotalpopulation• Meanageofonset– 60years• 1/100of>60years

JamesParkinson,1817

Parkinson’sdisease:depletionofdopamine

Parkinson Normal

Substantia nigra

Striatum

TyrosinehydroxylasecatalyzesL-DOPA,aprecursorfordopamine

D1D2

Effectsofdopaminedepletionondirectandindirectpathways

DirectpathwaypromotesactionIndirectpathwaysuppressesaction

DopaminereplacementtherapyofParkinson’sdisease

1967-9, George C. Cotzias: L-DOPA (a precursor of dopamine that cross the blood brain barrier) is established as the gold-standard therapeutic agent for Parkinson's disease.

1970 – today: Dopamine replacement therapy (L-DOPA, post synaptic agonists, etc)

Thelimitsofdopaminereplacementtherapy

Time

Bra

in D

A le

vel Best

Typical

S

Levodopa-induceddyskinesiaDystonia

TheMPTPmodelofParkinson’sdisease

From: Understanding Parkinson's Disease, Youdim and Riederer, Sci. American 276: 38 (1997)

MPPP (1-methyl-4-propionoxypiperidine)- a reverse ester of meperidine and a potent narcotic- easy to synthesize- synthesis typically results in MPTP as byproduct.

1976: A college student synthesized and abused MPPP for 6 months. - made a 'sloppy batch', and became severely Parkinsonian. - Pathology: severe cell loss limited to the SN (Davis et al. 1979).

1982: MPPP was distributed en-mass in California as 'synthetic heroin'- young drug abusers arriving in ER with advanced Parkinsonism.

- typical Parkinsonian rest tremor in about half (3-4/7) of MPTP patients (Langston et al. 1983, 1987, 1995).

MPTP: 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine

TheMPTPmodelofParkinson’sdisease

Appearanceofneuronaloscillations

• Theparkinsonian braindemonstratesoscillatoryactivity:– PDpatientsduringbrain

surgery– MPTPprimates

Nor

mal

GP

park

inso

nian

GP

o Neuraloscillations(5-15Hz)

Spontaneousactivity

• NeuronaloscillationsappearintheGPaswellasinMI

¨ Tremorfrequencydiffersfromcorticalfrequency

D1D2

Inactivationofthesubthalamic nucleusamelioratesParkinsonsymptomsoftheMPTPmonkey

Norm

MPTP

-STN

-STN

-STN

MPTP

MPTP

Norm

Norm

0

4 0 0

N o r m a lM P T P

Tre

mo

r T

ime

(s

)

S T N l e s i o n0

8

N o r m a lM P T PS T N l e s i o n0

6 0 0

N o r m a lM P T P

Mo

v.

Tim

e (

s)

Dis

pla

ce

me

nt

(de

g)

S T N l e s i o n

A. Movement B. Rigidity C. Tremor

Bergman,Wichmann andDeLong,1990

Deepbrainstimulation(DBS)

• Deepbrainstimulation(DBS)isusedasatreatmentforadvancedPD.

• AnelectrodeislocatedintheSTN/GPi andhighfrequencystimulation(~130Hz)isgiventhroughtheelectrode.

BGhyperkineticdisorders

• Huntington’sdisease– striatalprojectionneuronsbecomedysfunctionalanddegenerate

– causesdefectsinbehavioranduncontrolledmovements.

– hereditarydisease• Hemiballismus

– Reducedactivityinthesubthalamic nucleus– Repetitive,largeamplitudeinvoluntarymovementsofthelimbs

BGnon-motordisorders

• Tourettesyndrome• Obsessive-compulsivedisorder• Attention-deficithyperactivitydisorder(ADHD)• Addiction