New Blueprint OfBrain ConnectionsReveals ExtensiveReach Of CentralRegulatorApril 6, 2021 | UC San Diego

Thousands of our daily activities, from makingcoffee to taking a walk to saying hello to aneighbor, are made possible through anancient collection of brain structures tuckedaway near the center of the cranium.

The cluster of neurons known as the basalganglia is a central hub for regulating a vastarray of routine motor and behavior functions.But when signaling in the basal ganglia isweakened or broken, debilitating movementand psychiatric disorders can emerge,including Parkinson s disease, Tourette s

disorder (ADHD) and obsessive-compulsive

disorder.

Despite its central importance in controllingbehavior, the specific, detailed paths acrosswhich information flows from the basal gangliato other brain regions have remained poorlycharted. Now, researchers at the University ofCalifornia San Diego, Columbia University’sZuckerman Institute and their colleagues havegenerated a precise map of brain connectivityfrom the largest output nucleus of the basalganglia, an area known as the substantia nigrapars reticulata, or SNr. The findings offer ablueprint of the area’s architecture thatrevealed new details and a surprising level ofinfluence connected to the basal ganglia.

The results, spearheaded by Assistant ProjectScientist Lauren McElvain and carried out inthe Neurophysics Laboratory of ProfessorDavid Kleinfeld at UC San Diego, and thelaboratory of Zuckerman Institute PrincipalInvestigator Rui Costa, are published April 5 inthe journal Neuron.

Researchers at University of California, SanDiego, and Columbia University mapped thecomplete set of brain-wide outputs from a partof the brain called the basal ganglia. Here,individual neurons receive parcels of input(from striatum) that are nominally transformedinto commands that are delivered to regions ofthe brain that drive behavior as well as toexecutive regions that track intent. The breadthof connections, revealed with modern tools forthe first time, gives critical insight into howanimals both move and assess their ownmovements. Original art by Julia Kuhl.The research establishes a new understandingof the position of the basal ganglia in thehierarchy of the motor system. According to theresearchers, the newly identified pathwaysemerging from the connectivity map couldpotentially open additional avenues forintervention of Parkinson’s disease and otherdisorders tied to the basal ganglia.

“With the detailed circuit map in hand, we cannow plan studies to identify the specificinformation conveyed by each pathway, howthis information impacts downstream neuronsto control movement and how dysfunction ineach output pathway leads to the diversesymptoms of basal ganglia diseases,” saidMcElvain.

With support from the NIH’s Brain Research

through Advancing InnovativeNeurotechnologies® (BRAIN) Initiative, theresearchers developed the new blueprintworking in mice by applying a modernneuroscience toolset that combines techniquesfrom genetics, virus tracing, automatedmicroscopic imaging of whole-brain anatomyand image processing. The results revealedsurprising new insights about the breadth ofconnections.

“These results are an example of howresearchers supported by the BRAIN Initiativeare using the latest brain mapping tools tochange in a fundamental way ourunderstanding of how the connections in thebrain’s circuits are organized,” said John J.Ngai, director of the NIH’s BRAIN Initiative.

Shown here in red are branches, or axons,

from cells in the substantia nigra brain regionthat connect to the superior colliculus region.(Credit: Lauren McElvain / Kleinfeld lab / UCSan Diego)Previous work had emphasized that the basalganglia architecture is dominated by a closed-loop with output projections connecting back toinput structures. The new study reveals theSNr broadcasts even to lower levels of themotor and behavior system. This includes alarge set of brainstem regions with directconnections to the spinal cord and motor nucleithat control muscles via a small number ofintervening connections.

“The new findings led by Dr. McElvain offer animportant lesson in motor control,” saidKleinfeld, a professor in the Division ofBiological Sciences (Section of Neurobiology)and Division of Physical Sciences (Departmentof Physics). “The brain does not controlmovement though a hierarchy of commands,like the ‘neural networks’ of self-driving cars,but through a scheme of middle managementthat directs motor output while informing theexecutive planners.”

Remarkably, according to the researchers, theSNr neurons that project to the low levels ofthe motor system have branched axons thatsimultaneously project back up to the brainregions responsible for higher-order control

and learning. In this way, the newly describedconnectivity of SNr neurons fundamentallylinks operations across high and low levels ofthe brain.

“The fact that specific basal ganglia outputneurons project to specific downstream brainnuclei but also broadcast this information tohigher motor centers has implications for howthe brain chooses which movements to do in aparticular context, and also for how it learnsabout which actions to do in the future,” saidCosta, a professor of neuroscience andneurology at Columbia’s Vagelos College ofPhysicians and Surgeons, as well as directorand chief executive officer of the ZuckermanInstitute.

Contributors to the study include ByungkookLim and Brenda Bloodgood at UC San Diego,Jeffrey Moore at Harvard, Yuncong Chen atNEC Laboratories America and G. StefanoBrigidi, now at the University of Utah School ofMedicine.

This work was supported by the EuropeanResearch Council, Howard Hughes MedicalInstitute, the National Institutes of Health (T32NS007220, U19 NS107466, U01 NS090595,R01 NS111162 and U19 NS104649), theTourette Association of America and equipmentfunds from the Dr. George Feher ExperimentalBiophysics Chair.