Abstract

Despitetheenormouscomplexityofthebrain,itisbecomingincreasinglyapparentthatstructureslikethe cerebralcortexaremodular,relyingonasetofcanonicalcomputationsthatoccuracrossbrainregionsand modalitiestomediateperception,cognitionandbehavior.Oneimportantexampleofacanonicalcomputation isthesummationofvariousdriving,contextual,andmodulatoryneuronalinputstoyieldspikingoutput.The questionofhowcorticalnetworksintegratetheseinputsandtransformthemintospikingoutputsofindividual neuronsisofcentralimportancetoneuroscience.Asignificantchallengetounderstandingthesecomputations isthateachneuronisembeddedwithinalargercircuitofneurons,eachmodulatingoneanother?sactivity.So, understandinghowaparticularneuronrespondstoinputnecessarilyinvolvesunderstandingthelargercircuit. Recentoptogeneticstudieshavefounddifferentpatternsofinputsummationinmousevs.monkeyV1. Recentlydevelopedtheoreticalmodelshaveproducedspecificpredictionsaboutthedifferencesinnetwork circuitrythatcanleadtodifferencesinsummation,andpredicthowsummationnon-linearitiesdependon inputstothenetwork.Theproposedresearchwilltestthesepredictionsandseektounderstandthesecircuit computationsusingacombinationoftheoreticalworkandoptogeneticmodulationofcircuitsinmouseand monkey.
Aim1 :VaryingEandIoptogeneticstimulationandvisualcontrastindependentlytomeasure spikeresponsesummationtomultipleinputs.InthisAim,theoreticalmodelsofinputsummationacross varyingcorticalcircuitregimeswillbedeveloped,andrecentlydevelopedoptogenetictoolswillbeusedin awakemouseandmonkeyV1totestpredictionsgeneratedbythesemodelsandidentifythecorresponding regimes.Theoptogenetictoolsincludeanewviralstrategythatdirectsexpressionofdifferentopsinsto inhibitoryvs.excitatoryneocorticalneuronsinthemacaque.SimultaneousandindependentactivationofEand Iandthevisualstimulus,allwithinthistheoreticalframework,willenableustotestwhetherobserved differencesinsummationpropertiesreflectfundamentalspeciesdifferencesorreflectacommoncomputation operatingindifferentparameterregimes.
Aim2 :Determinethecircuitelementscontrollingdynamicsof corticalnetworkresponsesusingdynamicoptogeneticstimulation.InthisAim,experimentsusing dynamicoptogeneticandvisualstimulationpatternsandtheoreticalanalysisofthemodelswithdynamicinputs willbeusedtoelucidatethetemporaldynamicsofsummation.
Aim3 :Determineifdifferentinhibitory subclassescontroldifferentaspectsofinputintegration.Differentinhibitorysubclasseswillbestimulated optogeneticallytodeciphertheirrespectiverolesininputsummation.Takentogether,theseAimswillhelp definetherolesplayedbyexcitatoryandinhibitoryneuronsinmediatingsummationofneuronalinputstoyield spikingoutput.Thisinformationwillbecriticalforunderstandingbraindisordersassociatedwithfailuresin perceptionandattention,asisseenwithautism,schizophrenia,andAlzheimer?sdisease.

Public Health Relevance

PublicHealthRelevance Despitetheenormouscomplexityofthebrain,itisbecomingincreasinglyapparentthatstructureslikethe cerebralcortexaremodular,relyingonasetofcanonicalcomputationsthatareusedindifferentbrainregions andacrossawiderangeofscalestomediateperception,cognitionandbehavior.Theproposedexperiments willuseacombinationofneuralnetworkcomputationalmodels,theoptogeneticmanipulationofspecificcell typeswithinneuralcircuits,andneurophysiologicalanalysesinthebehavingmouseandmonkeyto understandonesuchcanonicalcomputation:thetransformationofmultipleneuralinputsintospikingoutput. Thisinformationwillbecriticalforunderstandingbraindisordersassociatedwithfailuresinperceptionand cognition,asisseenwithautism,schizophrenia,andAlzheimer?sdisease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS108683-01
Application #
9615853
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
David, Karen Kate
Project Start
2018-09-30
Project End
2021-06-30
Budget Start
2018-09-30
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037