- Thegoalofthisproposalistodeterminetheroleofactivityinthedevelopmentofthecircuitsthat mediatedirectionselectivityintheretina.Directionselectiveganglioncells(DSGCs)firemanyactionpotentials inresponsetolightstimulimovinginapreferreddirectionandfewactionpotentialstolightmovinginthe opposite,ornull,direction.OurlabhasusedpopulationcalciumimagingofDSGCs,whosepreferreddirections tightlyclusteraroundthefourcardinalaxesofvisualspace,toshowthatdeprivinganimalsofvisualexperience reducestheclusteringofpreferreddirections.Dark-rearedadultDSGCswereinsteadbroadlydistributedin theirpreferreddirections,similartoDSGCstuningobservedateyeopening.However,themechanismby whichdark-rearingpreventsclusteringremainsunknown.Thispromptsaninvestigationoftheroleofvisual experienceinthematurationofmechanismsforthedirection-selectivecomputation. There are two important circuit elements for direction selectivity. First, asymmetric release of gamma- aminobutyricacid(GABA)fromstarburstamacrinecellsdendritesconfersdirectionselectivetuningtoDSGCs through asymmetric synaptic wiring. Second, DGSC dendrites integrate inputs in a directional manner. This second mechanism is revealed in a subtype of DSGC, the ventral-preferring DSGCs, which exhibit inhibitory- independentdirectionaltuning,speculatedtoarisefromtheirasymmetricdendrites. In this proposal, I explore the contribution of synaptic and dendritic mechanisms to directional tuning across development. I focus on these ventral-preferring DSGCs to dissect the relative contributions of asymmetric inhibition and asymmetric dendrites to directional tuning during development. Asymmetric inhibitoryinputfromstarburstamacrinecellshasbeenshowntoestablishdirectionaltuninginDSGCsaround thetimeofeye-opening,byformingmoresynapsesonthenullside.Asafirststeptowardsunderstandingthe contribution of synaptic mechanisms for establishing directional tuning, in Aim 1, I will use electrophysiology, pharmacology and cellular reconstructions to examine the contribution of inhibitory input on directional tuning duringdevelopment(Aim1.1,1.2).Next,Iwilltestwhetheractivity,mediatedbyasymmetricinhibitoryinput,is necessary for establishing directional tuning and asymmetric dendrites in a mouse model where that lacks functional GABA release in SACs (Aim 1.3). To understand the contribution of asymmetric dendrites to inhibitory-independent tuning of DSGCs, in Aim 2, I propose to use simultaneous 2-photon calcium imaging and visual stimulation of dendrites. I askwhether active conductances in the dendrites of DSGCs exist, and if so, I propose to use localized pharmacological manipulations uncover the ion channels mediating these nonlinear conductances, across development. Lastly, in Aim 3, I propose to rear animals in the dark to examine how activity, mediated by visual experience, alters both the synaptic physiology and dendritic computation of directional selectivity. These findings will provide key insights into how early signaling in the retinacontributestodevelopmentoffunctionalneuralcircuits.
- Understandingtheroleofsensoryexperienceinthedevelopmentofneuralcircuitsinthebrainisasignificant goalofhumanhealthresearch.Neurodevelopmentalpathologiesofneuralconnectivityanddendriticfunction havebeenlinkedtodiseasessuchasschizophrenia,autismandmentalretardation;?dissectinghowprecise neuralconnectionsarenormallyestablishedinthebrainisnecessaryforourunderstandingofthese pathologies.Inaddition,knowledgeoftheroleofsensoryexperienceinthematurationofneuralcircuitsand cellularcomputationswillaidintheaccuratedesignofneuralprostheticsfortreatingcongenitalandacquired sensorydisordersincludingblindness,deafness,andparalysis.
