Visionrequiresthepreciseorganizationandfunctionofneuronalcircuitsintheretina.Our overallgoalhereistoadvancethebasicunderstandingofthecellularmechanismsthat regulatetheformationandthemaintenanceofsynapticconnectionsinthemammalian retina.Likeelsewhereinthenervoussystem,signalsnotonlyconvergeontoindividual neurons from multiple input types, but signals from an individual neuron are also distributed across multiple targets. Together, these two basic motifs of synaptic connectivity, convergence and divergence, underlie the complex but highly organized processing of neuronal information. Our knowledge of the mechanisms that sculpt stereotypicpatternsofconvergenceisexpanding.Incontrast,ourunderstandingofhow divergenceisshapedduringdevelopmentanddisruptedinneurodegenerativeconditions isscarce.Tofillthisgapinknowledge,wewillfocusontheAIIamacrinecellcircuitrythat is integral to the rod pathway, which is responsible for scotopic vision. This circuit will enableustogaininsightintothedevelopmentalmechanismsthatorganizeanexquisite arrangementofsynapticdivergenceatasinglesynapse(Aim1),aswellasmechanisms that distribute synapses from a single cell in a biased but consistent manner across distinct targets (Aim 2). We will use a combination of novel imaging approaches, electrophysiologyandtransgenicanimalsto:
(Aim1) Determinethecellularmechanisms thatorganizesynapticdivergenceattherodbipolarcell-AII/A17amacrinecelldyad,and ascertainthefactorsthatleadtodisruptionofthissynapseafterneurodegenerationdue toariseinintraocularpressure(IOP),and:
(Aim2) Determinethecellularprocessesthat shape output connections of AII amacrine cells onto bipolar cells and ganglion cells during normal development, and identify the processes that disrupt these connections upon IOP elevation. Together, our findings will greatly advance knowledge of the mechanismsresponsibleforprecisionincircuitassembly,aswellasoffernewknowledge ofhowthisprecisionbecomesalteredinconditionsofneuronaldegeneration.
Theproperfunctioningofcircuitsinthenervoussystemrequirestheassemblyand maintenanceofprecisewiringpatternsofneurons.Thebroadgoalsofthisprojectareto improveourunderstandingofthecellularmechanismsthatareresponsibleforcircuit developmentinthevertebrateretinaandtoadvanceknowledgeofhowretinalcircuits becomedisruptedinconditionsofneuronaldegeneration.
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