My long-term goal is to understand the biological basis of visual processing at the level of neural circuits and synapses. I am pursuing this goal in the mammalian retina, where we can efficiently study the tissue's natural function in vitro;and where we have a basic understanding of the cell types that compose the circuits: 3-4 photoreceptors (rods and cones), ~50 interneurons (horizontal, bipolar and amacrine cells), and ~20 output neurons (ganglion cells). A major obstacle to understanding retinal circuitry is the unknown function of the majority of the ~40 types of amacrine cell. These (primarily) inhibitory interneurons play a major role in ganglion cell receptive field computations, but we presently have a fairly detailed understanding of just four types, specialized for rod vision (AII, A17), direction selectivity (starburst) and neuromodulation (dopaminergic). Hypothesized functions for the remaining 30+ types include feature selectivity (e.g., orientation tuning), generation of receptive field surrounds, 'cross-over'inhibition between the ON and OFF pathways, and feed- forward inhibition within either the ON or OFF pathways. However, there are major barriers to understanding the role of amacrine cells in retinal circuitry: we lack the ability to assign specific functions to individual amacrine cell types, and in most cases we do not know a specific cell type's postsynaptic targets and its associated role in network function. To move the field forward, we propose to test between alternative hypothesized functions for novel amacrine cell circuits using an integrated, multidisciplinary approach.
Aim 1 will determine receptive field properties of genetically-identified amacrine cell types by recording Ca signals in their dendrites, the sites of neurotransmitter release.
Aim 2 will determine a specific amacrine cell type's postsynaptic ganglion cell targets using optogenetics.
Aim 3 will determine the functional role of an amacrine cell type in the circuit by measuring how its reversible inactivation affects ganglion cell receptive field properties. The combination of these three approaches will provide major advances over existing methods for studying amacrine cells and should be broadly applicable to the study of neural circuit function throughout the mammalian central nervous system. Furthermore, studying the function of amacrine cells and their interconnections with other retinal neurons will contribute to the long-term goal of developing new diagnoses and treatments (i.e., optogenetic, prosthetic) for eye disease.

Public Health Relevance

Studying the function and organization of healthy retinal circuits will facilitate our understanding of how these circuits are impacted by eye diseases. For example, networks of retinal interneurons, including many types of amacrine cell, are disrupted in mouse models of retinitis pigmentosa and diabetic retinopathy. Furthermore, understanding the role of amacrine cells in retinal processing could facilitate the development of prostheses and optogenetic treatments for eye disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY014454-11
Application #
8631245
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Greenwell, Thomas
Project Start
2002-12-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
11
Fiscal Year
2014
Total Cost
$416,250
Indirect Cost
$166,250
Name
Yale University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Park, Silvia J H; Kim, In-Jung; Looger, Loren L et al. (2014) Excitatory synaptic inputs to mouse on-off direction-selective retinal ganglion cells lack direction tuning. J Neurosci 34:3976-81
Borghuis, Bart G; Looger, Loren L; Tomita, Susumu et al. (2014) Kainate receptors mediate signaling in both transient and sustained OFF bipolar cell pathways in mouse retina. J Neurosci 34:6128-39
Stafford, Benjamin K; Park, Silvia J H; Wong, Kwoon Y et al. (2014) Developmental changes in NMDA receptor subunit composition at ON and OFF bipolar cell synapses onto direction-selective retinal ganglion cells. J Neurosci 34:1942-8
Ke, Jiang-Bin; Wang, Yanbin V; Borghuis, Bart G et al. (2014) Adaptation to background light enables contrast coding at rod bipolar cell synapses. Neuron 81:388-401
Stafford, Benjamin K; Manookin, Michael B; Singer, Joshua H et al. (2014) NMDA and AMPA receptors contribute similarly to temporal processing in mammalian retinal ganglion cells. J Physiol 592:4877-89
Marvin, Jonathan S; Borghuis, Bart G; Tian, Lin et al. (2013) An optimized fluorescent probe for visualizing glutamate neurotransmission. Nat Methods 10:162-70
Beier, Kevin T; Borghuis, Bart G; El-Danaf, Rana N et al. (2013) Transsynaptic tracing with vesicular stomatitis virus reveals novel retinal circuitry. J Neurosci 33:35-51
Borghuis, Bart G; Marvin, Jonathan S; Looger, Loren L et al. (2013) Two-photon imaging of nonlinear glutamate release dynamics at bipolar cell synapses in the mouse retina. J Neurosci 33:10972-85
Demb, Jonathan B; Singer, Joshua H (2012) Intrinsic properties and functional circuitry of the AII amacrine cell. Vis Neurosci 29:51-60
Weick, Michael; Demb, Jonathan B (2011) Delayed-rectifier K channels contribute to contrast adaptation in mammalian retinal ganglion cells. Neuron 71:166-79

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