The goal of this proposal is to dissect and understand functional neural circuits in the mammalian retina, with a focus on the newly identified glutamatergic amacrine cell (GAC) circuit. The proposed studies are based on our recent finding of unconventional glutamatergic synaptic transmission from GACs to specific ganglion cell types (Lee et al. Neuron, 2014). This finding suggests intriguing neuronal circuits of GACs and new forms of visual computation in the inner retina. Although little is currently known about the GAC circuitry, several distinct advantages of the GAC system in the mouse retina present a rare opportunity for us to investigate (1) how a defined amacrine cell type makes functional connections with its upstream input neurons, (2) how this cell type responds to and processes visual inputs, and (3) how this cell type forms synaptic circuits with downstream target neurons and contributes to visual computation in the inner retina. Being an excitatory (and potentially dual excitatory/inhibitory) amacrine cell type, GACs also provide a unique opportunity for us to investigate the possibility of new forms of co-neurotransmission and test new theories of amacrine cell function in the retina. The proposed studies will address the above questions using a combination of electrophysiology, two-photon imaging, optogenetics, and chemogenetics in a powerful wholemount retinal preparation of a transgenic mouse line in which GACs can be specifically identified and genetically manipulated. The ability to integrate these advanced techniques in a set of carefully designed experiments will allow us to obtain detailed physiological, neurochemical, and circuit information about the GAC network at a level unattainable by other experimental approaches. The proposal will pursue three specific aims: (1) understand the cellular and dendritic response properties of GACs, (2) understand the connectivity and the function of the GAC output circuit, and (3) understand the functional inputs from bipolar cell types to GACs. Results from these studies are expected to provide novel insights into both the connectome and the physiology of a novel retinal circuit and shed important light on retinal circuitry and retinal function in health and disease.

Public Health Relevance

The proposed research is directly relevant to public health, because the results of the studies are expected to provide new insights into neuronal connections and functions in the human retina, which are important for a wide range of neural diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY026065-03
Application #
9392173
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Greenwell, Thomas
Project Start
2015-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520