The goal of this proposal is to understand the synaptic mechanism and neuronal circuitry underlying complex visual processing in the mature mammalian retina, with a focus on the function and organization of individual synapses in the direction selective circuit. The proposed study is based on recent findings that identified critica synaptic interactions underlying the generation of direction selectivity. These findings suggested a previously unappreciated level of synaptic intricacy in the underlying neuronal circuit. They revealed the importance, as well as the possibility, to understand the mechanism of directional computation at a microcircuit level. In order to gain direct knowledge of the function and organization of the direction-selective microcircuits, a novel experimental approach is proposed here, which integrates two-photon imaging, dual patch-clamp recording, spot UV uncaging, and transgenic technology, so that neuronal connectivity and interactions at individual synaptic sites can be measured in an intact retinal network and correlated with the morphological and functional properties of the cells in the same experiment. The proposed experiments are designed to understand (1) the synaptic mechanism of cholinergic transmission in the mature retina, (2) the functional organization of individual cholinergic and GABAergic synapses between starburst amacrine and direction-selective ganglion cells, (3) the functional organization of GABAergic synapses between starburst amacrine cells, and (4) the synaptic interactions at bipolar cell axon terminals. Results from these experiments are expected to provide novel insights into the nature of dendritic and axonal computation at a synaptic level and in an intact retinal circuit. This approach may also provide a novel experimental paradigm for studying the function and connectivity at individual synapses in other CNS circuits.

Public Health Relevance

The proposed research is relevant to public health, because the results of the studies are expected to provide novel insights into the function of the human retina and the mechanism of nicotinic neurotransmission, which is important for a wide range of neural functions and diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017353-09
Application #
8699774
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Greenwell, Thomas
Project Start
2006-05-05
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Xu, Hong-Ping; Burbridge, Timothy J; Ye, Meijun et al. (2016) Retinal Wave Patterns Are Governed by Mutual Excitation among Starburst Amacrine Cells and Drive the Refinement and Maintenance of Visual Circuits. J Neurosci 36:3871-86
Lee, Seunghoon; Zhang, Yi; Chen, Minggang et al. (2016) Segregated Glycine-Glutamate Co-transmission from vGluT3 Amacrine Cells to Contrast-Suppressed and Contrast-Enhanced Retinal Circuits. Neuron 90:27-34
Zhou, Elton K; Xu, Hong-Ping (2015) GABAergic regulation of spontaneous spike patterns in the developing rabbit retina. Neurosci Lett 600:137-42
Kuenzel, Wayne J; Kang, Seong W; Zhou, Z Jimmy (2015) Exploring avian deep-brain photoreceptors and their role in activating the neuroendocrine regulation of gonadal development. Poult Sci 94:786-98
Hafler, Brian P; Klein, Zoe A; Jimmy Zhou, Z et al. (2014) Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice. Brain Res 1588:168-74
Burbridge, Timothy J; Xu, Hong-Ping; Ackman, James B et al. (2014) Visual circuit development requires patterned activity mediated by retinal acetylcholine receptors. Neuron 84:1049-64
Chen, Minggang; Lee, Seunghoon; Park, Silvia J H et al. (2014) Receptive field properties of bipolar cell axon terminals in direction-selective sublaminas of the mouse retina. J Neurophysiol 112:1950-62
Lee, Seunghoon; Chen, Lujing; Chen, Minggang et al. (2014) An unconventional glutamatergic circuit in the retina formed by vGluT3 amacrine cells. Neuron 84:708-15
Ackman, James B; Burbridge, Timothy J; Crair, Michael C (2012) Retinal waves coordinate patterned activity throughout the developing visual system. Nature 490:219-25
Xu, Hong-ping; Furman, Moran; Mineur, Yann S et al. (2011) An instructive role for patterned spontaneous retinal activity in mouse visual map development. Neuron 70:1115-27

Showing the most recent 10 out of 13 publications