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)
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
Project End
Budget Start
Budget End
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
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
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
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
Lee, Seunghoon; Kim, Kyongmin; Zhou, Z Jimmy (2010) Role of ACh-GABA cotransmission in detecting image motion and motion direction. Neuron 68:1159-72
Zhou, Z Jimmy; Lee, Seunghoon (2008) Synaptic physiology of direction selectivity in the retina. J Physiol 586:4371-6
Lee, Seunghoon; Zhou, Z Jimmy (2006) The synaptic mechanism of direction selectivity in distal processes of starburst amacrine cells. Neuron 51:787-99