In the retina, direction selective ganglion cells fire many action potentials in response to light stimuli moving in a preferred direction and few action potentials to light moving in the opposite direction. Asymmetric release of gamma-aminobutyric acid (GABA) from starburst amacrine cells dendrites is thought to confer this direction selective tuning to direction selective ganglion cells. Starburst amacrine cells have been shown to exhibit a larger increase in Ca2+ in their distal dendrites near GABA release sites during stimulation with light moving from their soma toward the distal dendrites compared with light moving from the distal dendrites toward the soma. The source and consequence of this asymmetry in Ca2+ levels are not well understood. In this proposal, I explore the hypothesis that starburst amacrine cells compute direction autonomously in individual dendrites. How a dendrite integrates its inputs is of broad importance because it is one of the key steps in neuronal signaling in all neurons with multiple inputs. Starburst amacrine cells are distinct from many other cell types because their integration point is located in the distal end of the dendrite rather than at the soma. In addition, in contrast to many other neuron types, the question of how the starburst amacrine cell integrates its inputs is relevant to the known physiological function of the cell sine the order of inputs is directly related to the direction of moving light stimuli. Therefore understanding integration in starburst cell dendrites will contribute directly to our understanding of the role of starburst amacrine cells in the retinal circuit. Using electrophysiology, glutamate uncaging and imaging techniques, I will determine whether an intrinsic non-linearity in the starburst cell dendrites favors bipolar cell inputs arriving sequentially from the soma toward the release sites in the distal dendrites over inputs arriving in the opposite order (Aim 1). In additin, I propose experiments to determine whether the previously observed increase in Ca2+ during stimulation toward distal dendrites leads to an increase in inhibition from starburst amacrine cells onto direction selective ganglion cells (Aim 2). Lastly, I propose experiments to determine the role of voltage-gated Ca2+ channels in establishing the asymmetry in Ca2+ influx and GABA release from starburst amacrine cell dendrites (Aim 3).

Public Health Relevance

Understanding the function of dendrites in the brain is a significant goal of human health research. Pathologies of dendritic function and structure have been linked to diseases such as autism, Alzheimer's disease, neuropsychiatric disorders, and mental retardation;understanding a dendrite's normal role in the brain will contribute to our understanding of these pathologies. In addition, knowledge of normal dendritic computations in sensory systems will aid in the accurate design of neural prosthetics for treating sensory disorders including blindness, deafness, and paralysis.

National Institute of Health (NIH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Stewart, Randall R
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University of California Berkeley
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United States
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