Here we study how intrinsically photosensitive retinal ganglions cells (ipRGCs) initiate neuronal signaling in the developing retina. Recently, it has been demonstrated that light alters the properties of the early spontaneous activity of the retina, called retinal waves, before rod and cone photoreceptors develop their light responses. The light-dependent modulation of retinal waves requires the ipRGC-specific photopigment melanopsin. Since retinal waves are critical for proper development of visual neural circuits, ligh activation of ipRGCs might play a role in the development of the visual system. In order to understand how ipRGCs influence retinal waves it is necessary to elucidate the neural circuits underlying ipRGC intra-retinal signaling. This proposal will reveal the neural circuits relevant fo ipRGC intra-retinal signaling, their modulation by retinal waves, and their role in generating earl light responses. When the circuits generating retinal waves are disrupted IpRGCs affect retinal activity more strongly. During the first postnatal week cholinergic circuits generate waves. During cholinergic waves, light activation of ipRGCs leads to a small increase in the duration of retinal waves but has no effect on their frequency. If cholinergic signaling is blocked, pharmacologically or genetically, the retina generates compensatory waves that depend on gap junction networks. During compensatory waves, light activation of ipRGCs dramatically increases the frequency of retinal waves. The proposed research will elucidate the mechanisms by which sustained blockade of cholinergic signaling enhances ipRGC intra-retinal signaling. Our proposal aims to investigate the functional and anatomical basis of ipRGC intra-retinal signaling.
In aim 1 we will combine optical and electrophysiological techniques with pharmacology to demonstrate that ipRGCs signal to subsets of neurons within the retina through gap junctions.
In aim 2 we will use gap junction tracers to identify the organization of tracer-coupled networks of ipRGCs.
In aim 3 we will combine optical techniques, and pharmacology to test how ipRGC intra-retinal signaling influences light responses in the developing retina. In all aims we will disrupt retinal waves and determine how this alters the different properties of ipRGC intra-retinal signaling. Several adult functions, physiological and behavioral, have been associated with ipRGCs, including sleep/wake cycles and the pupillary light reflex. In developing animals, ipRGCs are implicated in light- avoidance behavior, and the development of the eye vasculature. This project will address the role of ipRGCs and their associated retinal circuits in generating light responses during development. Understanding the details of ipRGC intra-retinal signaling might change the way we think ipRGCs act in the retina to influence the visual system both in the adult and during development.

Public Health Relevance

Light detection through intrinsically photosensitive retinal ganglions cells (ipRGCs) is implicated in critical aspects of human physiology. Specifically, ipRGCs detect ambient light to regulate sleep and wake cycles and hormonal levels, which if altered cause pathologies such as sleep disorders and depression. The proposed research aims to reveal how ipRGCs use neural circuits to encode light detection in the developing retina and will help us understand how light influences human physiology and development.

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