The Role of a Novel Population of Intrinsically Photosensitive Retinal Ganglion Cells in the Dorsal Retina

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Project Summary Modern technological changes have lead to circadian misalignment in large portions of the population. This has resulted in increased rates of metabolic, sleep, and mood disorders. The dysfunction is due to the vast range of biological clocks that regulate many aspects of physiology. Entrainment of these clocks is achieved through the light and dark of the day- night cycle sensed by a unique class of photoreceptors in the retina referred to as the intrinsically photosensitive retinal ganglion cells (ipRGCs). Distinct from the rod and cone photoreceptors, which underlie the majority of visual perception, ipRGCs form direct connections to non-visual areas of the brain and exercise bio-synchronous control over many hormonal and neuronal aspects of body function. ipRGC-mediated light/dark entrainment is important for health maintenance and interruptions can lead to endogenous clock dysregulation. This significant health burden demonstrates a clear need for methods of circadian realignment and maintenance. IpRGCs are responsible for encoding changes in ambient light across the entire retina but are far more complex than originally anticipated. Though they only make up 2-5% of the RGC population in the eye, ipRGCs are diverse, consisting of at least 6 distinct subpopulations that project to more than 30 discrete brain regions. While each of these classes express melanopsin, they are thought to have distinct downstream signal transduction pathways. Therefore, each subpopulation is extracting, encoding, and projecting different aspects of visual information in order to influence a separate collection of light-driven behaviors. The specific functional roles of the majority of ipRGC subpopulations remain unclear. To address this shortcoming we will investigate a previously undescribed subpopulation of ipRGCs present only in the dorsal hemisphere of the retina. These ventral-coding ipRGCs express Cre under control of the glycine transporter and are immunopositive for melanopsin and GABA. Their distribution and neurotransmitter type are characteristics that are thus far unique among RGCs. Our goal is to understand their functional sensitivity, central connectivity, and signal transduction pathways. I will do this using electrophysiology in isolated preparations of retina, Cre-dependent viral tracing, and novel photochemical tools. We hypothesize that this dorsally located subpopulation of ipRGCs extract, encode, and project information differently from the greater ipRGC population. This will be the first study describing this novel neuronal population and will serve to generate techniques that can be applied to future investigations in the retina and brain. Artificial light contributes to interference of the biological clocks through the function of the ipRGCs. However, the distribution and inhibitory neurotransmission of this novel subpopulation may suggest that location of light within the visual field is important for regulation. The clinical relevance of this information may lead to location-based methods of realignment in patients suffering from circadian derangements.