Properties and Mechanisms of Melanopsin Photoreception

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M1 ipRGCs are ocular neurons that sense light directly, using a G-protein coupled receptor called melanopsin, and indirectly, through synaptic inputs from retinal circuitry. Unlike the classical rod and cone photoreceptors, which use graded voltages to signal locally within the retina, these cells generate electrical spikes and send them directly to over a dozen brain areas. Moreover, they are specialized for "non-image" visual functions such as circadian regulation, hormonal control, and pupillary constriction. These functions respond to the overall intensity of environmental illumination, or irradiance. Much remains unknown about how M1 ipRGCs sense light for non-image vision. The overarching hypothesis of this proposal is that their intrinsic and synaptic mechanisms are specialized for irradiance encoding—which benefits from slow and integrative responses— even as they couple to the rapid events that generate spikes. We will identify M1 ipRGCs using techniques that preserve their extrinsic and intrinsic drives, and employ a combination of electrophysiological, optical, pharmacological, and molecular-genetic strategies that allow systematic and quantitative analysis in vitro. M1 ipRGCs are linked to several aspects of human health. For example, they are crucial regulators of the circadian clock, whose dysregulation is implicated in mental illness, cancer, obesity, and other ailments. Through a rigorous investigation of M1 ipRGC function, our research has the potential to reveal systems that maintain health, are compromised in disease, and may be targeted for treatment.