A Molecular Toolbox for the Manipulation of Non-Image-Forming Visual Behaviors

The external light environment exerts profound control over a broad range of innate mammalian behaviors outside of image formation, including circadian rhythms, body temperature regulation, sleep, affect, memory, and learning. In mammals, the retina acts as the primary sensor of light and conveys light information to the brain through axonal projections of retinal ganglion cells (RGCs). A subset of RGCs, called intrinsically photosensitive retinal ganglion cells (ipRGCs) comprise a rare and specialized population of photoreceptive neurons that are the sole conduit for light to modulate non-image-forming visual behaviors. This is accomplished through ipRGCs’ unique projection patterns to more than a dozen brain nuclei outside of the classical image-forming system. It is now appreciated that the ipRGC population contains a substantial amount of morphological and physiological diversity and is comprised of at least 6 distinguishable subtypes. Despite these well-characterized differences between ipRGC subtypes, little work has been done to understand the genetic differences that underlie this diversity. Furthermore, though ipRGC projections have been studied extensively, a detailed description of the cellular and molecular architecture of ipRGC-recipient brain regions is currently lacking. Contained in this thesis is a body of work that I have pioneered to investigate the molecular identity of ipRGC subtypes as well as several of their primary central targets. Using a combination of molecular biology, bioinformatics, and mouse genetics, I identified marker genes for ipRGC subpopulations, demonstrated that ipRGCs express a unique and previously unappreciated suite of neuropeptide signaling molecules, generated new genetic tools to facilitate the study of ipRGC-driven behaviors, and curated the first detailed cell-type atlases of ipRGC-recipient brain regions. Elucidating the underlying circuits and key molecular players that regulate non-image-forming behaviors is an important step in understanding light-influenced pathologies including seasonal depression, cognitive impairment, and others. Using insights from these and future studies, we can begin to develop molecular and behavioral interventions to improve health and disease conditions that are adversely affected by light