We sense light for a diverse array of functions that include regulation of the circadian clock, pupil diameter, hormone levels, and alertness. These non-image visual functions are distinguished from visual perception in that they are insensitive to details in the scene, being driven instead by the absolute level of illumination. Our goal is to understand the basis of these functions in a diurnal species whose visual system has strong homologies with that of humans. We focus on the intrinsically photosensitive retinal ganglion cells (ipRGCs), which respond directly to light using a receptor molecule called melanopsin, while also receiving inputs from rod- and cone-driven pathways. IpRGCs project their axons from the eye to numerous targets in the brain, with their two principal targets being the suprachiasmatic nucleus (SCN), which is the master circadian clock, and the pretectal olivary nucleus (PON), which is a control center for the pupillary light reflex. The clock and pupil exhibi marked, quantitative differences in their light responses. The clock integrates light over many minutes to produce an accurate measurement of overall irradiance, which provides a proxy for time of day; by contrast, the pupil senses light on a time scale of seconds to dynamically regulate the amount of light reaching the retina. Our broad hypothesis is that signaling mechanisms within the ipRGC system are suited to the integrative character of non-image vision in a diurnal mammal, and tuned to specific downstream functions. To test this hypothesis, we will determine the phototransduction mechanisms and spatiotemporal dynamics of ipRGCs that innervate the SCN or PON; furthermore, we will connect these features to the spatiotemporal dynamics of SCN and PON neurons. Our experiments rely on a synergy of in vitro and in vivo neurophysiological techniques. We have established a logistical and technological platform that allows the ipRGC system to be defined in stepwise fashion across multiple levels of biological organization, from photon absorption by melanopsin to the chromatic sensitivities of downstream neurons and behavioral outputs. Our experiments will constitute the first extensive and systematic investigation of the ipRGC system in a diurnal mammal, and will lay the foundation for a precise understanding of links that have been made between dysregulation within this system and human diseases that include cancer, cardiovascular disease, metabolic disorders, psychiatric disorders, and jet lag. The strong commonalities between our model organism and humans make the translational relevance of our research especially direct.
Alignment of the physiological processes of the body with environmental time is crucial for health - misalignment is responsible for the debilitating effects of jet lag and contributes to more serious afflictions such as cancer, psychiatric illness, metabolic disorder, and cardiovascular disease. To a large degree, correct alignment is mediated by specialized cells in the eye that sense light and communicate directly with the brain. These cells are poorly understood, particularly in organisms that parallel humans, and we therefore propose to bridge this gap in knowledge by studying a diurnal mammal.
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| Boye, Shannon E; Alexander, John J; Witherspoon, C Douglas et al. (2016) Highly Efficient Delivery of Adeno-Associated Viral Vectors to the Primate Retina. Hum Gene Ther 27:580-97 |
| Liao, Hsi-Wen; Ren, Xiaozhi; Peterson, Beth B et al. (2016) Melanopsin-expressing ganglion cells on macaque and human retinas form two morphologically distinct populations. J Comp Neurol 524:2845-72 |
| Choudhury, Shreyasi; Strang, Christianne E; Alexander, John J et al. (2016) Novel Methodology for Creating Macaque Retinas with Sortable Photoreceptors and Ganglion Cells. Front Neurosci 10:551 |
| McDougal, David H; Gamlin, Paul D (2015) Autonomic control of the eye. Compr Physiol 5:439-73 |
