F. M. Kirby Neurobiology Center | Boston Children's Hospital | Harvard Medical School
We take a biophysical approach to investigating the mammalian visual system, primarily by applying electrophysiological and optical techniques to in vitro neural tissue. We focus on two circuits that serve distinct functions. By comparing these circuits within and across species, we gain insight into mechanisms that are shared and those that are diversified to serve distinct needs.
The first circuit employs unusual photoreceptors; these are not the classical rods and cones, but rather a population of retinal output neurons that capture light with a molecule called melanopsin. These intrinsically photosensitive retinal ganglion cells (ipRGCs) drive "non-image" visual functions such as the regulation of sleep, circadian rhythms, and hormone levels. We study the mechanisms of signal generation by melanopsin cells and interpret these signals within the context of downstream circuits in the retina and brain.
The second circuit is a specialization of the retina called the fovea. The fovea provides a thematic counterpoint to the melanopsin system, as it produces high spatiotemporal resolution in the perception of images. We study the function of individual neurons within the fovea. Although much is known about their structural specializations--for example, their tiny size and close packing allows them to form a high-density pixel array--their functional properties are largely unexplored.
The melanopsin pathway, by serving as the principal regulator of the circadian clock, is responsible for setting the normal pattern of gene regulation throughout the body; circadian dysregulation has been implicated in jet lag, metabolic disorders, cancer, and other ailments. The fovea is destroyed in macular degeneration, the leading cause of blindness in developed nations. Understanding the normal physiology of these systems provides a first step toward maintaining and repairing them.
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Depicted in the image above (left panel) is a cell in the mammalian retina that is unusual in being both a photoreceptor and an output neuron. Here, we have filled one of these intrinsically photosensitive retinal ganglion cells (ipRGCs, the brightest cell in the image) with a soluble tracer. The tracer has diffused into a number of other neurons (small, dimly-labeled cells). The function of this local network is presently unknown. Also shown is an electrophysiological recording from another ipRGC (right panel). The cell fires action potentials in response to a brief pulse of light (light monitor below trace) despite being isolated pharmacologically from the retinal network. The mechanism by which the cell proceeds from photon capture to electrical signaling remains largely unclear. Intriguingly, the mechanism is more typical of invertebrate photoreceptors than vertebrate ones, even though this is a vertebrate cell.