We have identified a novel photoreceptor of the mammalian retina, a rare retinal ganglion cell (RGC) that directly innervates the circadian pacemaker of the hypothalamus. These intrinsically photosensitive RGCs (ipRGCs) respond to light even when synaptically isolated from other retinal neurons. They contain the novel opsin photopigment melanopsin. They exhibit lower sensitivity and more sluggish kinetics than rods and cones. Their remarkably tonic light responses encode ambient light levels. Besides their key role in circadian synchronization, these cells form a specialized retinal output channel that signals integrated retinal irradiance and drives a variety of 'non-image-forming'visual reflexes such as the pupillary light reflex, seasonal adaptations in physiology, photic inhibition of nocturnal melatonin release, and modulation of sleep, alertness and activity. We propose the first direct investigation of whether ipRGCs, like rods and cones, exhibit light and dark adaptation, adjusting their sensitivity according to current or recent light exposure. Such adaptation greatly extends the dynamic range of rods and cones so that together they encompass the full spectrum of physiological light levels. Adaptation appears weak or absent in some 'non-image-forming'visual responses. While this might suggest a lack of adaptation in ipRGCs, some behavioral evidence and our preliminary electrophysiological data suggest that ipRGCs do adapt under some conditions. Characterizing adaptation in these cells is a critical step in advancing our understanding of circadian photoreception and other non- image-forming photic systems. We will make intracellular recordings of ipRGC responses to light after manipulating prior light exposure. We will assess the magnitude, time course and spectral dependency of any adaptation. We will also determine whether these occur within the photoreceptor itself, altering the gain of the phototransduction cascade, or whether they require interactions with other retinal cells. The studies will also determine whether ipRGCs sensitivity is under circadian control. The findings will advance our understanding of the functional organization of a novel photosensory system in the mammalian retina with well-defined roles in circadian timing and other homeostatic functions related to ambient illumination and the solar cycle.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017137-05
Application #
7756613
Study Section
Special Emphasis Panel (ZRG1-CB-G (02))
Program Officer
Greenwell, Thomas
Project Start
2006-02-01
Project End
2011-09-29
Budget Start
2010-02-01
Budget End
2011-09-29
Support Year
5
Fiscal Year
2010
Total Cost
$300,154
Indirect Cost
Name
Brown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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Renna, Jordan M; Chellappa, Deepa K; Ross, Christopher L et al. (2015) Melanopsin ganglion cells extend dendrites into the outer retina during early postnatal development. Dev Neurobiol 75:935-46
Lucas, Robert J; Peirson, Stuart N; Berson, David M et al. (2014) Measuring and using light in the melanopsin age. Trends Neurosci 37:1-9
Weng, Shijun; Estevez, Maureen E; Berson, David M (2013) Mouse ganglion-cell photoreceptors are driven by the most sensitive rod pathway and by both types of cones. PLoS One 8:e66480
Van Hook, Matthew J; Wong, Kwoon Y; Berson, David M (2012) Dopaminergic modulation of ganglion-cell photoreceptors in rat. Eur J Neurosci 35:507-18
Renna, Jordan M; Weng, Shijun; Berson, David M (2011) Light acts through melanopsin to alter retinal waves and segregation of retinogeniculate afferents. Nat Neurosci 14:827-9
Van Hook, Matthew J; Berson, David M (2010) Hyperpolarization-activated current (I(h)) in ganglion-cell photoreceptors. PLoS One 5:e15344
Berson, David M; Castrucci, Ana Maria; Provencio, Ignacio (2010) Morphology and mosaics of melanopsin-expressing retinal ganglion cell types in mice. J Comp Neurol 518:2405-22
Weng, Shijun; Wong, Kwoon Y; Berson, David M (2009) Circadian modulation of melanopsin-driven light response in rat ganglion-cell photoreceptors. J Biol Rhythms 24:391-402
Isayama, Tomoki; O'Brien, Brendan J; Ugalde, Irma et al. (2009) Morphology of retinal ganglion cells in the ferret (Mustela putorius furo). J Comp Neurol 517:459-80

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