Past work under this grant documented the existence of a peculiar type of mammalian ganglion cell that functions as an autonomous photoreceptor. These intrinsically photosensitive retinal ganglion cells (ipRGCs) use the invertebrate-like photopigment melanopsin. They encode ambient light intensity and help to drive various reflexive responses to daylight, such resetting the circadian clock and adjusting pupil diameter. Much of the work in the next grant period is inspired by two surprising lines of pilot evidence. First, we now believe that there is at least one additional type of intrinsically photosensitive ganglion cell. Second, we have evidence that signals from ganglion-cell photoreceptors propagate not only to the non-image-forming visual networks of the brain, but also within the eye itself to other retinal neurons. Targets appear to include certain ganglion cells and dopaminergic amacrine (DA) cells. The influence of ipRGCs on DA cells is apparently reciprocated, and we will study the mutual interactions between these cells in detail. DA cells and ipRGCs are further linked by the fact that both stratify in the same OFF sublamina of the IPL, yet receive a paradoxical synaptically driven ON input of unknown origin. Here, we will work to identify a neural circuit that could account for this input.
The specific aims of the proposal are: 1) to characterize the structure and function of a new type of ganglion-cell photoreceptor;2) to characterize the inputs to ipRGCs from dopaminergic amacrine cells and ON bipolar cells; and 3) to characterize the influences of ipRGCs on dopaminergic amacrine cells and other retinal neurons. These studies extend our understanding of the photoreceptive capacity that persists in human outer retinal degenerations such as retinitis pigmentosa. They also bear on fundamental mechanisms of circadian and adaptational modulation of retinal function. Project Narrative This project is to study the structure and function of specialized retinal cells that can independently detect light and regulate the biological clock, the amount of the hormone melatonin in the bloodstream, and the size of the eye's pupil. We want to explore the possibility that there are more varieties of such cells than previously recognized and to understand the reciprocal interactions between these cells and other retinal neurons. Because of the key role these cells play in the body's responses to daylight, these studies are relevant to such public health issues as jet lag, seasonal affective disorder, circadian disruption in the blind, and the negative consequences of shift work including impaired performance, increased risk of injury and even elevated cancer rates.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012793-13
Application #
8304879
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Greenwell, Thomas
Project Start
2000-02-07
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
13
Fiscal Year
2012
Total Cost
$477,550
Indirect Cost
$173,167
Name
Brown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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
Dhande, Onkar S; Estevez, Maureen E; Quattrochi, Lauren E et al. (2013) Genetic dissection of retinal inputs to brainstem nuclei controlling image stabilization. J Neurosci 33:17797-813
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
Osterhout, Jessica A; Josten, Nicko; Yamada, Jena et al. (2011) Cadherin-6 mediates axon-target matching in a non-image-forming visual circuit. Neuron 71:632-9
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
Ecker, Jennifer L; Dumitrescu, Olivia N; Wong, Kwoon Y et al. (2010) Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision. Neuron 67:49-60
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
Dumitrescu, Olivia N; Pucci, Francesco G; Wong, Kwoon Y et al. (2009) Ectopic retinal ON bipolar cell synapses in the OFF inner plexiform layer: contacts with dopaminergic amacrine cells and melanopsin ganglion cells. J Comp Neurol 517:226-44
Graham, Dustin M; Wong, Kwoon Y; Shapiro, Peter et al. (2008) Melanopsin ganglion cells use a membrane-associated rhabdomeric phototransduction cascade. J Neurophysiol 99:2522-32
Zhang, Dao-Qi; Wong, Kwoon Y; Sollars, Patricia J et al. (2008) Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons. Proc Natl Acad Sci U S A 105:14181-6

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