Circadian Clock Regulation of the Mammalian Retina

We now know that mammals have multiple circadian clocks.  The first clock identified was that of the suprachiasmatic nucleus, shown to regulate behavioral activity.  The next was that of the retina, and more recently circadian clocks have been found in peripheral organs and at various sites in the central nervous system.  In contrast to the SCN clock, the importance of circadian clocks outside the SCN is not yet established for any aspect of physiology in vivo. This issue is of major importance for understanding mammalian physiology.  The general objective of this proposal is to determine the importance in vivo of a non-SCN circadian clock and characterize its functions in molecular terms.  The circadian clock in the mammalian retina provides great advantages for this purpose:  1) many retinal phenomena show circadian regulation, 2) much is known about the retina and the precise physiological roles of its constituent cell types, 3) tools are available that permit selective genetic manipulation of the retina, 4) retinas can be conveniently collected for molecular studies, and 5) electroretinography provides a rapid and informative test of retinal function in living animals.  The specific aims are 1) to determine if circadian clock function is important for retinal responses to light in vivo; 2) to characterize on a comprehensive scale genes regulated in the retina by a circadian clock, light, or both; 3) to determine the contribution of circadian clocks within the retina to retinal responses to light and to rhythms of retinal gene expression; and 4) to determine if circadian clock function within the retina influences the function of the SCN circadian clock in constant darkness. Deeper general understanding of the mammalian circadian system will likely have important implications for human health and disease, particularly with regard to the control of complex physiological systems, such as sleep/wake regulation, fertility, and glucose homeostasis/diabetes.  Detailed knowledge of the circadian biology of the retina will likely provide new insights into retinal physiology and metabolism and pathophysiology of retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration.