Circadian clocks generate daily biological rhythms that provide adaptive advantage to organisms by allowing them to anticipate and prepare for regular daily changes in their environment, such as changes of light intensity between day and night. The retina contains multiple circadian clocks located in a variety of retinal cell types, including amacrine, ganglion, photoreceptor, Muller, and retinal pigment epithelial (RPE) cells. These clocks fine tune visual processing and generate a circadian rhythm of sensitivity to photo-oxidative stress. The molecular basis of circadian clocks involves transcriptional-translational feedback loops that uses a conserved set of clock gene products, most of which function as transcription factors. At the core of the clockwork mechanism is BMAL1, a transcription factor that is required for circadian rhythms. CLOCK and NPAS2 are homologous circadian proteins with overlapping roles in the feedback loops. Either can heterodimerize with BMAL1 to drive circadian rhythms, but the relative contributions of CLOCK and NPAS2 to retinal circadian oscillators have not been explored? In addition, the mechanisms whereby diverse retinal clocks are entrained to the light-dark cycle and are synchronized to regulate retinal function are still unclear. Dopamine (DA) is a circadian neuromodulator that optimizes retinal physiology for bright light, high-resolution vision during the daytime. Our hypothesis is that DA synchronizes circadian clocks in distinct retinal cell types that modulate visual processing and sensitivity to photo-oxidative stress via specific DA receptors. We also hypothesize that CLOCK plays a primary role in the circadian rhythms of photopic ERG and sensitivity to light-induced retinal degeneration, while NPAS2 and CLOCK both contribute the rhythm of contrast sensitivity. Using established genetic models and novel mouse models in which DA and specific clock genes are depleted selectively from retinal cells by conditional gene disruption, we will test the following three predictions of our hypotheses: (1) Dopaminergic modulation of contrast sensitivity involves retinal neurons via dopamine D4 receptor (D4R) - mediated regulation of cAMP signaling and circadian oscillators that involve both CLOCK and NPAS2. (2) Circadian rhythms of photopic ERG amplitudes are modulated by DA effects on photoreceptors via D4Rs, cAMP, and oscillators that utilize CLOCK but not NPAS2. (3) DA protects photoreceptors against photo-oxidative stress via D4Rs on photoreceptors and via dopamine D5 receptors (D5Rs) and dopamine D2-like receptors on RPE cells by modulating a CLOCK-dependent circadian rhythm of susceptibility to light damage. The proposed research is significant because it will to provide clearer understanding of the organization of retinal circadian clocks and the mechanisms of circadian physiology that underlie healthy vision. This in turn will lead to novel approaches for the treatment of retinal degenerative diseases.

Public Health Relevance

Modern society exposes us to light at night, which disrupts our bodies'circadian rhythms and may predispose us to blinding retinal disorders. This research investigates how retinal neuromodulators regulate natural circadian rhythms to provide high-resolution vision and protection from environmental or endogenous stressors that may contribute blinding diseases such as age-related macular degeneration (AMD). This study will increase our understanding of the risks to our visual health of circadian disruption and may lead to development of novel therapeutic approaches for AMD and other retinal degenerative diseases.

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Greenwell, Thomas
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Emory University
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