In mammals, many physiological systems demonstrate endogenous rhythmic patterns. Under normal environmental conditions many of these intrinsic rhythms are entrained, very early in development, by the light-dark cycle resulting in a 24 hour, or circadian rhythmicity. Much evidence suggests that the pineal hormone melatonin, an indoleamine derived from serotonin, is responsible for transducing photic information into physiological responses. Melatonin can alter the phase of the endogenous melatonin rhythm itself, sleep-wake patterns, reproductive cycles, and has been used to alleviate jet lag and treat seasonal affective disorder(s). The pineal melatonin rhythm is generated by a circadian clock which likely resides in the superchiasmatic nucleus (SCN) of the hypothalamus, and which receives photic information directly from the retina. Recent evidence suggests that aging reduces the plasticity of the entrainment process. The biochemical and molecular events involved in age-dependent loss of rhythm and rhythmic plasticity, however, have not been characterized. The physiological effects of melatonin are transduced by a specific melatonin receptor; interestingly, the SCN contains high levels of melatonin receptors, implying a feedback loop between signals generated in the SCN and hormonal output from the pineal. We propose to investigate the distribution, biosynthesis and regulation of melatonin receptors as a function of circadian period and aging. Specifically, we will: 1)Isolate molecular clones encoding melatonin receptors and generate antisera specific for those receptors. Using these reagents, we will define the anatomical profile of melatonin receptor mRNA and protein. 2)Determine the distribution of SCN cells expressing melatonin receptors as a function of circadian cycle. 3)Using inbred mice deficient in melatonin production, and mice that have a demonstrable circadian cycle, characterize high affinity SCN melatonin binding sites. Determine whether these sites demonstrate circadian rhythmicity and investigate the underlying molecular and cellular mechanisms. 4)Investigate the effects of aging on the regulation of melatonin receptor biosynthesis, distribution, density, pharmacology, and the effects of aging on these characteristics during the circadian cycle.
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