MELATONIN RECEPTORS IN AGING SUPRACHIASMATIC NUCLEUS

随着年龄的增长，睡眠和昼夜节律会受到干扰。昼夜节律系统的阶段和习惯性就寝时间之间的不一致似乎是造成这种破坏的主要因素。一种改善老年人睡眠质量和昼夜节律组织的治疗方法，将对这一日益增长的人群的健康和福利产生重大而积极的影响。一种治疗方法包括定时给药松果体激素，褪黑激素。服用褪黑素可以改善年轻人的睡眠。有人提出褪黑素对睡眠的促进作用。服用褪黑素可以改善年轻人的睡眠。有人提出，褪黑素的促进睡眠作用是由于褪黑素能够抑制下丘脑视交叉上核（SCN）生物钟产生的促宽信号。使用褪黑素治疗与衰老有关的失眠需要老化的大脑，特别是老化的SCN，保持对褪黑素的敏感性。当前项目的研究将评估衰老的SCN对褪黑素的敏感性，并将研究褪黑素在SCN中的作用机制。具体来说，人类SCN中褪黑激素受体的密度将被研究为年龄的函数，使用在尸检中收集的大脑标本。动物模型将用于研究褪黑激素在衰老过程中对SCN功能影响的改变。小鼠SCN中褪黑激素受体的发育和年龄相关改变将被证明，随后将检查褪黑激素抑制SCN电活动的能力，作为年龄和褪黑激素受体密度的函数。褪黑激素与其他能够重置SCN生物钟的药物的相互作用，以及褪黑激素改变电活动的机制将在体外进行研究。这些研究将确定衰老的大脑是否保留对褪黑素的敏感性，因此是评估褪黑素治疗老年人睡眠和昼夜节律紊乱的潜力的总体目标的必要组成部分。

Disruption of sleep and circadian rhythms occurs with aging. Misalignment between the phase of the circadian timing system and habitual bedtime appears to be a major factors contributing to this disruption. A treatment producing improvement in sleep quality and circadian organization in the elderly would have a significant, positive impact on the health and welfare on this growing segment of our population. One avenue of treatment involves timed administration of the pineal hormone, melatonin. Melatonin administration improves sleep in young people. It has been proposed that the sleep promoting effects of melatonin. Melatonin administration improves sleep in young people. It has been proposed that the sleep-promoting effects of melatonin are due to melatonin's ability to silence a wide-promoting signal generated by the biological clock in the suprachiasmatic nuclei (SCN) of the hypothalamus. The use of melatonin as a treatment for aging-related insomnia requires that the aging brain, and particularly the aging SCN, retains sensitivity to melatonin. Studies in the current project will assess sensitivity of the aging SCN to melatonin,a nd will investigate the mechanisms of melatonin action in the SCN. Specifically, the density of melatonin receptors in the human SCN will e studied as a function of age, using brain specimens collected at autopsy. An animal model will be used to study alterations in melatonin efficacy in influencing SCN function in aging. Developmental- and age-related alterations in melatonin receptors in the mouse SCN will be demonstrated, followed by examination of the ability of melatonin to suppress SCN electrical activity as a function of age and melatonin receptor density. The interaction of melatonin with other agents capable of resetting the SCN circadian clock, and the mechanisms by which melatonin alters electrical activity will be examined in vitro. These studies will determine whether the aging brain retains sensitivity to melatonin, and thus are a necessary part of the overall objective of assessing the potential of melatonin to treat sleep and circadian disorders in the elderly.