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。昼夜节律计时系统的相位和习惯性就寝时间之间的不一致似乎是导致这种中断的主要因素。改善老年人的睡眠质量和昼夜节律组织的治疗将对我们人口中这一不断增长的部分的健康和福利产生重大的积极影响。 一种治疗方法是定时给予松果体激素，褪黑激素。褪黑激素管理改善睡眠的年轻人。已经提出褪黑激素的睡眠促进作用。褪黑激素管理改善睡眠的年轻人。已经提出，褪黑激素的睡眠促进作用是由于褪黑激素能够使下丘脑的视交叉上核（SCN）中的生物钟产生的广泛促进信号沉默。使用褪黑激素作为与衰老相关的失眠的治疗需要衰老的大脑，特别是衰老的SCN，保持对褪黑激素的敏感性。本研究将评估老化SCN对褪黑激素的敏感性，并探讨褪黑激素在SCN中的作用机制。具体而言，将使用尸检时收集的脑标本研究人SCN中褪黑激素受体的密度作为年龄的函数。将使用动物模型来研究褪黑激素在老化中影响SCN功能的功效的改变。将证明小鼠SCN中褪黑激素受体的发育和年龄相关的改变，然后检查褪黑激素抑制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对褪黑激素保持敏感性，因此是评估褪黑激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.