NEUROLOGIC REGULATION OF THE SCN CIRCADIAN CLOCK

描述：（申请人的摘要）正常昼夜节律的去极化 模式，由正常睡眠-觉醒周期的变化引起，不规则的工作 模式或各种疾病状况，已知会对 生产力，增加事故的风险和影响情绪状态。 在开发用于改善衰弱的治疗方法方面的进展 昼夜节律的影响在于了解神经系统 调节内源性昼夜节律的基础。 的广泛目标 目前的研究是表征特定的调节作用， 与生物钟相关的神经递质位于 视交叉上核（SCN）。 主要基于药理学和 损伤的研究，单胺递质，5-羟色胺（5-HT），已被 作为一个重要的参与者，在日常的昼夜节律的调节 睡眠-活动周期以及其他昼夜节律。 然而，迄今为止， 内源性5-HT在SCN生物钟中的作用尚未被证实。 直接研究。 这已经成为理解的一个主要缺点。 SCN时钟中5-HT作用的基础生物学。 拟议的研究， 因此，被设计来研究多巴胺能神经元的生理学， 从叙利亚仓鼠的中缝核投射到SCN。 的 具体目标如下：1）表征体内动力学 5-HT在电刺激特异性神经元引起的SCN释放中的作用 中缝核：2）精确操纵中缝核活动，以表征中缝核的活动。 内源性5-HT对光信号传导过程的调节作用 SCN），包括光诱导的即刻早期基因激活和相移 自由活动节律）和时钟相位重置;以及 3)评估SCN区域5-HT释放的24小时曲线， 在光线下自由移动的动物 或暗）条件来确定光环境之间的关系， SCN中的神经状态和肾上腺素能活性。 5-HT发生率 将在活动引起的相移期间测量释放， 特异性确定5-HT是否介导生物钟中非光偏移 相位 这些实验的结果可能会导致战略， 操纵电子能系统以对抗 昼夜节律

DESCRIPTION: (Applicant's abstract) Desynchronization of normal circadian patterns, induced by shifts of the normal sleep-wake cycle, irregular work patterns or various disease conditions, is known to adversely affect productivity, increase the risks of accident and affect emotional state. Progress towards developing treatments for ameliorating the debilitating effects of circadian desynchrony lies in understanding the neurological basis for the regulation of endogenous circadian rhythms. The broad goal of the present studies is to characterize the regulatory roles of specific neurotransmitters associated with the circadian clock located within the suprachiasmatic nuclei (SCN). Based primarily on pharmacological and lesioning studies, the monoamine transmitter, serotonin (5-HT), has been implicated as a major participant in the regulation of the daily circadian sleep-activity cycle as well as other circadian rhythms. To date, however, the action of endogenous 5-HT in the SCN circadian clock has not been directly studied. This has become a major shortcoming in understanding the basic biology of 5-HT action in the SCN clock. The proposed studies, therefore, are designed to study the physiology of the serotonergic projection to the SCN from the raphe nuclei of the Syrian hamster. The specific objectives are as follows: 1) to characterize the in vivo dynamics of 5-HT release in the SCN induced by electrical stimulation of specific raphe nuclei: 2) to precisely manipulate raphe activity to characterize the modulatory effects of endogenous 5-HT on photic signalling processes in the SCN )including light-induced immediate-early gene activation and phase-shift of the free-running activity rhythm) and phase resetting of the clock; and 3) to assess the 24 hour profile of 5-HT release in the SCN region of freely-moving animals under light entrained and free-running (constant light or dark) conditions to determine relationships between photic environment, neurological state and serotonergic activity in the SCN. Rates of 5-HT release will be measured during activity-induced phase shifts to specifically determine if 5-HT mediates non-photic shifts in circadian clock phase. Results from these experiments could lead to strategies for manipulating the serotonergic system to counter the disruptive effects of circadian desynchrony.