RUI: Opioid Modulation of Circadian Rhythms

将动物行为组织成24小时或昼夜节律周期是哺乳动物神经系统的基本特征。哺乳动物体内似乎有许多生理系统能够产生自己的24种节奏，尽管每一种节奏都可能由大脑中的一个主计时起搏器同步。这个主起搏器位于一组组织成视交叉上核的细胞中，在哺乳动物大脑底部的视交叉上方发现。视交叉上核接受来自多个大脑区域的输入，但主要的输入来自视网膜、丘脑的膝状体间核和脑干的中缝核。生物钟的时间可以通过来自这些区域中的每一个的输入来调整，类似于在时间上向前或向后移动时钟的指针。 在这项研究中，我们将集中在输入从膝状体小叶，输入调整时钟响应于行为刺激独立的光信息到达视网膜。在仓鼠中，向视交叉上核的膝状体间输入部分由内源性脑啡肽阿片系统介导，并且可以通过施用激活脑啡肽受体（δ阿片受体）的δ阿片药物来模拟。仓鼠的昼夜节律可以通过在新的轮子上跑步来改变，也可以通过苯二氮卓类药物和类阿片肽药物来改变。这些刺激中的每一种都涉及膝状体间核，因此可能由δ阿片受体介导。因此，本项目将研究δ阿片受体与跑步行为和苯二氮卓类药物对昼夜节律的改变之间的联系。这个项目的结果将加强我们对视交叉上核如何整合来自不同大脑区域的信息以确定时钟时间如何调整的理解。该项目还将大大加强对理科本科生的培训，其中许多人正计划从事理科教师的职业。

The organization of animal behavior into twenty-four hour, or circadian, rhythmic cycles is a fundamental feature of the mammalian nervous system. There appear to be many physiological systems within mammals that are capable of generating their own twenty-four rhythms, although each is probably synchronized by one master time-keeping pacemaker within the brain. This master pacemaker is located in a group of cells organized into the suprachiasmatic nucleus, found just above the optic chiasm at the base of the mammalian brain. The suprachiasmatic nucleus receives input from multiple brain regions, but the major inputs come from the retina, intergeniculate nuclei of the thalamus, and the raphe nuclei in the brainstem. The timing of the circadian clock can be adjusted by input from each of these areas, analogous to moving the hands of the clock forward or backward in time. In this study, we will be focusing on input from the intergeniculate leaflet, input that adjusts the clock in response to behavioral stimuli independent of photic information arriving from the retina. In hamsters, intergeniculate input to the suprachiasmatic nucleus is mediated in part by endogenous enkephalin opioid systems and can be mimicked by administration of delta opioid drugs that activate the receptors for enkephalins (delta opioid receptors). Circadian rhythms in hamsters are modified by running in novel wheels, and also by the administration of benzodiazepines and serotonin-like drugs. Each of these stimuli involves the intergeniculate nuclei and thus may be mediated by delta opioid receptors. Therefore, this project will examine the connection between delta opioid receptors and the modification of circadian rhythms by running behavior and benzodiazepines. The results of this project will enhance our understanding of how the suprachiasmatic nuclei integrates information from various brain regions in determining how the time of the clock will be adjusted. This project will also significantly enhance the training of undergraduate students in the sciences, many of whom are planning a career as science teachers.