BIOLOGICAL RHYTHMS, PLASTICITY AND BEHAVIOR

描述（改编自申请人摘要）： 由正常睡眠-觉醒周期的变化引起的正常昼夜节律功能， 已知不规则的工作模式或各种疾病状况 影响生产力，增加事故风险， 情绪/心理状态。 在开发治疗方法方面的进展 改善昼夜节律性疾病的衰弱作用在于 了解内源性调节的神经学基础 昼夜节律 拟议研究的总体目标是 表征特定细胞表面成分在调节 细胞与细胞之间的相互作用， 下丘脑前部的视交叉上核（SCN）。 的 多聚唾液酸化NCAM（PSA-NCAM）是细胞表面组分，其起关键作用。 在神经发生中起作用，并保留在成人大脑的某些区域， 具有神经可塑性的潜力。 最近的示威活动， SCN细胞的强表达导致了胚胎样细胞的假设， 可塑性形态重排可能对生物钟很重要 功能，例如其每天通过光重置的能力。 的 因此，拟议的研究旨在研究PSA-NCAM的作用 在SCN中使用生物化学、形态学和行为终点。 我们 将利用成年大脑中缺乏PSA-NCAM的转基因小鼠， 在体内特异性地从NCAM中去除PSA的酶（endo N）。 我们将 首先在光学和电子显微镜水平上确定哪些细胞在 SCN表达PSA-NCAM，以及其 表情 然后，我们将评估PSA-NCAM缺失对PSA-NCAM表达的影响。 昼夜运动节律的时间保持特征，包括 节奏产生和夹带。 最后，我们将研究 PSA去除对SCN细胞-细胞相互作用的形态学指标，包括 突触和神经并置的变化。 这些研究的结果将 提供了重要的洞察细胞间通讯的动力学， 哺乳动物SCN生物钟

DESCRIPTION (Adapted from applicant's abstract): Desynchronization of normal circadian functions induced by shifts in 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/psychological 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 proposed studies is to characterize the roles of specific cell surface components in regulating cell-cell interactions within the circadian clock located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The polysialylated NCAM (PSA-NCAM) is a cell surface component which plays key roles in neurogenesis and is retained in regions of the adult brain that have the potential for neural plasticity. The recent demonstration of its robust expression by SCN cells had led to the hypothesis that embryonic-like plastic morphological rearrangements may be important to circadian clock function, such as its ability to be reset on a daily basis by light. The proposed studies, therefore, are designed to study the role(s) of PSA-NCAM in the SCN using biochemical, morphological and behavioral endpoints. We will utilize transgenic mice that lack PSA-NCAM in the adult brain and an enzyme (endo N) that specifically removes PSA from NCAM in vivo. We will first determine at the light- and electron-microscopic levels which cells in the SCN express PSA-NCAM and whether there are daily fluctuations in its expression. We will then assess the effects of PSA-NCAM deletion on time-keeping characteristics of the circadian locomotor rhythm, including rhythm generation and entrainment. Finally, we will examine the effects of PSA removal on morphological indices of SCN cell-cell interaction, including changes in synapses and neural appositions. Results from these studies will provide important insight into the dynamics of cell-cell communication in the mammalian SCN circadian clock.