Development Alcohol and Circadian Clock Function

描述(申请人提供)：预计2,000-12,000名婴儿 每年出生时都患有胎儿酒精综合症(Fas)(Stratton等人，1996年)。 迄今为止，Fas在中枢神经系统功能障碍中最令人衰弱的特征是 从结构上讲会一直持续到成年期。然而，关于 这种酒精相关脑损伤的长期神经行为相关性 是有限的。生物钟对大多数身体活动的昼夜节律 视交叉上核(SCN)代表一个受限的区域 关于发育期酒精暴露的后果的信息可用 在人类或动物模型中。子代暴露在重度母体酒精中 据报道，怀孕期间的消费表现出身体机能紊乱。 睡眠-觉醒模式(Rosett等人，1979)。与这一发现一致，我们的 初步研究表明，在第三次饮酒期间 相当于三个月的大鼠昼夜节律发生永久性变化 活动的节奏。因此，本提案中的实验将利用 多学科方法来检查三个方面的长期影响 不同剂量酒精对人体解剖活动昼夜节律的影响， SCN时钟的细胞和分子组织。轮子的图案- 成年大鼠的跑步行为将被评估与酒精相关的变化 基本属性，如昼夜节律周期和节奏幅度。 在此行为分析之后，将评估SCN的证据 一般的细胞丢失和其节律性表达中的扰动 可能的时钟基因，Perl，PER2和Cry2，以及输出信号，加压素 血管活性肠肽与脑源性神经营养 因子(BDNF)。与中枢神经系统不同的是，它参与了大多数 行为，昼夜节律功能的离散定位于SCN 提供了一个独特的机会来确定细胞和分子的相关性 与酒精有关的神经行为障碍。通过确定SCN和 它的昼夜节律功能受到发育期酒精暴露的影响，这些 预计研究将产生关于基本机制的重要信息。 在发育过程中潜在的酒精引起的脑损伤。这样的信息 可能导致治疗已知行为相关性的新策略 Fas与睡眠问题及精神和身体障碍相关 与睡眠-觉醒异常有关。

DESCRIPTION (Provided by applicant): It is estimated that 2,000-12,000 babies are born each year with fetal alcohol syndrome (FAS) (Stratton et al., 1996). By far the most debilitating feature of FAS in CNS dysfunction that results from structure are known to persist into adulthood. However, information on the long-term neurobehavioral correlates of this alcohol-related brain damage is limited. The circadian regulation of most body processes by the clock in the suprachiasmatic nucleus (SCN) represents an area in which limited information is available on the consequences of developmental alcohol exposure in humans or animal models. Offspring exposed to heavy maternal alcohol consumption during pregnancy have been reported to show disturbances in their sleep-wake patterns (Rosett et al., 1979). Consistent with this finding, our PRELIMINARY STUDIES demonstrate that alcohol exposure during the third trimester equivalent in rats produces permanent changes in the circadian rhythm of activity. Therefore, experiments in this proposal will utilize multidisciplinary approaches to examine the long-term effects of three different alcohol doses on the circadian rhythm of activity on the anatomical, cellular and molecular organization of the SCN clock. The patterns of wheel- running behavior in adult rats will be assessed for alcohol-related changes in fundamental properties such as circadian period and rhythm amplitude. Subsequent to this behavioral analysis, the SCN will be evaluated for evidence of general cell loss and perturbations in its rhythmic expression of the putative clock genes, Perl, Per2 and Cry2, and the output signals, vasopressin (AVP), vasoactive intestinal polypeptide (VIP) and brain-derived neurotrophic factor (BDNF). Unlike CNS involvement in the neural regulation of most other behaviors, the discrete localization of circadian clock function to the SCN provides a unique opportunity to identify cellular and molecular correlates of alcohol-related neurobehavioral disturbances. By determining how the SCN and its circadian function are affected by developmental alcohol exposure, these studies are expected to yield important information on the basic mechanisms underlying alcohol-induced brain injury during development. Such information could lead to new strategies in the treatment of known behavioral correlates of FAS related to sleep problems and to mental and physical disorders associated with sleep-wake abnormalities.