Development Alcohol and Circadian Clock Function

描述（申请人提供）：据估计，2000 - 12000名婴儿 每年都有胎儿酒精综合征（FAS）出生（Stratton等人，1996年）。 到目前为止，FAS在CNS功能障碍中最令人衰弱的特征是 从结构上来说，已知会持续到成年期。 然而，关于 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过程的昼夜节律调节， 视交叉上核（SCN）代表了一个区域， 关于发育期酒精暴露的后果， 在人类或动物模型中。 后代暴露于母体酒精 据报道，怀孕期间的消费显示， 睡眠-觉醒模式（Rosett等人，1979年）。 与这一发现相一致，我们的 初步研究表明，在第三次饮酒期间， 在大鼠中相当于三个月的时间产生昼夜节律的永久性变化 活动的节奏。 因此，本提案中的实验将利用 多学科方法来研究三个长期影响 不同酒精剂量对人体生理活动节律的影响， SCN时钟的细胞和分子组织。 轮子的形状- 将评估成年大鼠的跑步行为中与酒精相关的变化， 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 细胞的丢失和紊乱， 假定的时钟基因Perl、Per 2和Cry 2，以及输出信号加压素 (AVP)、血管活性肠肽（VIP）和脑源性神经营养素 脑源性神经营养因子（BDNF）。 与CNS参与大多数其他神经调节不同， 行为，生物钟功能的离散定位到SCN 提供了一个独特的机会，以确定细胞和分子相关的 酒精相关的神经行为障碍 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， 预计研究将产生关于基本机制的重要信息， 在发育过程中酒精引起的脑损伤。 此类信息 可能导致治疗已知行为相关性的新策略 与睡眠问题和精神和身体疾病有关的FAS 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.