STRESS EFFECTS ON SLEEP--INFLUENCE OF GENES AND GENDER

本申请中提出的实验的总体目标是发展小鼠作为动物模型，以阐明睡眠调节的遗传和分子机制，并测试关于雄性和雌性小鼠的遗传背景和生理状态在睡眠调节中的重要性以及压力对睡眠的影响的具体假设。压力会对睡眠和生物钟产生重大的破坏作用，生物钟本身在调节睡眠方面起着基础性的作用。遗传和环境因素都有助于调节睡眠，以及任何一个人的睡眠和生物钟系统将如何受到压力的影响。在拟议的研究中，将确定急性应激、慢性轻度应激和短期睡眠剥夺对小鼠睡眠和昼夜节律的影响。遗传差异的小鼠将被研究。对于一些研究来说，这些遗传差异将是多基因的，或者将测试单个候选基因在其他研究中的作用。鉴于在其他物种(主要是人类)中观察到的睡眠和对压力反应的性别差异，拟议的研究将包括处于发情周期不同阶段和与年龄相关的周期性丧失之后的女性。这项提案的另一个目标是开发和验证一种新的自动睡眠分析系统在小鼠中的使用。预计这些研究将有助于理解压力影响睡眠调节的机制。这些研究的结果也将为利用小鼠遗传学工具识别可能影响睡眠中断的遗传和生理因素奠定关键基础。这些信息最终可能导致对因压力或相关因素而遭受睡眠障碍的人类进行更有效的干预，并可能导致与睡眠工资异常相关的精神和身体疾病的新疗法。

The overall objectives of the proposed experiments in this application are to develop the mouse as an animal model for elucidating the genetic and molecular mechanisms for sleep regulation and to tet specific hypotheses regarding the importance of the genetic background and physiological state of both male and female mice in the regulation of sleep as well as the effects of stress on sleep. Stress can have major disruptive effects on sleep as well as the circadian clock, which itself plays a fundamental role in the regulation of sleep. Both genetic and environmental factors contribute to the regulation of sleep as well as to how the sleep and circadian clock systems of any one individual will be affected by stress. In the proposed studies, the effects in mice of acute stress, chronic mild stress, and short- term sleep deprivation on sleep and circadian rhythms will be determined. Mice with genetic differences will be studied. These genetic differences will be polygenic for some studies, or will test the roles of single candidate genes in others. In view of gender differences in both sleep and the response to stress that have been observed in other species, primarily in humans, the proposed studies will include females in different stages of the estrous cycle and after the age-related loss in cyclicity. An additional objective of this proposal is to develop and validate the use of a novel automated sleep analysis system in the mouse. It is anticipated that these studies will contribute to an understanding of the mechanisms whereby stress impacts sleep regulation. The results of these studies also will form a critical basis for use of the tools of mouse genetics to identify genetic and physiological factors which may influence sleep disruption. Such information is likely ultimately to lead to more effective interventions for humans who suffer from sleep disturbances due to stress or related factors, and may lead to new treatments for mental and physical disorders associated with sleep-wage abnormalities.