Limbic modulation of stress-induced alterations in sleep

描述（由申请人提供）：我们的研究项目的长期目标是了解压力事件对睡眠的影响，反过来，睡眠的改变是如何与压力的持续影响相关的。压力源和对压力源的条件反射/习得性提醒会导致行为和睡眠的显著改变。这些改变可能随压力源的强度和可控性以及是否制定了成功的应对策略而变化。在神经生物学水平上，这种改变可能涉及与压力和情绪有关的边缘区域的CRH，以及对觉醒的控制。然而，压力诱发的行为和睡眠改变之间的关系，以及它们的行为和神经生物学基础，却知之甚少。在这个项目中，我们打算确定应激源强度和可控性的变化如何影响应激后睡眠，我们打算确定杏仁核中CRH和CRH相关神经肽在调节唤醒和应激诱导的睡眠改变中的作用。最后，我们将确定杏仁核对压力引起的觉醒变化的调节是否与与压力有关的大脑区域和与睡眠和压力调节有关的脑干单胺能细胞群的活动改变有关。为达成此申请的目标，我们将：1)确定应激源强度和可控性在应激对睡眠和行为的影响中的作用，2)确定杏仁核中CRH1和CRH2受体在调节唤醒和睡眠中的作用，3)确定杏仁核中CRH1和CRH2受体在应激诱导的唤醒和睡眠改变中的作用，以及4)我们将确定涉及应激和应激诱导的快速眼动睡眠改变的区域。受压力影响最大的睡眠状态。我们还将测量心脏和呼吸频率以及应激反应的血浆标志物。了解由可控和不可控压力引起的睡眠变化背后的神经生物学原理，应该能增进我们对压力和与压力相关的情绪如何影响睡眠的理解，反过来，改变的睡眠可能在压力相关病理的发展中发挥作用。这样的理解可能会对失眠等睡眠障碍和影响睡眠的情绪障碍提供深入的了解。这对于了解创伤后应激障碍（PTSD）尤其重要，PTSD的特征是在心理创伤性应激源后睡眠受到干扰。这项研究的目的是了解压力事件对睡眠的影响，反过来，睡眠的改变是如何与压力的持续影响相关的。压力源，甚至是对压力源的条件提醒，都能在行为和睡眠方面产生重大改变。众所周知，应激源强度和可控性的影响是影响应激长期效应的重要因素。然而，目前尚不清楚这些因素是如何影响睡眠的，也不知道睡眠改变在压力的长期影响中可能起什么作用。我们将确定压力源强度和可控性是如何影响应激后睡眠的，我们将研究杏仁核中促肾上腺皮质激素释放激素在调节应激后睡眠中的作用。杏仁核是大脑中的情绪中心。这些研究提供的见解可能会改善失眠等睡眠障碍的治疗方法，以及影响睡眠的情绪障碍。这对于理解和潜在的创伤后应激障碍（PTSD）的治疗尤其重要，PTSD的特征是在心理创伤性应激源后睡眠受到干扰。

DESCRIPTION (provided by applicant): The long-term goal of our research program is to understand the impact of stressful events on sleep, and, in turn, how alterations in sleep are related to the persisting effects of stress. Stressors and conditioned/learned reminders of stressors can produce significant alterations in behavior and sleep. These alterations may vary with the intensity and controllability of the stressor and whether a successful coping strategy was developed. At the neurobiological level, the alterations may involve CRH in limbic regions implicated in stress and emotion, and in the control of arousal. However, the relationship between stress-induced behaviors and alterations in sleep, and their behavioral and neurobiological bases, are poorly understood. In this project, we intend to determine how variations in stressor intensity and controllability can influence post-stress sleep, and we intend to determine the role of CRH and CRH-related neuropeptides in the amygdala in regulating arousal and stress- induced alterations in sleep. Lastly, we will determine whether amygdalar modulation of stress-induced changes in arousal is associated with alterations in activity in brain regions implicated in stress and in brainstem monoaminergic cell groups that have been linked to the regulation of sleep and stress. To accomplish the objectives of this application we will: 1) determine the role(s) of stressor intensity and controllability in the effects of stress on sleep and behavior, 2) determine the role(s) of CRH1 and CRH2 receptors in the amygdala in regulating arousal and sleep, 3) determine the role(s) of CRH1 and CRH2 receptors in the amygdala in stress-induced alterations in arousal and sleep, and 4) we will identify regions involved in stress and in stress-induced alterations in rapid eye movement sleep, the sleep state that may be most impacted by stress. We will also measure heart and respiratory rate and plasma markers of the stress response. Understanding the neurobiology underlying the changes in sleep induced by controllable and uncontrollable stress should increase our understanding of how stress and stress-related emotion affect sleep and, in turn, the role altered sleep may play in the development of stress-related pathology. Such understanding may provide insight into sleep disorders such as insomnia and into emotional disorders in which sleep is affected. It will be especially relevant for insight into posttraumatic stress disorder (PTSD), which is characterized by disturbed sleep after a psychologically traumatic stressor. PUBLIC HEALTH RELEVANCE The goal or this research is to understand the impact of stressful events on sleep, and, in turn, how alterations in sleep are related to the persisting effects of stress. Stressors and even conditioned reminders of stressors can produce significant alterations in behavior and sleep. It is known that the effects of stressor intensity and controllability are important factors in the long-term effects of stress. However, it is not know how these factors impact sleep, or what role altered sleep may play in the long-term effects of stress. We will determine how stressor intensity and controllability affect post-stress sleep, and we will examine the role of corticotropin releasing hormone in the amygdala, a center of emotion in the brain, in regulating post-stress sleep. The insight provided by these studies may lead to improved treatments for sleep disorders such as insomnia and into emotional disorders in which sleep is affected. It will be especially relevant for understanding and potential treatment of posttraumatic stress disorder (PTSD), which is characterized by disturbed sleep after a psychologically traumatic stressor.