Impact of stress-induced circuit-specific changes in locus coeruleus opioid signaling on anxiety-like behavior

项目摘要 焦虑症干扰日常生活，是美国最普遍的精神疾病之一。贫困 患者群体中的结果可能部分地由于缺乏对这些病症如何发展的知识而出现。鉴于 焦虑症的个人，公共卫生和经济成本，通过以下方式深入了解机制 慢性焦虑样行为的发展将有助于开发新的更有效的治疗方法 符合国家利益蓝斑（LC）是脑干核团，参与多种中枢神经系统的活动。 系统功能。压力激活LC并促进高度警惕的焦虑样行为。尽管过去的许多研究都 研究了压力如何在短时间内影响LC的功能，但对压力暴露如何导致长时间的LC功能知之甚少。 长期变化的核心是与长期改变行为状态。我们最近的观察 实验室研究表明，急性创伤性应激源可导致焦虑样行为和LC活性长期升高， 这些作用可能与降低LC阿片受体的表达和敏感性有关。确认时 阿片受体在LC中的抗焦虑作用，特别是在解剖学定义的LC神经元亚群中，将是有益的 慢性焦虑样行为发展的细胞和电路机制。了解压力源如何 暴露产生LC基因表达、功能和阿片信号传导的长期变化， 治疗方法，以抵消焦虑症患者人群中出现的一些异常行为。一个 在这个提议中，一个重要的考虑因素是LC细胞的独特作用，它与其他两个大脑区域相互作用， 焦虑行为的不同方面，内侧前额叶皮层和杏仁核的中央核。通过证明 压力诱导LC细胞中与这些区域中的每一个通信的相反的遗传和生理变化，我们将 深入了解焦虑样行为发生的细胞和电路机制，这些行为变得持久， 在几种情绪障碍中适应不良。此外，认识到LC细胞支配这些区域中的每一个的独特作用， 调解压力敏感性或弹性将提供一个重要的背景下，新的实验可以 旨在验证这些神经元在对压力的行为反应中起着因果作用的假设。的目标 该项目首先确定了这些细胞中发生的遗传和生理变化，这些变化是对压力的反应，从而导致焦虑。 比如行为然后，我们将对这些类别的神经元进行遗传修饰，以操纵它们在压力下的激活水平， 或增加或降低其对内源性阿片类药物的敏感性。这些研究将揭示LC神经元活动的变化 和阿片受体功能是焦虑症行为的重要因素。这些实验将阐明 中枢去甲肾上腺素能系统在调节应激反应的情绪和行为分支中所起的作用， 它适应压力暴露后，以及这些变化如何可能导致慢性行为变化，表现为焦虑 类似紊乱的症状

Project Summary Anxiety disorders interfere with daily life and are amongst the most prevalent psychiatric conditions in the United States. Poor outcomes in patient populations likely arise in part due to missing knowledge of how these conditions develop. Given the personal, public health, and economic costs of anxiety disorders, gaining a thorough understanding of the mechanisms by which chronic anxiety-like behavior develops will aid in the development of novel more effective treatments for these conditions and is in the national interest. The locus coeruleus (LC) is a brainstem nucleus involved in a wide array of central nervous system functions. Stress activates LC and promotes hypervigilant anxiety-like behavior. Although many studies in the past have investigated how stress affects the function of the LC at short intervals, less is known about how stressor exposure causes long term changes in the nucleus that are associated with a chronically altered behavioral state. Recent observations from our laboratory show that an acute traumatic stressor can produce long-lasting elevations in anxiety-like behavior and LC activity, and furthermore, these effects may be related to decreased expression and sensitivity of LC opioid receptors. Recognition of an anxiolytic role for opioid receptors in LC, particularly within anatomically defined subsets of LC neurons, will be informative of cellular and circuit mechanisms through which chronic anxiety-like behavior develops. Understanding how stressor exposure produces long-term changes in LC gene expression, function and opioid signaling may provide insights towards therapeutic approaches to counteract some of the abnormal behaviors seen in anxiety disorder patient populations. An important consideration in this proposal is the unique roles of LC cells that interact with two other brain regions that mediate distinct aspects of anxiety-like behavior, the medial prefrontal cortex and the central nucleus of the amygdala. By demonstrating that stress induces opposing genetic and physiological changes in LC cells that communicate with each of these areas, we will gain insights to cellular and circuit mechanisms of the genesis of anxiety-like behavior which becomes persistent and maladaptive in several mood disorders. Furthermore, recognizing unique roles for LC cells innervating each of these areas in mediating stress susceptibility or resilience will provide an important backdrop against which new experiments can be designed to test the hypothesis that these neurons have causal roles in mounting a behavioral response to stress. The goals of this project are first to identify the genetic and physiological changes that occur in these cells in response to stress to drive anxiety like behavior. We will then genetically modify these classes of neurons to either manipulate their level of activation during stress, or to increase and decrease their sensitivity to endogenous opioids. These studies will reveal that changes in LC neuronal activity and opioid receptor function are important contributors to behaviors seen in anxiety disorders. These experiments will clarify the role that the central noradrenergic system plays in mediating the emotional and behavioral limb of the stress response, how it adapts following stressor exposure, and how these changes might lead to chronic changes in behavior that manifest as anxiety disorder-like symptoms.