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

应激引起的蓝斑阿片类信号通路特异性变化对焦虑样行为的影响

• 批准号: 10044465
• 负责人: Daniel Chandler
• 金额: $ 40.25万
• 依托单位: ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044465
• 关键词: Acute; Adenovirus Vector; Affect; Amygdaloid structure; Anatomy; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Area; Arousal; Behavior; Behavioral; Brain; Brain Stem; Brain region; CAV2 gene; Cell Nucleus; Cells; Characteristics; Chronic; Data; Dependovirus; Designer Drugs; Development; Disease; Electrophysiology (science); Emotional; Enterobacteria phage P1 Cre recombinase; Exposure to; Feeling; Fright; Gene Expression; Generations; Genetic; Genetic Techniques; Genetic Transcription; Goals; Health Care Costs; Hyperactive behavior; Knock-out; Knowledge; Label; Laboratories; Lead; Life; Limb structure; Maintenance; Medial; Mediating; Molecular; Mood Disorders; Nervous System Physiology; Neuraxis; Neurons; Odors; Opioid; Opioid Receptor; Outcome; Panic; Patients; Physical Restraint; Physiological; Physiological Adaptation; Physiology; Play; Population; Predisposition; Prefrontal Cortex; Property; Public Health; Rattus; Regulation; Research; Role; Series; Signal Transduction; Stress; Structure; Symptoms; System; Techniques; Testing; Therapeutic; Time; Tissues; United States; acute stress; anxiety-like behavior; behavioral phenotyping; behavioral response; biological adaptation to stress; cell cortex; design; economic cost; effective therapy; endogenous opioids; experimental study; genetic manipulation; indexing; insight; interest; locus ceruleus structure; neurobiological mechanism; noradrenergic; novel; overexpression; patch clamp; patient population; receptor; receptor expression; receptor function; resilience; response; restraint; retrograde transport; stress resilience; stressor; trait; virus genetics

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.

项目摘要 焦虑症会干扰日常生活，是美国最普遍的精神病。贫穷的 患者人群的结果可能部分是由于缺少这些疾病的知识。鉴于 个人，公共卫生和焦虑症的经济成本，从 慢性焦虑般的行为发展将有助于为这些条件开发新的更有效的治疗方法 并且符合国家利益。基因座（LC）是脑干核，涉及广泛的中枢神经 系统功能。应力激活LC并促进过度焦虑样行为。尽管过去许多研究有 研究了压力如何在短时间间隔影响LC的功能，对应力暴露的造成长时间的了解较少 与慢性行为状态相关的细胞核中的项变化。我们最近的观察 实验室表明，急性创伤压力源可以在焦虑行为和LC活性中产生持久的海拔， 此外，这些作用可能与LC阿片受体的表达和敏感性降低有关。认可 LC中阿片类药物受体的抗焦虑作用，尤其是在解剖学上定义的LC神经元子集中，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 暴露会导致LC基因表达，功能和阿片类药物信号的长期变化，可能会提供有关的见解 治疗方法来抵消焦虑症患者人群中某些异常行为。一个 该提案中的重要考虑是LC细胞与其他两个介导的大脑区域相互作用的独特作用 焦虑样行为，内侧前额叶皮层和杏仁核的中央核的不同方面。通过演示 这会引起与每个区域通信的LC细胞中相对的遗传和生理变化，我们将 获得焦虑样行为起源的细胞和电路机制的见解，这种行为变得持久，并且 多种情绪障碍的适应不良。此外，认识到在这些区域中支配的LC细胞的独特作用 介导压力敏感性或韧性将提供重要的背景 旨在检验这些神经元在安装对压力的行为反应中具有因果关系的假设。目标 该项目首先确定这些细胞中发生的遗传和生理变化，以应对焦虑的压力。 喜欢行为。然后，我们将基因修改这些类别的神经元以操纵其在压力期间的激活水平， 或增加和降低其对内源性阿片类药物的敏感性。这些研究将表明LC神经元活性的变化 阿片受体功能是焦虑症中看到的行为的重要因素。这些实验将澄清 中央去甲肾上腺素系统在介导压力反应的情绪和行为肢体中所扮演的作用，如何 它适应压力源暴露后，以及这些变化如何导致行为的慢性变化，表现为焦虑 异常症状。