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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要焦虑症干扰日常生活，是美国最普遍的精神疾病之一。贫穷的患者群体中出现的结果可能部分是由于对这些疾病如何发展的了解不足。鉴于焦虑症的个人、公共卫生和经济成本，通过以下方式全面了解其机制慢性焦虑样行为的发展将有助于开发针对这些疾病的新的更有效的治疗方法并且符合国家利益。蓝斑 (LC) 是脑干核，参与广泛的中枢神经系统系统功能。压力会激活 LC 并促进过度警惕的焦虑样行为。尽管过去的许多研究研究了压力如何在短时间内影响 LC 的功能，但对于压力源暴露如何导致长时间的 LC 功能知之甚少。与长期改变的行为状态相关的细胞核的术语变化。我们最近的观察实验室表明，急性创伤性应激源可以导致焦虑样行为和 LC 活动持久升高，此外，这些作用可能与LC阿片受体表达和敏感性降低有关。认可阿片受体在 LC 中的抗焦虑作用，特别是在解剖学上定义的 LC 神经元子集中，将提供信息慢性焦虑样行为发展的细胞和回路机制。了解压力源如何暴露会对 LC 基因表达、功能和阿片类信号传导产生长期变化，可能会为以下方面提供见解：抵消焦虑症患者群体中出现的一些异常行为的治疗方法。一个该提案中重要的考虑因素是 LC 细胞与另外两个大脑区域相互作用的独特作用，这些区域介导焦虑样行为的不同方面，内侧前额叶皮层和杏仁核中央核。通过演示压力会导致与这些区域进行交流的 LC 细胞发生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回路机制，这种行为会变得持续且持续多种情绪障碍的适应不良。此外，认识到 LC 细胞在神经中支配这些区域的独特作用调节压力敏感性或恢复力将为新实验提供重要的背景旨在检验这些神经元在对压力做出行为反应方面具有因果作用的假设。的目标该项目首先确定这些细胞在应对压力以引发焦虑时发生的遗传和生理变化喜欢的行为。然后，我们将对这些类别的神经元进行基因改造，以操纵它们在压力期间的激活水平，或增加或减少他们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贡献者。这些实验将澄清中枢去甲肾上腺素能系统在调节应激反应的情绪和行为方面所起的作用，如何它会在暴露于压力源后进行适应，以及这些变化如何导致表现为焦虑的行为的慢性变化类似紊乱的症状。