Amygdalar Neuropeptides and Anxiety

项目总结（Fadel/Wilson）：焦虑和情感障碍代表了一个重要的临床 然而，我们对这些疾病和用于治疗它们的药物的理解仍然有限。大脑 成像研究显示这些疾病患者的杏仁核发生变化。目前的研究使用一个 多方面的方法来阐明杏仁核阿片系统如何调节焦虑和恐惧相关 流程.这些研究将增强我们对控制不同方面的杏仁核回路的理解 通过比较几种引起焦虑的刺激，探讨焦虑和恐惧的关系，并阐明mu的具体作用 阿片受体（莫尔）在这些不同的反应。因为我们之前的研究表明μ阿片类药物 杏仁核中的莫尔受体和脑啡肽可以调节基础焦虑反应， 苯二氮卓类抗焦虑药物，拟议的研究将检查莫尔受体如何调节 杏仁核回路来改变这些与焦虑相关的反应。我们假设不同的神经元 回路被不同的条件和非条件焦虑诱发情境激活， 位于特定杏仁核神经回路的突触前莫尔受体调节 杏仁核谷氨酸和GABA的释放，以改变焦虑相关的反应，在一个依赖于上下文的 方式四个引发焦虑的测试，包括高架迷宫（不可预测的威胁），捕食者 气味诱导的防御性掩埋（特定威胁），约束应激（心因性刺激）和线索- 条件冻结（学习恐惧），将在这些研究中进行比较。AIM 1使用病毒介导的基因 转移以检查是否减少杏仁核中莫尔的表达会改变焦虑相关行为 和/或内分泌反应的约束压力，如果选择性地针对这些减少到锥体 基底外侧杏仁核的神经元产生相同的效果。目的2使用cFos免疫反应性， 比较由不同的焦虑诱发情况激活的细胞表型，莫尔的定位 在这些激活的神经元群体中，如果激活模式通过降低杏仁核莫尔而改变， 表情目的3在杏仁核中使用体内微透析来评估1）莫尔激活是否改变GABA或 谷氨酸外流，2）如果焦虑诱发的情况下诱导释放脑啡肽，GABA，或谷氨酸，和3）如果 降低莫尔表达改变了MOR诱导或焦虑诱导的GABA或谷氨酸释放。的 研究将增强我们对杏仁核和阿片系统如何调节焦虑的理解 反应，并可以提供新的治疗策略，治疗情感和焦虑相关的 紊乱由于杏仁核中的阿片样物质系统在慢性疼痛状态下被修改，并且被 药物滥用，这些研究的结果也将加强我们对神经基础的理解， 在慢性疼痛患者中或在从阿片类药物，苯二氮卓类药物， 和酒精。相关性：焦虑症是最常见的精神疾病， 数百万美国成年人，但我们对这些疾病的理解和用于治疗它们的药物 仍然有限。目前的研究使用动物模型来阐明大脑中的电路是如何被激活的。 情绪行为背后的大脑区域，即杏仁核，控制着三个方面的反应。 不同的引发焦虑的情境对内源性吗啡样化学物质的关注 （阿片类药物）可能会导致焦虑症的新治疗策略，并增加我们的 了解慢性疼痛状态或从处方或滥用阿片类药物中戒断的原因 导致焦虑增加。

PROJECT SUMMARY (Fadel/Wilson): Anxiety and affective disorders represent an important clinical problem, yet our understanding of the disorders and the drugs used to treat them remains limited. Brain imaging studies show amygdala changes in patients with these disorders. The present studies use a multifaceted approach to elucidate how amygdalar opioid systems regulate anxiety and fear-related processes. These studies will enhance our understanding of amygdala circuits that control distinct aspects of anxiety and fear by comparing several anxiety-evoking stimuli, and elucidate the specific role of mu opioid receptors (MOR) in these different responses. Since our previous studies suggested that mu opioid receptors (MOR) and enkephalin in the amygdala can modulate basal anxiety responses and the actions of benzodiazepine anxiolytic drugs, the proposed studies will examine how MOR receptors modulate amygdalar circuitry to alter these anxiety-related responses. We hypothesize that distinct neuronal circuits are activated by different conditioned and unconditioned anxiety-evoking situations, and that presynaptic MOR receptors localized in specific amygdalar neurocircuits regulate changes in amygdala glutamate and GABA release to shift anxiety-related responses in a context-dependent manner. Four anxiety-evoking tests, including the elevated plus maze (unpredictable threat), predator odor-induced defensive burying (specific threat), restraint stress (psychogenic stimulus) and cue- conditioned freezing (learned fear), will be compared in these studies. Aim 1 uses virus-mediated gene transfer to examine if decreasing the expression of MOR in the amygdala alters anxiety-related behaviors and/or endocrine responses to restraint stress, and if selectively targeting these decreases to pyramidal neurons of the basolateral amygdala produces the same effects. Aim 2 uses cFos immunoreactivity to compare the cellular phenotype(s) activated by distinct anxiety-evoking situations, the localization of MOR in these activated neuron populations, and if activation patterns are altered by decreasing amygdala MOR expression. Aim 3 uses in vivo microdialysis in the amygdala to assess 1) if MOR activation alters GABA or glutamate efflux, 2) if anxiety-evoking situations induce release of enkephalin, GABA, or glutamate, and 3) if decreasing MOR expression modifies MOR-induced or anxiety-induced release of GABA or glutamate. The studies will enhance our understanding of how the amygdala and the opioid system regulate anxiety responses, and could provide novel therapeutic strategies for treating affective and anxiety-related disorders. Since opioid systems in the amygdala are modified during chronic pain states and altered by drugs of abuse, the results of these studies will also enhance our understanding of the neural basis of heightened anxiety states seen in chronic pain patients or during withdrawal from opiates, benzodiazepines, and alcohol. Relevance: Anxiety disorders are the most common mental illness and affect more than19 million US adults, yet our understanding of these disorders and the drugs used to treat them remains limited. The present studies use animal models to elucidate how the circuitry in the brain region underlying emotional behaviors, namely the amygdala, controls responses in three different anxiety-evoking situations. The focus on endogenous morphine-like chemicals (opioids) could lead to new treatment strategies for anxiety disorders, and increase our understanding of why chronic pain states or withdrawal from prescribed or abused opioid drugs lead to increased anxiety.