Amygdalar Neuropeptides and Anxiety

项目总结(法德尔/威尔逊)：焦虑和情感障碍是一个重要的临床问题 尽管这是一个问题，但我们对这些疾病和用于治疗这些疾病的药物的了解仍然有限。脑区 影像研究显示，患有这些疾病的患者杏仁核发生了变化。本研究使用了一种 多方面研究杏仁核阿片系统如何调节焦虑和恐惧相关 流程。这些研究将加强我们对控制不同方面的杏仁核回路的理解 通过比较几种焦虑诱发刺激对焦虑和恐惧的影响，阐明Mu的具体作用 阿片受体(MOR)在这些不同的反应。因为我们之前的研究表明Mu阿片类药物 杏仁核中的受体(MOR)和脑啡肽可调节基础焦虑反应和 苯二氮卓类抗焦虑药物，拟议的研究将检查MOR受体如何调节 杏仁核回路来改变这些焦虑相关的反应。我们假设不同的神经元 不同的条件性和非条件性焦虑唤起情况激活了电路，并且 突触前MOR受体定位于特定的杏仁核神经回路，调节 杏仁核谷氨酸和GABA的释放改变上下文依赖的焦虑相关反应 举止。四项引发焦虑的测试，包括高架加迷宫(不可预测的威胁)、捕食者 气味诱导的防御性掩埋(特定威胁)、束缚应激(心理刺激)和线索- 这些研究将对条件性冰冻(习得恐惧)进行比较。AIM 1使用病毒介导的基因 转移研究：减少杏仁核中MOR的表达是否会改变焦虑相关行为 和/或对束缚应激的内分泌反应，如果选择性地以这些反应为靶点，则减少到锥体 杏仁基底外侧核的神经元也会产生同样的效果。AIM 2使用CFO免疫反应性 比较不同焦虑诱发情景激活的细胞表型(S)，MOR的定位 在这些激活的神经元群体中，如果通过减少杏仁核Mor来改变激活模式 表情。AIM 3在杏仁核中使用体内微透析来评估1)MOR激活是否改变GABA或 谷氨酸外流，2)如果引起焦虑的情况导致脑啡肽、GABA或谷氨酸的释放，以及3)如果 减少MOR的表达可以改变MOR诱导或焦虑诱导的GABA或谷氨酸的释放。这个 研究将加强我们对杏仁核和阿片系统如何调节焦虑的理解 反应，并可为治疗情感和焦虑相关疾病提供新的治疗策略 精神错乱。由于杏仁核中的阿片系统在慢性疼痛状态下被修改，并被 这些研究的结果也将加深我们对药物滥用的神经基础的理解 慢性疼痛患者或在阿片类药物、苯二氮类药物、 还有酒。相关性：焦虑症是最常见的精神疾病，影响超过19 数百万美国成年人，然而我们对这些疾病和用于治疗它们的药物的了解 仍然是有限的。目前的研究使用动物模型来解释大脑中的回路是如何 情绪行为背后的大脑区域，即杏仁核，控制着三个区域的反应 不同的引起焦虑的情况。对内源性吗啡类化学物质的关注 (阿片类药物)可能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停用处方或滥用阿片类药物的原因 导致焦虑加剧。

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.