Neuronal mapping of anxiety and panic

描述（由申请人提供）：惊恐障碍是一种常见的精神疾病，终生患病率约为4.5%。这种疾病的特征是反复发作的惊恐发作，可能突然和意想不到地出现，包括明显的恐惧，以及心血管和呼吸反应。这些患者的初始病理表现为调节正常恐慌反应的中枢神经通路的某个地方发生改变，从而使患者在暴露于通常轻度的内感受性应激源时易产生无端恐慌症状。了解恐慌发作的神经基础将显著改善结果和治疗。神经递质下丘脑分泌素（Hcrt），也被称为食欲素，最近被认为与过度觉醒、焦虑和恐慌有关，但具体的效应回路尚不清楚。解剖学和功能证据表明，Hcrt/orexin可能的靶点之一是脑干中含有去甲肾上腺素（NE）的神经元。在这里，我们将测试Hcrt/orexin通过腹侧去甲肾上腺素A2神经元及其输出产生焦虑和恐慌反应的不同成分的总体假设。我们将使用解剖示踪和光遗传学工具获得连接A2神经元及其几个解剖靶点的神经元回路的功能图谱，即室旁下丘脑核（PVN）和终纹床核（BNST）。我们还将确定这些回路与下丘脑外侧促进Hcrt/orexin神经元觉醒之间的联系。我们的实验将增加我们对与细胞特异性焦虑相关的电路的理解，并可能导致对焦虑和恐慌障碍的潜在更多选择性治疗。

DESCRIPTION (provided by applicant): Panic disorder is a common psychiatric illness with a lifetime prevalence of about 4.5%. The hallmark of the disorder is recurring panic attacks, which can appear suddenly and unexpectedly, consisting of pronounced fear, as well as cardiovascular and respiratory responses. The initial pathology in these patients appears to be an alteration somewhere in the central neural pathways regulating normal panic responses, thus rendering the patients susceptible to unprovoked panic symptoms when exposed to ordinarily mild interoceptive stressors. Understanding the neuronal underpinnings of panic attacks would significantly improve the outcomes and treatment. The neurotransmitter hypocretin (Hcrt), also known as orexin, has been recently linked to hyperarousal, anxiety and panic, but the specific effector circuits are unknown. Anatomical and functional evidence suggests that one of the possible Hcrt/orexin targets are norepinephrine (NE)-containing neurons in the brainstem. Here, we will test the overall hypothesis that Hcrt/orexin acts through ventral norepinephrine A2 neurons and their efferents to produce different components of the anxiety and panic responses. We will use anatomical tracing and optogenetic tools to obtain a functional map of the neuronal circuitry connecting A2 neurons with several of its anatomical targets, namely the paraventricular hypothalamic nucleus (PVN) and the bed nucleus of the stria terminalis (BNST). We will also determine the connectivity between these circuits and the arousal promoting Hcrt/orexin neurons in the lateral hypothalamus. Our experiments will increase our understanding of the circuitry associated with anxiety with cellular specificity and may lead to potentially more selective treatments for anxiety and panic disorders.