Dissection of Hypothalamic-Brainstem Circuits in Panic-Related Escape Behavior

项目总结/摘要 惊恐发作是许多焦虑症患者的常见症状。这些 压倒性的攻击尤其常见于遭受严重创伤的人群，如强奸受害者或退伍军人。 从窒息等迫在眉睫的威胁中逃脱的电路在这一代人中有很大的牵连 恐慌症发作在复杂的环境中，动物必须迅速地 通过最有效的路线逃跑。一个不正确的选择特定的环境逃生计划可能会导致死亡。 先前的研究已经确定了在神经刺激期间产生逃避运动的区域，例如跳跃。 然而，这些运动往往不会导致最佳逃生路线的选择。迄今为止，电路诱导 尚未确定针对具体情况的逃生路线选择。现在，我们发现光遗传学刺激 乳头体前背核（PMd）中的一氧化氮合酶1（nos 1）+细胞产生环境特异性逃逸， 类似于自然主义的逃避。在一个空的盒子里，PMD刺激会引起跳跃，但在增加了一个爬升后， 绳子逃生，刺激导致通过攀爬绳子逃生。相反，刺激背外侧 中脑导水管周围灰质（dlPAG）是在惊恐相关逃避中研究最深入的区域， 在任何情况下都要跑，即使这些动作不允许逃跑。有趣的是，首相是 输入到恐慌诱导dlPAG，但它从来没有被直接激活。nos 1 +PMd-dlPAG的激活 投射也导致与刺激nos 1 PMd细胞体相同的恐慌相关症状，包括逃避 和厌恶这一发现表明PMd通过作用于dlPAG来产生情境特异性逃避。到 研究这个电路，我们开发了两个具有逃避挑衅威胁的新颖范例：一个走廊， 捕食者（未被屏障隔开的清醒大鼠）和暴露于15% CO2的室，刺激 会引起人类恐慌在这两种模式中，只有使用特定于上下文的 需要协调行动的逃生计划这些范例产生了一系列的防御行为（风险- 评估、冻结、跳跃/跑步和使用最佳路线的计划逃生），具体取决于威胁强度 （与大鼠的距离或二氧化碳浓度），使我们能够精确地识别哪些行为是由 PMd-dlPAG电路。我们的目标是：1）光遗传学解剖PMd-dlPAG电路如何产生这些 症状，2）表征致恐慌性威胁如何影响PMd活性和PMd-dPAG回路中的同步性 以及3）检查PMd输入如何影响dlPAG中的威胁编码以及它如何在突触上影响dlPAG 细胞由于PMd-dlPAG激活选择性地诱导逃避，而不是其他防御行为，我们 假设nos 1 +PMd-dlPAG回路特别影响计划的情境特异性逃避。我们也 预测这个回路中的神经活动与逃跑密切相关。这些目标将揭示新的 与恐慌相关的逃避威胁的电路机制。

Project Summary/Abstract Panic attacks are a common symptom in patients suffering from numerous anxiety disorders. These overwhelming attacks are particularly common populations with severe trauma, such as rape victims or veterans. Circuits mediating escape from imminent threats such as asphyxiation are strongly implicated in the generation of panic attacks. Naturalistic escape from threats occur in complex environments in which animals must quickly flee through the most efficient route. A single incorrect choice of context-specific escape plan may result in death. Prior studies have identified regions that produce escape movements during neural stimulation, such as jumping. However, these movements often do not result in choice of optimal escape routes. To date, circuits inducing context-specific choice of escape routes have not been identified. Now, we show that optogenetic stimulation of nitric oxide synthase1 (nos1)+ cells in the dorsal premammillary nucleus (PMd) creates context-specific escape, similarly to naturalistic escape. In an empty box, PMD stimulation causes jumping, but after adding a climbing rope escape, stimulation causes escape by climbing the rope. In contrast, stimulation of the dorsolateral periaqueductal gray (dlPAG), which is the region most deeply studied in panic-related escape, causes jumping and running in all situations, even when these actions do not allow escape. Intriguingly, the PMd is the densest input to the panic-inducing dlPAG, but it has never been activated directly. Activation of the nos1+PMd-dlPAG projection also led to the same panic-related symptoms as stimulation of nos1 PMd cell bodies, including escape and aversion. This finding suggests the PMd is creating context-specific escape by acting on the dlPAG. To study this circuit, we developed two novel paradigms with escape-provoking threats: a corridor containing a live predator (an awake rat that is not separated by a barrier) and a chamber for exposure to 15% CO2, a stimulus known to cause panic in humans. In both paradigms threat exposure can only be maximized with context-specific escape plans requiring coordinated action. These paradigms produce a full range of defensive behaviors (risk- assessment, freezing, jumping/running and planned escape using optimal routes) depending on threat intensity (distance to rat or CO2 concentration), allowing us to precisely identify which behaviors are controlled by the PMd-dlPAG circuit. Our aims are to: 1) Optogenetically dissect how the PMd-dlPAG circuit produces these symptoms, 2) Characterize how panicogenic threats affect PMd activity and synchrony in the PMd-dPAG circuit and 3) Examine how PMd input influences threat-encoding in the dlPAG and how it synaptically affects dlPAG cells. Since PMd-dlPAG activation selectively induced escape, but not other defensive behaviors, we hypothesize that the nos1+PMd-dlPAG circuit specifically affects planned context-specific escape. We also predict that neural activity in this circuit is most strongly correlated with escape. These aims will reveal novel circuit mechanisms underlying panic-related escape from threat.