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

恐慌相关逃生行为中下丘脑脑干回路的剖析

• 批准号: 9890009
• 负责人: Avishek Adhikari
• 金额: $ 43.57万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890009
• 关键词: Affect; Agonist; Animals; Anxiety Disorders; Asphyxia; Behavior; Brain Stem; Carbon Dioxide; Cell Nucleus; Cells; Cessation of life; Cholecystokinin; Complex; Data; Dissection; Dorsal; Electrophysiology (science); Environment; Exposure to; Forcible intercourse; Freezing; Generations; Glutamates; Heart Rate; Human; Hypothalamic structure; In Situ; Infusion procedures; Lead; Link; Mediating; Mediator of activation protein; Modality; Modeling; Monitor; Movement; Mus; Nitric Oxide; Nitric Oxide Synthase Type I; Panic; Panic Attack; Paper; Patients; Pharmacology; Phase; Population; Prevalence; Rattus; Risk Assessment; Rodent; Role; Route; Running; Site; Stimulus; Symptoms; Synapses; Techniques; Testing; Time; Trauma; Veterans; Work; awake; common symptom; in vivo; insight; midbrain central gray substance; neural model; neural stimulation; novel; optogenetics; patch clamp; receptor; relating to nervous system

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.

项目摘要/摘要 恐慌症发作是患有多种焦虑症的患者的常见症状。这些 压倒性攻击是特别常见的具有严重创伤的人群，如强奸受害者或退伍军人。 调节逃避迫在眉睫的威胁的电路，如窒息，强烈地牵涉到这一代 恐慌症发作。自然主义的逃避威胁发生在复杂的环境中，在这种环境中动物必须迅速 通过最有效的路线逃走。根据具体情况选择一个不正确的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过程中产生逃逸运动的区域，如跳跃。 然而，这些行动往往不会导致最佳逃生路线的选择。到目前为止，电路感应 还没有确定具体情况下的逃生路线选择。现在，我们展示了光遗传刺激 乳头体前背核(PMD)中的一氧化氮合酶1(NOS1)+细胞产生上下文特异性逃逸， 类似于自然主义的逃生。在空盒子中，PMD刺激会导致跳跃，但在添加攀登后 绳索逃逸，刺激通过攀爬绳索导致逃生。相反，刺激背外侧 中脑导水管周围灰质(DlPAG)是惊恐相关逃避中研究最深入的区域，它会导致跳跃。 并在所有情况下奔跑，即使这些动作不允许逃脱。有趣的是，PMD是密度最大的 输入到引起恐慌的dlPAG，但它从未被直接激活。NOS1+pmd-dlPAG的激活 投射也会导致与刺激NOS1 PMD细胞体相同的惊恐相关症状，包括逃避 和厌恶感。这一发现表明，PMD通过作用于dlPAG来创造上下文特定的逃逸。至 研究这条线路，我们开发了两种具有引发逃生威胁的新范例：一条走廊，其中包含一条带电的 捕食者(未被屏障隔开的清醒大鼠)和暴露在15%二氧化碳中的密室，这是一种刺激 已知会引起人类的恐慌。在这两种模式中，只有在特定于环境的情况下才能最大限度地增加威胁风险 需要协调行动的逃生计划。这些范例产生了全方位的防御行为(风险- 评估、冻结、跳跃/奔跑和使用最佳路线的计划逃生)取决于威胁强度 (与老鼠或二氧化碳浓度的距离)，使我们能够准确地识别哪些行为受 PMD-dlPAG电路。我们的目标是：1)光遗传学分析PMD-dlPAG电路是如何产生这些的 症状，2)表征恐慌威胁如何影响PMD活动和PMD-DPAG电路中的同步性 3)研究pmd输入如何影响dlPAG中的威胁编码，以及它如何从突触上影响dlPAG。 细胞。由于PMD-dlPAG激活选择性地诱导逃逸，而不是其他防御行为，我们 假设NOS1+PMD-dlPAG电路特别影响计划的上下文特定的逃逸。我们也 预测这个回路中的神经活动与逃避的关联最强。这些目的将揭示小说 与恐慌相关的逃避威胁的潜在电路机制。