Dissecting Cell-Specific Brainstem Circuits Mediating Escape Behavior

项目摘要/摘要 在美国，每年有数百万成年人受到恐慌症的影响。恐慌症发作的特点是 无法抗拒的恐惧，呼吸困难，心率加快，以及想要逃离的冲动。恐慌疗法是 往往是无效的，强调需要发展一种新的对恐慌症发作的机械理解，以 高级治疗。导水管周围灰质区域被强烈地牵涉到恐慌中，因为电信号 刺激中脑导水管周围灰质(PAG)会引起人类的恐慌，并导致逃逸、冰冻等 啮齿动物的防御行为。然而，特定细胞群体的遗传同一性选择性地 司机逃生的原因不明。缩胆囊素(CCK)是一种神经肽，表达于外侧和腹外侧部。 PAG(L/vlPAG)专栏。我提议解剖一种新的涉及外侧CCK+神经元的神经回路 小鼠行为学捕食者暴露行为中腹外侧PAG(L/vlPAG)的逃逸作用 实验以阐明逃逸的机制。在目标1中，我将测试CCK+L/vlPAG神经活动是否充分，以及 对于使用化学遗传操作逃离活的捕食者来说是必要的。在目标2中，我将检查CCK+ L/vlPAG神经活动预测自由活动小鼠逃逸的微型显微镜钙成像 有活老鼠的存在。在目标3中，我将测试CCK+L/vlPAG细胞是否参与了逃避和威胁的编码 用化学遗传学方法调控CCK+L/v1PAG在泛神经元PAG细胞中的神经活动和记录 用微型显微镜观察CCK-PAG细胞的后续神经活动。这三个目标加在一起将 作为一种全面的方法来阐明逃避的神经机制，这将提供更好的 深入了解恐慌机制。

Project Summary/Abstract Panic disorder affects millions of adults in the U.S. every year. Panic attacks are characterized by overwhelming fear, difficulty breathing, accelerated heart rate, and an urge to escape. Panic therapies are often ineffective, emphasizing the need to develop a novel mechanistic understanding of panic attacks to advance treatment. The periaqueductal gray region has been strongly implicated in panic, as electrical stimulation of the periaqueductal grey (PAG) induces panic in humans and induces escape, freezing, and other defensive behaviors in rodents. However, the genetic identity of the specific cell population that selectively drives escape is unknown. Cholecystokinin (cck), a neuropeptide, is expressed in the lateral and ventrolateral PAG (l/vlPAG) columns. I propose to dissect a novel neural circuit involving cck+ neurons in the lateral ventrolateral PAG (l/vlPAG) underlying escape in mice during an ethological predator-exposure behavioral assay to elucidate the mechanism of escape. In Aim 1, I will test if cck+ l/vlPAG neural activity is sufficient and necessary for escape from a live predator using chemogenetic manipulations. In Aim 2, I will examine if cck+ l/vlPAG neural activity predicts escape using miniaturized microscope calcium imaging in freely-moving mice in the presence of a live rat. In Aim 3, I will test if cck+ l/vlPAG cells contribute to encoding of escape and threat in pan-neuronal PAG cells using chemogenetics to manipulate cck+ l/vlPAG neural activity and recording subsequent neural activity in cck- PAG cells using miniaturized microscopes. Together, these three Aims will serve as a comprehensive approach to elucidating the neural mechanism of escape, which will provide better insight into understanding panic mechanisms.