Dissecting Cell-Specific Brainstem Circuits Mediating Escape Behavior

项目总结/摘要 恐慌症每年影响美国数百万成年人。恐慌症的特征是 压倒性的恐惧，呼吸困难，心率加快，以及逃跑的冲动。恐慌疗法是 往往无效，强调需要发展一种新的机制理解恐慌发作， 先进的治疗。中脑导水管周围灰质区域与恐慌密切相关， 中脑导水管周围灰质（PAG）的刺激在人类中诱导恐慌，并诱导逃避、冻结和其他行为。 啮齿动物的防御行为然而，选择性地表达特定细胞群的遗传特性， 逃逸的原因不明。胆囊收缩素（Cholecystokinin，cck）是一种神经肽，表达于外侧和腹外侧 PAG（1/vlPAG）柱。我建议解剖一个新的神经回路涉及CCK+神经元在外侧 腹外侧PAG（l/vlPAG）在行为学捕食暴露行为过程中的小鼠逃避中的作用 分析以阐明逃逸机制。在目标1中，我将测试cck+1/vlPAG神经活动是否足够， 用化学遗传学的方法逃离一个活生生的捕食者。在目标2中，我将检查cck+ l/vlPAG神经活动预测逃避使用小型化显微镜钙成像在自由移动的小鼠， 一只活老鼠的存在。在目标3中，我将测试cck+ l/vlPAG细胞是否有助于编码逃避和威胁 在全神经元PAG细胞中，使用化学遗传学来操纵cck+1/vlPAG神经活性并记录 随后的神经活动的cck-PAG细胞使用微型显微镜。这三个目标将共同 作为一个全面的方法来阐明逃避的神经机制，这将提供更好的 对恐慌机制的理解。

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.