Dissecting Cell-Specific Brainstem Circuits Mediating Escape Behavior

剖析介导逃避行为的细胞特异性脑干回路

• 批准号: 10589043
• 负责人: Anita Torossian
• 金额: $ 3.95万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589043
• 关键词: Acceleration; Adult; Affect; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain Stem; Brain region; Breathing; Calcium; Cells; Cholecystokinin; Data; Electric Stimulation; Ethology; Experimental Designs; Exposure to; Feeling; Freezing; Fright; Genetic; Genetic Identity; Heart Rate; Human; Image; Impairment; Injections; Label; Lateral; Measures; Mediating; Methods; Microscope; Molecular Profiling; Mus; Neurons; Neuropeptides; Neurotransmitters; Panic; Panic Attack; Panic Disorder; Pharmaceutical Preparations; Population; Positioning Attribute; Preparation; Process; Rattus; Resolution; Rodent; Role; Slice; Testing; Training; cell type; genetic manipulation; in vivo calcium imaging; insight; midbrain central gray substance; miniaturize; neural; neural circuit; neural network; neuromechanism; novel; skills

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.

项目概要/摘要 恐慌症每年影响美国数百万成年人。惊恐发作的特点是 压倒性的恐惧、呼吸困难、心率加快以及逃跑的冲动。恐慌疗法有 通常无效，强调需要对恐慌发作建立一种新颖的机制理解 提前治疗。导水管周围灰色区域与恐慌密切相关，因为电 刺激导水管周围灰质（PAG）会引起人类恐慌，并导致逃跑、冻结和其他反应。 啮齿动物的防御行为。然而，特定细胞群的遗传特性选择性地 驱动器逃跑情况不明。胆囊收缩素 (cck) 是一种神经肽，在外侧和腹外侧表达 PAG (l/vlPAG) 柱。我建议剖析一种涉及外侧 cck+ 神经元的新型神经回路 腹外侧 PAG (l/vlPAG) 在行为学捕食者暴露行为期间是小鼠逃避的基础 分析以阐明逃逸机制。在目标 1 中，我将测试 cck+ l/vlPAG 神经活动是否足够，并且 使用化学遗传学操作逃离活体捕食者所必需的。在目标 2 中，我将检查 cck+ 是否 l/vlPAG 神经活动利用微型显微镜钙成像预测自由移动小鼠的逃跑 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 在泛神经元 PAG 细胞中使用化学遗传学操纵 cck+ l/vlPAG 神经活动并记录 使用微型显微镜观察 cck-PAG 细胞的后续神经活动。这三个目标共同将 作为阐明逃避神经机制的综合方法，这将提供更好的 深入了解恐慌机制。