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.

项目摘要/摘要 恐慌症每年都会影响美国数百万的成年人。惊恐发作的特征是 压倒性的恐惧，呼吸困难，心律加速和逃脱的冲动。恐慌疗法是 通常无效，强调需要对恐慌发作的新机械理解到 预先处理。围绕灰色区域已与恐慌相关，如电气 刺激周围灰色（PAG）会引起人类恐慌，并引起逃脱，冻结和其他 啮齿动物的防御行为。但是，特定细胞群的遗传身份有选择地 驱动器逃脱是未知的。神经肽胆囊菌（CCK）在侧面和腹外侧表达 PAG（L/VLPAG）列。我建议在侧面剖析涉及CCK+神经元的新型神经回路 在伦理捕食者暴露行为期间，小鼠的腹外侧PAG（L/VLPAG）在小鼠中逃脱 测定以阐明逃生机制。在AIM 1中，我将测试CCK+ L/VLPAG神经活动是否足够，并且 使用化学发生操作逃脱活捕食者所必需的。在AIM 2中，我将检查CCK+是否 l/vlpag神经活动可以预测使用微型显微镜钙成像在自由移动的小鼠中逃脱 活老鼠的存在。在AIM 3中，我将测试CCK+ L/VLPAG细胞是否有助于编码逃生和威胁 在泛神经元PAG细胞中使用化学遗传学操纵CCK+ L/VLPAG神经活动和记录 随后使用微型显微镜在CCK-PAG细胞中的神经活性。这三个目标在一起将 作为阐明逃生神经机制的全面方法，这将提供更好的 了解理解恐慌机制。