Dissecting Cell-Specific Brainstem Circuits Mediating Escape Behavior

点击翻译按钮获取中文摘要

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.