Neural circuits regulating flight and panic behavior.

调节飞行和恐慌行为的神经回路。

• 批准号: 10540228
• 负责人: Jonathan P Fadok
• 金额: $ 44.48万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540228
• 关键词: Alprazolam; Amygdaloid structure; Anxiety; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Brain; Calcium; Carbon Dioxide; Cells; Characteristics; Complex; Corticotropin-Releasing Hormone; Data; Development; Disease; Emotional; Foundations; Freezing; Fright; Glutamates; Goals; Hippocampus; Hypothalamic structure; Image; Knowledge; Mediating; Mental disorders; Mission; Modeling; Monitor; Mus; Neurobiology; Neurons; Neurosciences; Output; Panic; Panic Disorder; Pathway interactions; Pattern; Perception; Population; Population Projection; Positioning Attribute; Post-Traumatic Stress Disorders; Prevention; Psychological Theory; Public Health; Regulation; Research; Role; Source; Specific Phobia; Stimulus; Structure; Substance Use Disorder; System; Testing; Therapeutic; Trauma; United States National Institutes of Health; Viral Vector; Xanax; addiction; comorbidity; delivery vehicle; design; disability; emotional behavior; extracellular; in vivo; innovation; midbrain central gray substance; neural; neural circuit; neural correlate; neuromechanism; neuronal circuitry; novel; novel strategies; optogenetics; post-traumatic stress; response; theories

PROJECT SUMMARY Emotional behaviors, such as defensive responses to threat, are often dysregulated in mental illness. Currently, there is a poor understanding of the neural mechanisms that control transitions between modes and magnitudes of defensive responding. Obtaining such knowledge will provide significant progress toward the long-term goal of providing foundational knowledge used for the development of better therapeutics for mental illness. The overall objective of this application is to identify how distributed neuronal circuits control transitions to active forms of defensive behav- ior. The central hypothesis is that a widespread brain network that includes the central amygdala (CEA), ventromedial hypothalamus (VMH), periaqueductal grey (PAG), insular cortex (IC), and ventral hippocampus (vHIPP) controls defensive response transitions. The rationale that under- lies this proposal is that an enhanced understanding of these complex behavioral states and cir- cuits will provide foundational data for understanding multiple psychiatric disorders and their comorbidity. The proposed research tests the central hypothesis with three specific aims: 1) Iden- tify the functional role of specific projection pathways in defensive action selection; 2) Determine the impact of structures afferent to the CEA on flight behavior; and 3) Define the neuronal activity patterns that encode shifts in defensive states from freezing to flight to panic. The first aim will use viral vector delivery strategies and optogenetics to target and manipulate specific output path- ways of the CEA. The second aim will use retrograde targeting strategies to manipulate afferents to the CEA. Finally, the third aim will use deep-brain calcium imaging to monitor neural activity patterns in specific populations of projection neurons while mice transition through escalating lev- els of defensive responding. Successful completion of the proposed research will define mecha- nisms by which widespread brain networks mediate switching to active modes of defensive be- havior. The proposed research is innovative because it substantially departs from the status quo by investigating how the brain coordinates transitions between defensive behaviors. This will be significant because it will lay a foundation that facilitates understanding of the neuronal circuit basis of the maladaptive responses associated with mental illness. Indeed, this novel systems neuroscience approach to understanding how fear states are encoded will open new avenues of research into the neurobiological underpinnings of anxiety- and trauma-related mental health dis- orders, such as posttraumatic stress and panic disorder.

项目摘要 情绪行为，如对威胁的防御反应，通常在心理上失调， 病目前，人们对控制过渡的神经机制的理解还很差 防御性反应的模式和强度之间的关系。获得这些知识将提供 在实现提供基础知识用于 发展更好的治疗精神疾病的方法。本申请的总体目标是 以确定分布式神经元回路如何控制防御性神经元的主动形式的转变， 或核心假设是，包括中央杏仁核在内的广泛分布的大脑网络 (CEA)、下丘脑腹内侧（VMH）、导水管周围灰质（PAG）、岛叶皮质（IC）和 腹侧海马（vHIPP）控制防御反应的转换。根据- 这个建议是，加强对这些复杂行为状态和CIR的理解， 该研究将为了解多种精神疾病及其 科摩罗。拟议的研究测试的中心假设有三个具体目标：1）Iden- 明确特定投射通路在防御行为选择中的功能作用; 2）确定 传入CEA的结构对飞行行为的影响; 3）定义神经元活动 这些模式编码了防御状态从冻结到逃跑再到恐慌的转变。第一个目标将 使用病毒载体递送策略和光遗传学来靶向和操纵特定的输出路径- CEA的方式。第二个目标将使用逆行靶向策略来操纵传入神经 到CEA。最后，第三个目标将使用脑深部钙成像来监测神经活动 在特定群体的投射神经元的模式，而小鼠通过逐步升级的水平， 防御性反应。成功完成拟议的研究将定义机制- 广泛分布的大脑网络通过这种机制调节转换到积极的防御模式， 你好拟议的研究是创新的，因为它大大偏离了现状 通过研究大脑如何协调防御行为之间的转换。这将是 意义重大，因为它将为理解神经元回路奠定基础 与精神疾病相关的适应不良反应的基础。事实上，这种新的系统 神经科学的方法来理解恐惧状态是如何编码的，将开辟新的途径， 研究焦虑和创伤相关心理健康疾病的神经生物学基础， 例如创伤后应激障碍和恐慌症。