Neural circuits regulating flight and panic behavior.

调节飞行和恐慌行为的神经回路。

• 批准号: 10765755
• 负责人: Jonathan P Fadok
• 金额: $ 7.61万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10765755
• 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，例如对威胁的防御反应，通常在心理中失调 疾病。目前，对控制过渡的神经机制的理解很差 在防御性响应的模式和大小之间。获得此类知识将提供 朝着提供用于长期目标的重大进展，以提供用于的基础知识 开发更好的精神疾病治疗疗法。该应用程序的总体目标是 确定分布式神经元电路如何控制向防御行为的主动形式的过渡 - ior。中心假设是包括中央杏仁核在内的广泛的大脑网络 （CEA），腹侧下丘脑（VMH），灰灰色（PAG），岛状皮层（IC）和 腹海马（VHIPP）控制防御反应转变。不足的理由 这一建议是，对这些复杂的行为状态和CIR的了解增强了 inf将提供基本数据，以了解多种精神疾病及其 合并症。提出的研究以三个特定目的检验了中心假设：1） 提出特定投影途径在防御行动选择中的功能作用； 2）确定 CEA传播的结构对飞行行为的影响； 3）定义神经元活动 编码防御状态从冰冻到飞行再到恐慌的模式。第一个目标 使用病毒矢量输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定位策略来操纵传入 到CEA。最后，第三个目标将使用深脑钙成像来监测神经活动 小鼠通过升级的LEV-的小鼠过渡时的特定群体中的模式 防御性的回应。拟议研究的成功完成将定义机械 广泛的大脑网络可以介导切换到防御性模式的nisms。 Havior。拟议的研究具有创新性，因为它大大脱离了现状 通过研究大脑如何在防御行为之间进行过渡。这将是 意义重大，因为它将奠定促进对神经元电路的理解的基础 与精神疾病相关的适应不良反应的基础。确实，这个新颖的系统 神经科学的方法了解恐惧状态如何编码将打开新的途径 研究与焦虑和创伤有关的心理健康的神经生物学基础 命令，例如创伤后压力和恐慌症。