Title: The thalamic nucleus reuniens mediates the transition from reactive to proactive defensive behavior via feedforward inhibition

标题：丘脑团聚核通过前馈抑制介导从反应性防御行为到主动防御行为的转变

• 批准号: 10354461
• 负责人: Justin M Moscarello
• 金额: $ 7.17万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354461
• 关键词: Amygdaloid structure; Animals; Attenuated; Behavior; Behavioral; Brain; Bypass; Caring; Cells; Clinical; Complex; Conditioned Stimulus; Contralateral; Control Locus; Cues; Data; Environment; Fiber; Foundations; Freezing; Fright; Goals; Hippocampus (Brain); Horns; Immobilization; Interneurons; Learning; Life; Mediating; Memory; Mental Health; Methods; Modeling; Neurons; Outcome; Output; Pathway interactions; Pilot Projects; Play; Prefrontal Cortex; Problem Solving; Process; Prosencephalon; Publishing; Rattus; Reaction; Retrieval; Reuniens Thalamic Nucleus; Role; Safety; Shock; Side; Signal Transduction; Stimulus; Structure; Techniques; Testing; Thalamic structure; Therapeutic; Training; Viral; Work; aversive conditioning; avoidance behavior; conditioning; coping; designer receptors exclusively activated by designer drugs; experimental study; flexibility; innovation; neural circuit; neuromechanism; pre-clinical; prevent; recruit; resilience; response; selective expression

PROJECT SUMMARY/ABSTRACT Life often requires us to be proactive in the face of danger. When crossing the road, the adaptive response to the horn of an oncoming care is to cross to the other side as quickly as possible. Yet fear can have an immobilizing effect, creating a paradoxical situation in which a deeply engrained defense against danger must be suppressed in order to achieve safety. Thus, adaptive coping in a complex environment necessitates the ability to move past defensive reactions in favor of proactive, problem- solving behavioral strategies. Signaled active avoidance (SAA) is a behavioral conditioning paradigm that effectively models the process by which a learned, problem-solving action replaces the innate reactions elicited by a threatening cue. Past work suggests that the nucleus reuniens of the midline thalamus plays a crucial role in this process, acting to suppress immobilizing responses in favor of an adaptive behavioral strategy that prevents an aversive outcome. Work proposed here will extend this finding by using chemogenetic techniques to target the crucial outputs of the reuniens that function to suppress freezing and facilitate active avoidance. Our primary hypothesis is that projections from the nucleus reuniens engage feedforward inhibition by activating inhibitory interneurons in limbic regions, such as the ventral hippocampus and the basolateral amygdala, that mediate the expression of aversive associative memory and thus conditioned freezing. Successful execution of the proposed studies will establish an important neural mechanism that promotes behavioral flexibility and adaptive problem solving under threat. A proactive style of coping is associated with an internal locus of control and resilience, suggesting the mental health relevance of its underlying circuitry. By dissecting the function of this pathway, our goal is to generate preclinical data that hastens clinical advancement by providing targets for cutting-edge therapeutic innovations.

项目摘要/摘要 生活往往要求我们在危险面前保持积极主动。过马路时，自适应 对即将到来的危险的喇叭的反应是尽快地穿过到另一边。然而恐惧 会产生一种令人无法动弹的效果，造成一种自相矛盾的局面， 为了安全，必须压制危险。因此，适应性应对在一个复杂的 环境需要有能力超越防御性反应，转而采取积极主动的、有问题的、 解决行为策略 信号主动回避（SAA）是一种行为条件反射范式， 一种习得的、解决问题的行为取代由一种行为引起的先天反应的过程。 威胁提示过去的研究表明，中线丘脑的核团在大脑中起着至关重要的作用。 在这一过程中的作用，采取行动，以抑制固定反应，有利于适应性行为 防止出现令人厌恶的结果的策略。这里提出的工作将通过使用 化学遗传学技术，以抑制冻结功能的团聚体的关键输出为目标 并促进主动回避。我们的主要假设是来自细胞核的投射物 通过激活边缘区的抑制性中间神经元，如腹侧 海马体和基底外侧杏仁核，介导厌恶性联想的表达 记忆和条件冻结。成功执行拟议的研究将建立一个 重要的神经机制，促进行为的灵活性和适应性问题的解决， 威胁 积极的应对方式与内部控制点和弹性有关， 暗示了其潜在回路的心理健康相关性。通过剖析这一功能， 途径，我们的目标是通过提供靶点来生成加速临床进展的临床前数据， 用于尖端的治疗创新。