Dissecting the role of the bed nucleus of the stria terminalis in avoidant behavior

项目总结/摘要 回避是导致许多焦虑症有害影响的标志性症状。 尽管如此，我们对回避行为背后的神经回路的理解仍然存在重大差距。一 对这一关键症状的机械解释将推动基于大脑的创新的进展， 病理性焦虑的治疗 信号主动回避（SAA）是大鼠的一种行为过程，其中高度持续的回避 条件刺激（CS）与厌恶性非条件刺激（US）相关联，触发了条件反应。 由于回避反应阻止了美国的交付，收购SAA导致美国从一个 一旦响应变得更加频繁，从训练初期的迫在眉睫的威胁到训练后期的远程威胁。 动物行为学启发的厌恶情绪模型表明，这种威胁紧迫性的变化是一致的， 从恐惧到焦虑的转变，表明SAA表达是由焦虑样状态介导的。的 这个提议的首要假设是，焦虑样行为的神经回路在SAA中起着核心作用。 以前的工作涉及床核的终纹（BNST）的焦虑。完成网站 初步数据的总体假设的这一建议，初步实验进行了使用 抑制DREADD（设计师受体专门激活的设计师药物）的BNST神经元， 进行SAA的大鼠。这一操作表明，BNST是必要的，为维护的 回避反应拟议的研究将建立在这一结果的解剖功能的电路 主动回避机制，由BNST和为其提供突触输入的关键区域组成 （前额皮质，基底杏仁核）。 鉴于回避应对是许多焦虑症常见的行为障碍，这项工作 与公共卫生有明显的相关性。回避回路的发现可以为创新提供一个新的目标 病理性焦虑的治疗干预。这项工作的目标是产生严格的临床前数据 加速了临床进步。

PROJECT SUMMARY/ABSTRACT Avoidance is a hallmark symptom contributing to the deleterious impact of many anxiety disorders. Despite this, there are major gaps in our understanding of the neural circuits underlying avoidant behavior. A mechanistic account of this key symptom would advance progress toward brain-based innovations for the treatment of pathological anxiety. Signaled active avoidance (SAA) is a behavioral procedure for rats in which a highly persistent avoidance response is triggered by a conditioned stimulus (CS) associated with an aversive unconditioned stimulus (US). Because the avoidance response prevents US delivery, acquisition of SAA causes the US to transition from an imminent threat early in training to a remote threat later in training, once the response has become more frequent. Ethologically inspired models for aversive emotion suggest that this change in threat imminence is consistent with a shift from fear to anxiety, indicating that SAA expression is mediated by an anxiety-like state. The overarching hypothesis of this proposal is that neural circuits of anxiety-like behavior play a central role in SAA. Previous work implicates the bed nucleus of the stria terminalis (BNST) in anxiety. To generate preliminary data for the overarching hypothesis of this proposal, an initial experiment was conducted using an inhibitory DREADD (designer receptor exclusively activated by designer drugs) to inactivate BNST neurons in rats performing SAA. This manipulation demonstrated that BNST is necessary for the maintenance of the avoidance response. The proposed studies will build on this result by dissecting the function of a circuit mechanism for active avoidance, comprised of BNST and key regions that provide it with synaptic input (prefrontal cortex, basal amygdala). Given that avoidant coping is a behavioral disturbance common to many anxiety disorders, this work has clear relevance to public health. Discovery of an avoidance circuitry could provide a novel target for innovative therapeutic interventions for pathological anxiety. The goal of this work is to generate rigorous preclinical data that accelerates clinical advancement.