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

项目摘要/摘要 回避是导致许多焦虑症有害影响的一个显著症状。 尽管如此，我们对逃避行为背后的神经回路的理解仍有很大差距。一个 对这一关键症状的机械描述将推动基于大脑的创新 病理性焦虑的治疗。 信号主动回避(SAA)是一种大鼠的行为程序，在这种程序中，高度持续的回避 反应是由与厌恶的无条件刺激(US)相关的条件刺激(CS)触发的。 由于回避反应阻止了美国的交付，收购SAA导致美国从 一旦响应变得更加频繁，在训练初期将迫在眉睫的威胁转变为稍后训练中的远程威胁。 受行为学启发的厌恶情绪模型表明，威胁迫在性的这种变化是一致的 随着从恐惧到焦虑的转变，表明SAA的表达是由类似焦虑的状态调节的。这个 这一建议的主要假设是，焦虑样行为的神经回路在SAA中发挥核心作用。 先前的研究表明终纹床核(BNST)与焦虑有关。生成 这一建议的总体假设的初步数据，初步实验是使用 抑制DREADD(设计者受体，由设计者药物独占地激活)灭活BNST神经元 进行SAA的大鼠。这种操作表明，BNST对于维护 回避反应。拟议的研究将以这一结果为基础，通过剖析电路的功能 主动回避机制，由BNST和为其提供突触输入的关键区域组成 (前额叶皮质、基底杏仁核)。 考虑到回避性应对是许多焦虑症常见的行为障碍，这项工作 与公共卫生有明确的相关性。避让回路的发现可能为创新提供了一个新的目标 病理性焦虑的治疗干预。这项工作的目标是生成严格的临床前数据 这加速了临床的进步。

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.