Neural Circuits for Reinstatement of Fear

恢复恐惧的神经回路

• 批准号: 9267355
• 负责人: Travis David Goode
• 金额: $ 3.32万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267355
• 关键词: Amygdaloid structure; Animal Model; Animals; Anxiety; Attenuated; Beds; Behavior; Behavioral; Brain; Canine Adenoviruses; Cell Nucleus; Cells; Cholera Toxin; Clinical; Clozapine; Communication; Complex; Conditioned Stimulus; Corticosterone; Critical Pathways; Cues; Dangerousness; Data; Detection; Development; Disease; Economics; Enterobacteria phage P1 Cre recombinase; Event; Exposure to; Extinction (Psychology); FOS gene; Freezing; Fright; Future; Goals; Herpesvirus 1; Hormones; Hypothalamic structure; Immunohistochemistry; Income; Individual; Injectable; Injection of therapeutic agent; Label; Lesion; Ligands; Measures; Mediating; Methods; Modernization; Neurons; Output; Oxides; Panic Disorder; Pathologic; Pathway interactions; Pattern; Pharmacology; Phobias; Play; Population; Post-Traumatic Stress Disorders; Procedures; Rattus; Recombinants; Relapse; Research; Rodent; Role; Shock; Site; Societies; Stimulus; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Sum; System; Techniques; Testing; Therapeutic Intervention; Time; Tracer; Trauma; Viral; Work; adeno-associated viral vector; anxiety-related disorders; auditory stimulus; biological adaptation to stress; conditioned fear; designer receptors exclusively activated by designer drugs; experience; gene product; insight; interest; neural circuit; novel; paraventricular nucleus; prevent; public health relevance; relating to nervous system; response; skills; social; tool

 DESCRIPTION (provided by applicant): The long-term goal of the current project is to reveal the essential neural circuits underlying the shock-induced reinstatement of extinguished fear. Fear-related anxiety and trauma disorders (e.g., phobias, panic disorder, and post-traumatic stress disorder) are prevalent and pervasive; they represent a tremendous economic and social burden on our society. Regrettably, treatments for these illnesses are plagued by the relapse of extinguished fear: threatening and aversive events can reawaken fear responding after therapeutic interventions for pathological fear. Utilizing Pavlovian fear conditioning and extinction procedures in rats, this project will investigate the behavioral and brain mechanisms contributing to fear relapse after the exposure of rats to a dangerous (shock-associated) context (i.e., reinstatement). In particular, our lab has demonstrated a selective role for the bed nucleus of the stria terminalis (BNST) in mediating contextual fear and the reinstatement of extinguished fear after footshock. Others have revealed that BNST lesions also prevent stress responding (e.g., corticosterone release) when animals are in aversive contexts. However, no one has yet used modern tools to identify the precise circuits through which the BNST contributes to these effects. The BNST sends heavy projections to the central nucleus of the amygdala (CeA) and the paraventricular nucleus of the hypothalamus (PVN). The CeA is essential for the expression of conditioned fear, whereas the PVN has an important role in mediating stress responses. We propose that the BNST modulates freezing and stress responses in a shock-associated context by acting on these structures; this pattern of activity may contribute to reinstatement. We will test our hypothesis in two primary aims. In Aim 1, we will utilize retrograde (cholera toxin subuni B) neuronal tracing techniques combined with immunohistochemistry for markers of neural activity (c-Fos) to identify patterns of activity in CeA- and PVN-projecting cells of the BNST during aversive context exposure (Exp. 1). Additionally, we will use anterograde viral tracing methods (fluorescent recombinants of herpes simplex virus type 1, H129) combined with c-Fos detection to observe the degree of activity in CeA/PVN cells receiving BNST input during reinstatement (Exp. 2). Aim 2 will ask whether inactivation of BNST:CeA or BNST:PVN circuits make dissociable contributions to context fear, in the form of freezing and stress responding (respectively; Exp. 3), and whether BNST:CeA circuits are the critical pathway by which BNST promotes reinstatement of fear (Exp. 4). Using adeno-associated viral (AAV) vectors for designer receptors exclusively activated by designer drugs (DREADDs), we will selectively silence BNST efferents to the CeA and PVN during exposure to a shock-associated context and during reinstatement of fear. Additionally, we will measure corticosterone release to observe whether inactivation of either of these pathways is capable of modulating stress levels during in a dangerous context. In turn, this project will provide valuable scientific and clinical insight on how fear-regulating systems interact with stress-active nuclei of the brain.

 描述（由适用提供）：当前项目的长期目标是揭示冲击引起的恢复被扑灭的恐惧的基本中性电路。与恐惧相关的焦虑和创伤障碍（例如恐惧症，恐慌症和创伤后应激障碍）是普遍且普遍存在的。它们代表着我们社会上的巨大经济和社会伯恩。遗憾的是，这些疾病的治疗受到严重恐惧的复发的困扰：在治疗性干预措施对病理恐惧的治疗干预措施后，恐惧会反应恐惧。该项目利用大鼠的恐惧调节和扩展程序，将调查大鼠暴露于危险（震动相关）环境（即恢复原状）后导致恐惧缓解的行为和大脑机制。特别是，我们的实验室已经证明了床核的选择性作用 在介导情境恐惧和恢复脚印后扑灭恐惧的恢复时，质子终端（BNST）其他人则透露，当动物处于厌恶性情况下时，BNST病变也可以防止压力反应（例如，皮质酮释放）。但是，没有人还使用现代工具来识别BNST对这些效果贡献的确切电路。 BNST将繁重的项目发送到杏仁核（CEA）的中央核和下丘脑（PVN）的室室核核。 CEA对于表达条件恐惧是必不可少的，而PVN在介导压力反应中具有重要作用。我们建议，BNST通过对这些结构作用，在冲击相关的情况下调节冻结和压力反应。这种活动模式可能有助于恢复原状。我们将在两个主要目标中检验我们的假设。在AIM 1中，我们将利用逆行（霍乱毒素亚基B）神经元跟踪技术与免疫组织化学结合用于神经元活性标志物（C-FOS）来识别BNST在厌恶上下文中的CEA和PVN训练细胞中CEA-和PVN-PVN-PROCTON的活性模式（exp。1）。此外，我们将使用同类病毒追踪方法（疱疹病毒1型，H129的荧光重组分子）与C-FOS检测结合使用，以观察CEA/PVN细胞在重新定位期间接受BNST输入的CEA/PVN细胞的活性程度（Exp。2）。 AIM 2将询问BNST的失活：CEA或BNST：PVN电路是否以冻结和压力响应的形式（分别为;exp。3）以及BNST：CEA COUDDITS是BNST的关键途径，BNST促进了BNST促进恐惧（Exp。4）。使用与设计师药物（Dreadds）专门激活的设计器接收器的腺相关病毒（AAV）矢量，我们将在暴露于与冲击相关的环境以及恢复恐惧的过程中有选择地对CEA和PVN静音。此外，我们将测量皮质酮释放，以观察这些途径中的任何一种途径是否能够在危险情况下调节应力水平。反过来，该项目将提供有价值的科学和临床见解 恐惧调节系统如何与大脑的压力激活核I相互作用。