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（由申请人提供）：当前项目的长期目标是揭示休克引起的恐惧相关焦虑和创伤障碍（例如恐惧症、恐慌症和后遗症）恢复的基本神经回路。 -创伤性应激障碍）普遍存在；它们给我们的社会带来了巨大的经济和社会负担，遗憾的是，这些疾病的治疗受到已消失的恐惧的复发的困扰：威胁性和厌恶性。在对大鼠进行病理性恐惧的治疗干预后，事件可以重新唤醒恐惧反应，该项目将研究大鼠暴露于危险（与电击相关的）环境后导致恐惧复发的行为和大脑机制。特别是，我们的实验室已经证明了床核的选择性作用。 其他研究表明，当动物处于厌恶的环境中时，BNST 损伤也可以防止应激反应（例如皮质酮释放）。现代工具可识别 BNST 产生这些效应的精确回路 BNST 向杏仁核中央核 (CeA) 发送大量投射。下丘脑室旁核 (PVN) 对于条件性恐惧的表达至关重要，而 PVN 在介导应激反应中发挥重要作用，我们认为 BNST 在休克相关环境中调节冻结和应激反应。通过作用于这些结构；这种活动模式可能有助于恢复我们的假设，在目标 1 中，我们将利用逆行（霍乱毒素 B 亚群）神经元追踪技术。与神经活动标记物 (c-Fos) 的免疫组织化学相结合，以确定 BNST 的 CeA 和 PVN 投射细胞在厌恶环境暴露期间的活动模式（实验 1）。此外，我们将使用顺行病毒追踪方法（荧光）。单纯疱疹病毒1型H129重组体结合c-Fos检测观察接受BNST输入的CeA/PVN细胞恢复过程中的活性程度（实验 2）将询问 BNST:CeA 或 BNST:PVN 回路的失活是否会以冻结和压力反应的形式对情境恐惧产生可分离的影响（分别；实验 3），以及 BNST:CeA 回路是否会导致情境恐惧。是 BNST 促进恐惧恢复的关键途径（实验 4）。设计药物（DREADD），我们将在暴露于休克相关环境期间和恢复恐惧期间选择性地沉默 BNST 传出到 CeA 和 PVN 的信号。此外，我们将测量皮质酮释放，以观察这些途径中的任何一个的失活是否能够产生影响。反过来，该项目将为在危险环境下调节压力水平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活跃核相互作用。