Interactions between the ventral hippocampus and amygdala during renewal of fear

恐惧更新期间腹侧海马和杏仁核之间的相互作用

• 批准号: 7998303
• 负责人: Caitlin Anne Orsini
• 金额: $ 3.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998303
• 关键词: Accounting; Amygdaloid structure; Anxiety; Anxiety Disorders; Cell Nucleus; Cholera Toxin; Clinical; Contralateral; Extinction (Psychology); FOS gene; Face; Fright; GABA Agonists; Grant; Hippocampus (Brain); Immunohistochemistry; Individual; Injection of therapeutic agent; Intervention; Learning; Memory; Modeling; Muscimol; Neurons; Pathology; Post-Traumatic Stress Disorders; Public Health; Rattus; Recovery; Research; Retrieval; Stimulus; Testing; Therapeutic Intervention; Tracer; Work; conditioned fear; inhibitory neuron; insight; memory encoding; neural circuit; neuromechanism; public health relevance; response

DESCRIPTION (provided by applicant): Anxiety disorders are a significant public health problem. Extinction of classically conditioned fear is a useful model of therapeutic interventions, such as exposure therapy, for anxiety disorders. Interestingly, the memories learned during the extinction of fear are context-dependent, and this presents a considerable challenge to clinical interventions for anxiety. For example, presenting an extinguished conditional stimulus (CS) outside of the extinction context produces a renewal of conditioned fear. Recent work suggests that extinction memories are encoded in the amygdala, and that the hippocampus is essential for the renewal of fear to an extinguished CS after extinction. Accordingly, we hypothesize that direct axonal connections between the hippocampus and amygdala are essential for the context-dependent expression of an extinguished fear response. To test this hypothesis, we will first examine the consequences of functionally disconnecting the ventral hippocampus (VH) and basolateral nucleus of the amygdala (BA) on the renewal of fear after extinction. Microinfusions of the GABA agonist muscimol will be made into the VH in one hemisphere and the BA in the contralateral hemisphere prior to a retrieval test in which an extinguished CS is presented in either the extinction context or another context. We predict that pharmacological disconnection of the VH and BA will impair fear renewal of fear when the CS is presented outside the extinction context. To further characterize the contribution of the VH-BA projection to renewal, we will examine the effect of VH-BA disconnections on the expression of c-fos within the amygdala. Dual immunohistochemistry for c-fos and GAD67 will allow us to elucidate whether projection neurons or inhibitory neurons in the BA are driven by hippocampal input during the retrieval of fear or extinction memories. We expect that the renewal of fear will increase the number of c-fos positive projection neurons in the BA, and that VH-BA disconnections will limit this expression. Lastly, we will use c-fos immunohistochemistry and injection of retrograde tracers (cholera toxin b, CTb) into the BA to determine whether VH neurons projecting to the BA are engaged during the renewal of fear. We predict that the renewal of fear will be associated with c-fos expression in a greater proportion of BA-projecting VH neurons than in rats expressing extinction. Collectively, these results will provide insight into the neural circuit mechanisms for regulating the expression of fear memories after extinction. It is our hope that this work will inform effective therapeutic interventions for those individuals who suffer from anxiety and fear pathologies, such as post-traumatic stress disorder. PUBLIC HEALTH RELEVANCE: The work proposed in this grant will help elucidate the neural circuits involved in the recovery of fear, which is critical in understanding the pathology involved in post-traumatic stress disorder (PTSD). Though exposure therapy is commonly used to treat PTSD and anxiety disorders, one problem that clinicians regularly encounter is the persistence of fear even in the face of extensive therapy. The research in this grant will try to explain what neural mechanisms account for this phenomenon with the hope that further understanding will result in better treatment and therapy.

描述（由申请人提供）：焦虑症是一个重大的公共卫生问题。消除经典条件恐惧是治疗干预的一个有用模型，如暴露疗法，用于焦虑症。有趣的是，在消除恐惧过程中习得的记忆是情境依赖的，这对临床干预焦虑提出了相当大的挑战。例如，在消失情境之外呈现一个消失的条件刺激（CS）会产生条件恐惧的更新。最近的研究表明，消失记忆是在杏仁核中编码的，而海马体对于在消失后将恐惧恢复到已消失的CS至关重要。因此，我们假设海马体和杏仁核之间的直接轴突连接对于消失的恐惧反应的上下文依赖性表达是必不可少的。为了验证这一假设，我们将首先研究在功能上切断腹侧海马（VH）和杏仁核基底外侧核（BA）对恐惧消失后重建的影响。将GABA激动剂muscimol微量输注到一侧脑的VH和对侧脑的BA中，然后进行恢复测试，在恢复测试中，熄灭的CS在消失环境或另一个环境中呈现。我们预测，当CS出现在消失情境之外时，VH和BA的药理学断开将损害恐惧的更新。为了进一步表征VH-BA投射对更新的贡献，我们将研究VH-BA断开对杏仁核内c-fos表达的影响。c-fos和GAD67的双重免疫组化将使我们能够阐明在恐惧或消失记忆的检索过程中，BA中的投射神经元还是抑制神经元是由海马输入驱动的。我们预计恐惧的恢复会增加BA中c-fos阳性投射神经元的数量，而VH-BA的断开会限制这种表达。最后，我们将使用c-fos免疫组织化学和向BA注射逆行示踪剂（霍乱毒素b， CTb）来确定在恐惧更新过程中，向BA投射的VH神经元是否参与。我们预测，与表达灭绝的大鼠相比，在ba投射的VH神经元中，c-fos的表达与恐惧的更新有关。总的来说，这些结果将为恐惧记忆消失后调节表达的神经回路机制提供见解。我们希望这项工作能够为那些患有焦虑和恐惧病理（如创伤后应激障碍）的人提供有效的治疗干预措施。