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: 8133814
• 负责人: Caitlin Anne Orsini
• 金额: $ 3.15万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133814
• 关键词: Accounting; Address; Amygdaloid structure; Anxiety; Anxiety Disorders; Automobile Driving; Behavior; Behavior Therapy; Cell Nucleus; Cells; Cerebral hemisphere; Cholera Toxin; Clinical; Conditioned Stimulus; Contralateral; Dependence; Disease; Extinction (Psychology); FOS gene; Freezing; Fright; GABA Agonists; Grant; Heart; Hippocampus (Brain); Immunohistochemistry; Individual; Injection of therapeutic agent; Interneurons; Intervention; Learning; Lesion; Memory; Modeling; Muscimol; Neurons; Pathology; Population; Population Projection; Post-Traumatic Stress Disorders; Procedures; Property; Public Health; Rattus; Recovery; Reporting; Research; Retrieval; Shock; Source; Specificity; Stimulus; Structure; Testing; Therapeutic Intervention; Tracer; Training; Work; cellular imaging; conditioned fear; foot; inhibitory neuron; insight; memory encoding; neural circuit; neurobehavioral; neuromechanism; prevent; relating to nervous system; research study; response

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.

焦虑症是一个重大的公共卫生问题。经典条件的恐惧的灭绝是焦虑症的治疗干预措施（例如暴露疗法）的有用模型。有趣的是，在恐惧灭绝期间学到的记忆是上下文依赖的，这给焦虑的临床干预带来了巨大的挑战。例如，在灭绝环境之外呈现出灭绝的条件刺激（CS）会产生条件恐惧的更新。最近的工作表明，灭绝记忆是在杏仁核中编码的，并且海马对于灭绝后的恐惧恢复到灭绝的CS至关重要。因此，我们假设海马和杏仁核之间的直接轴突连接对于响应恐惧反应的上下文依赖性表达至关重要。为了检验这一假设，我们将首先检查杏仁核（BA）（BA）在灭绝后更新恐惧的功能上断开腹侧海马（VH）和基底外侧核的后果。 GABA激动剂Muscimol的微诱导将在一个半球中以VH和BA在对侧半球中的BA进行，然后在检索测试中，在灭绝情况下或其他情况下呈现了灭绝的CS。我们预测，当CS在灭绝环境之外呈现CS时，VH和BA的药理断开将损害恐惧的恐惧。为了进一步表征VH-BA投影对更新的贡献，我们将研究VH-BA断开连接对杏仁核内C-FOS表达的影响。 C-FOS和GAD67的双重免疫组织化学将使我们能够阐明BA中的投射神经元或抑制性神经元是否在恐惧或灭绝记忆中被海马输入驱动。我们预计，恐惧的更新将增加BA中C-FOS阳性投影神经元的数量，而VH-BA断开将限制这种表达。最后，我们将使用C-FOS免疫组织化学并将逆行示踪剂（霍乱毒素B，CTB）注射到BA中，以确定在更新恐惧期间投射到BA的VH神经元是否参与。我们预测，与表达灭绝的大鼠相比，恐惧的更新将与c-fos表达相关。总的来说，这些结果将提供有关调节灭绝后恐惧记忆表达的神经回路机制的见解。我们希望这项工作将为那些患有焦虑和恐惧病理（例如创伤后应激障碍）的人提供有效的治疗干预措施。