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.

焦虑症是一个重要的公共卫生问题。消除经典的条件性恐惧是一个有用的治疗干预模型，如暴露疗法，用于焦虑症。有趣的是，在恐惧消退期间学到的记忆是依赖于上下文的，这对焦虑的临床干预提出了相当大的挑战。例如，在灭绝情境之外呈现一个熄灭的条件刺激（CS）会产生条件恐惧的更新。最近的研究表明，灭绝记忆是在杏仁核中编码的，而海马体对于灭绝后将恐惧更新到消失的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除恐惧反应的上下文依赖性表达至关重要。为了验证这一假设，我们将首先检查功能断开腹侧海马（VH）和杏仁核（BA）的恐惧灭绝后的更新的后果。将GABA激动剂蝇蕈醇微量输注到一个半球的VH和对侧半球的BA中，然后进行恢复测试，其中在消退背景或另一种背景下呈现熄灭的CS。我们预测，药理学断开的VH和BA将损害恐惧的恐惧更新时，CS是灭绝的背景之外。为了进一步描述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GAD 67的双重免疫组化将使我们能够阐明BA中的投射神经元或抑制神经元是否在恐惧或灭绝记忆的检索过程中由海马输入驱动。我们预计，恐惧的更新将增加BA中c-fos阳性投射神经元的数量，而VH-BA切断将限制这种表达。最后，我们将使用c-fos免疫组织化学和注射逆行示踪剂（霍乱毒素B，CT B）到BA，以确定是否VH神经元投射到BA在更新的恐惧。我们预测，更新的恐惧将与c-fos表达在更大比例的BA投射VH神经元比大鼠表达灭绝。总的来说，这些结果将提供深入了解神经回路机制，用于调节灭绝后恐惧记忆的表达。我们希望，这项工作将为那些患有焦虑和恐惧症的人提供有效的治疗干预措施，如创伤后应激障碍。