Hippocampal Mechanisms of Fear Extinction

海马消除恐惧的机制

• 批准号: 10329899
• 负责人: MICHAEL R DREW
• 金额: $ 38.48万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10329899
• 关键词: Award; Behavioral; Clinic; Clinical Treatment; Code; Data; Exposure to; Extinction (Psychology); Fright; Head; Hippocampus (Brain); Image; Immediate-Early Genes; Immunohistochemistry; Label; Lead; Learning; Light; Memory; Methods; Microscope; Monitor; Mus; Neurons; Output; Pathologic; Pathway interactions; Pattern; Play; Population; Process; Recovery; Relapse; Research; Retrieval; Role; Stimulus; Techniques; Testing; Time; Training; Trauma; base; behavior influence; conditioned fear; dentate gyrus; experience; experimental study; fear memory; gain of function; in vivo; in vivo imaging; innovation; learned behavior; learning extinction; neural patterning; novel; novel strategies; optogenetics; public health relevance; relating to nervous system; time use

Project Summary: The primary clinical treatment for maladaptive fear is extinction—repeated exposure to a fearful stimulus in the absence of threat. Extinction does not permanently eliminate maladaptive fear. Extinguished fear resurfaces with the passage of time or if a new trauma is experienced. The transience of extinction suggests that it does not erase learned fear but, instead, establishes a new memory that competes with the fear memory for expression. To understand why fear returns, we must know more about the mechanisms controlling the retrieval or expression of extinction. Here we propose a highly novel approach to elucidate these mechanisms. Our proposal focuses on the dentate gyrus (DG), a region of the hippocampus that plays a critical role in acquisition of context fear memory—fear of a place in which an aversive experience occurred. We recently discovered that DG neural activity is also required for context fear extinction. Under this award, we will use using activity-dependent neural tagging, a technique that allows us to tag (and later manipulate) neural ensembles that are active during a behavioral experience, to investigate how neural ensembles in DG orchestrate the expression of fear and extinction memories. Our central hypothesis is that extinction causes DG to generate a new context representation, and activation of this extinction representation suppresses fear. Consistent with this hypothesis, our preliminary studies indicate (1) that fear learning and fear extinction activate distinct ensembles of “fear neurons” and “extinction neurons” in DG in mice, and (2) the activity of these ensembles modulates expression of fear and extinction. The proposed studies will leverage these findings to (1) test the hypothesis that the recovery of fear after extinction reflects changes in the activity of DG fear and extinction ensembles, (2) identify mechanisms through which these ensembles modulate fear, and (3) visualize the processing of fear and extinction memory in real-time using in vivo imaging with head-mounted miniature microscopes. We anticipate that the proposed research will uncover mechanisms controlling the expression of fear and extinction, reveal why fear recovers after extinction, and identify strategies for making extinction more durable.

项目概要： 适应不良恐惧的主要临床治疗方法是消退——反复暴露于恐惧刺激下。 没有威胁。灭绝并不能永久消除适应不良的恐惧。熄灭的恐惧再次浮现 随着时间的推移或经历新的创伤。灭绝的短暂性表明它确实 不会消除习得的恐惧，而是建立一种新的记忆，与恐惧记忆竞争 表达。要理解恐惧为何卷土重来，我们必须更多地了解控制恐惧的机制。 检索或表达灭绝。在这里，我们提出了一种非常新颖的方法来阐明这些机制。 我们的建议重点关注齿状回（DG），这是海马体的一个区域，在 获得背景恐惧记忆——对发生令人厌恶的经历的地方感到恐惧。我们最近 发现 DG 神经活动也是情境恐惧消退所必需的。根据该奖项，我们将使用 使用依赖于活动的神经标记，这种技术允许我们标记（并随后操纵）神经 在行为体验过程中活跃的集成，以研究 DG 中的神经集成如何 协调恐惧和灭绝记忆的表达。我们的中心假设是灭绝导致 DG 生成新的上下文表示，并且激活该消退表示会抑制恐惧。 与这一假设一致，我们的初步研究表明（1）恐惧学习和恐惧灭绝 激活小鼠 DG 中不同的“恐惧神经元”和“消退神经元”集合，以及（2） 这些整体调节恐惧和灭绝的表达。拟议的研究将利用这些 (1) 检验以下假设：灭绝后恐惧的恢复反映了 DG 活动的变化 恐惧和灭绝整体，（2）确定这些整体调节恐惧的机制，以及（3） 使用头戴式体内成像实时可视化恐惧和消退记忆的处理过程 微型显微镜。我们预计拟议的研究将揭示控制机制 恐惧和灭绝的表达，揭示恐惧在灭绝后恢复的原因，并确定应对策略 灭绝更持久。