Hippocampal Mechanisms of Fear Extinction

项目总结： 适应不良恐惧的主要临床治疗方法是消退--反复暴露在可怕的刺激下 没有威胁。灭绝并不能永久消除不适应的恐惧。消失的恐惧卷土重来 随着时间的推移，或者如果经历了新的创伤。物种灭绝的短暂现象表明确实如此。 不是消除习得的恐惧，而是建立一种新的记忆，与恐惧记忆竞争 表情。为了理解为什么恐惧会回来，我们必须更多地了解控制恐惧的机制 灭绝的恢复或表示灭绝。在这里，我们提出了一种非常新颖的方法来阐明这些机制。 我们的建议集中在海马齿状回(DG)，这是海马区的一个区域，在 背景恐惧记忆的获得--对一个发生了令人厌恶的经历的地方的恐惧。我们最近 发现DG神经活动也是背景恐惧消退所必需的。在这个奖项下，我们将使用 使用依赖活动的神经标记，这是一种允许我们标记(并随后操纵)神经的技术 在行为体验期间活跃的集成，以研究DG中的神经集成是如何 精心安排恐惧和灭绝记忆的表达。我们的中心假设是物种灭绝导致 DG来产生一个新的情境表征，而激活这种消亡表征可以抑制恐惧。 与这一假设一致，我们的初步研究表明：(1)害怕学习和害怕灭绝 激活小鼠DG中不同的“恐惧神经元”和“消亡神经元”，以及(2) 这些组合调节了恐惧和灭绝的表达。拟议的研究将利用这些 (1)检验以下假设的发现：消亡后恐惧的恢复反映了DG活动的变化 恐惧和消亡组合，(2)确定这些组合调节恐惧的机制，以及(3) 使用头戴式活体成像技术实时可视化处理恐惧和消退记忆的过程 微型显微镜。我们预计，拟议的研究将揭示控制 表达恐惧和灭绝，揭示为什么恐惧在灭绝后会恢复，并确定制定 灭绝更持久。

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.