Microcircuits governing conflicting memories of threat and safety

恐惧学习使动物能够通过形成记忆来检测和保护自己免受危险情况的伤害 这将创伤期间遇到的刺激与身体或心理伤害的经历联系在一起。相反， 限制这些行为的主要机制是通过灭绝，在这种机制中，重复 再次暴露在条件性刺激中而不产生令人厌恶的后果，可以减轻恐惧。研究表明， 灭绝形成了一种新的安全记忆，在记忆回忆过程中与最初的恐惧联系竞争。 然而，尽管回忆阶段的缺陷是病理性恐惧的主要因素，但回路机制 潜在的灭绝回忆以及它们如何区分相互竞争的恐惧和灭绝记忆 这在很大程度上仍然是个谜。这是一个基本的知识鸿沟，限制了对灭绝和潜在的洞察 它在精神障碍方面失败的原因。在这个项目中，我们假设一个重要的机制 背景恐惧消退是腹侧海马区生长抑素中间神经元的招募，而这些 信元控制相互竞争的上下文表示之间的切换，一个信令威胁和另一个安全。在……里面 支持这一假设，我们发现生长抑素中间神经元优先被熄灭的 在这种情况下，环境及其操纵会调节恐惧的表达，但在其他情况下则不会。使用以下组合 交叉遗传学、电生理学、光遗传学和钙成像，我们将研究这些特性 以及支持上下文相关行为的生长抑素中间神经元的离散群体的功能。在……里面 特别是，我们将研究这些细胞是否控制着高恐惧状态和低恐惧状态之间的转换，并阐明 这种转换背后的机制在兴奋性神经元群体的水平上涉及到恐惧和 消亡记忆。这些目标的成功完成将有助于阐明大脑是如何管理冲突的 不明确环境的内部模型以及提供电路动态的详细说明 促进恐惧的消失，并防止它再次出现。

Fear learning allows animals to detect and defend themselves from dangerous situations by forming a memory that links stimuli encountered during trauma with the experience of physical or psychological harm. Conversely, the primary mechanism through which these behaviors are constrained is through extinction, in which repeated re-exposure to conditioned stimuli without aversive consequences attenuates fear. Research suggests that extinction forms a new memory of safety that competes with the original fear association during memory recall. However, while deficits at the recall stage are a major factor in pathological fear, the circuit mechanisms underlying extinction recall and how they might differentiate between competing fear and extinction memories remain largely enigmatic. This is a fundamental knowledge gap that limits insight into extinction and the potential reasons for its failure in psychiatric disorders. In this project we hypothesize that an important mechanism in context fear extinction is recruitment of somatostatin interneurons in the ventral hippocampus, and that these cells control switching between competing context representations, one signaling threat and the other safety. In support of this hypothesis, we find that somatostatin interneurons are preferentially activated by an extinguished context and their manipulation modulates fear expression in this context but not others. Using a combination of intersectional genetics, electrophysiology, optogenetics and calcium imaging, we will investigate the properties and function of discrete populations of somatostatin interneurons underlying context-dependent behavior. In particular, we will examine whether these cells control transitions between high and low fear states and elucidate the mechanisms underlying this switch at the level of excitatory neuronal populations involved in fear and extinction memory. Successful completion of these aims will shed light on how the brain governs conflicting internal models of an ambiguous environment as well as provide a detailed account of circuit dynamics that promote the loss of fear and prevent it from reemerging.