Microcircuits governing conflicting memories of threat and safety

恐惧学习使动物能够通过形成记忆来发现危险情况并保护自己 将创伤期间遇到的刺激与身体或心理伤害的经历联系起来。相反地， 这些行为受到约束的主要机制是通过灭绝，其中重复的 再次暴露于条件刺激而没有令人厌恶的后果会减弱恐惧。研究表明 消失形成了一个新的安全记忆，在记忆回忆过程中与原始的恐惧联系竞争。 然而，虽然回忆阶段的缺陷是病理性恐惧的主要因素，但回路机制 潜在的灭绝记忆以及他们如何区分竞争性恐惧和灭绝记忆 仍然是个谜这是一个基本的知识差距，限制了对灭绝和潜在的 其在精神疾病中失败的原因。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体中生长抑素中间神经元的募集，这些中间神经元 单元控制在竞争上下文表示（一个信令威胁和另一个信令安全）之间的切换。在 支持这一假设，我们发现生长抑素中间神经元优先激活的熄灭， 背景和它们的操纵调节了这种背景下的恐惧表达，而不是其他情况。结合使用 交叉遗传学，电生理学，光遗传学和钙成像，我们将研究的性质 和功能的离散群体的生长抑素interneurons潜在的上下文依赖性行为。在 特别是，我们将研究这些细胞是否控制高和低恐惧状态之间的转换，并阐明 在涉及恐惧的兴奋性神经元群体水平上这种转换的潜在机制， 消失记忆这些目标的成功实现将揭示大脑如何控制冲突 模糊环境的内部模型，并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.