Microcircuits governing conflicting memories of threat and safety

微电路管理威胁和安全的冲突记忆

• 批准号: 10753931
• 负责人: Roger L Clem
• 金额: $ 62.24万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753931
• 关键词: Amygdaloid structure; Animals; Attenuated; Behavior; Behavior Therapy; Brain; Calcium; Cells; Dangerousness; Data; Disinhibition; Electrophysiology (science); Environment; Exhibits; Exposure to; Extinction; Failure; Fright; Genetic; Genetic Recombination; Goals; Hippocampus; Human; Image; Impairment; Interneurons; Knowledge; Label; Learning; Link; Maps; Mediating; Membrane; Memory; Mental disorders; Modeling; Mus; Neurons; Nicotinic Receptors; Output; Pathologic; Patients; Play; Population; Property; Publishing; Receptor Signaling; Relapse; Reporter; Research; Retrieval; Role; Safety; Signal Transduction; Somatostatin; Stimulus; Stress; Surface; Synapses; System; Testing; Time; Trauma; Trauma recovery; Work; attenuation; excitatory neuron; experience; experimental study; genetic approach; insight; memory recall; memory retrieval; optogenetics; prevent; psychologic; recruit; relapse prevention

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.

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的情况