The central amygdala circuits in fear learning and fear expression

恐惧学习和恐惧表达中的中央杏仁核回路

• 批准号: 8701575
• 负责人: Bo LI
• 金额: $ 47.25万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701575
• 关键词: Amygdaloid structure; Anxiety Disorders; Auditory; Cells; Clinical; Complex; Conditioned Stimulus; Cues; Data; Disinhibition; Electrophysiology (science); Ensure; Environment; Excitatory Synapse; Fright; Functional disorder; Generalized Anxiety Disorder; Genetic; Genetic Techniques; Goals; Impairment; In Vitro; Insula of Reil; Lateral; Learning; Light; Link; Medial; Mediating; Memory; Methodology; Methods; Modification; Molecular Genetics; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Output; Participant; Population; Post-Traumatic Stress Disorders; Probability; Process; Protein Kinase C; Regulation; Research; Role; Somatostatin; Stimulus; Synapses; Synaptic plasticity; Techniques; Testing; base; cell type; chemical genetics; conditioned fear; design; experience; in vivo; inhibitory neuron; memory recall; midbrain central gray substance; neural circuit; neuromechanism; optogenetics; parabrachial nucleus; prevent; programs; public health relevance; response; tool

DESCRIPTION (provided by applicant): The amygdala is critical for fear processing and fear regulation. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear learning. In particular, neurons in the lateral subdivision of the CeA (CeL), which tonically inhibits the medial subdivision of CeA (CeM) and thereby gates fear expression, are thought to encode learned fear. However, the mechanisms by which CeL contributes to fear learning remain unknown. In addition, the link between the role of CeL in fear learning and its known role in fear expression is also unclear. The objective of the proposed project is to elucidate the mechanisms by which the central amygdala contributes to fear learning and orchestrates fear expression in Pavlovian fear conditioning. We will focus on distinct classes of inhibitory neurons in the CeL. Our central hypothesis is that fear conditioning induces cell type-specific synaptic modifications in CeL circuits that serve as fear memory traces. We further propose that these memory traces act to promote the inhibition of CeL output during fear memory recall, thereby disinhibiting CeM and releasing fear expression. We designed an integrated approach, combining molecular genetic tools, in vitro and in vivo electrophysiology, and optogenetic and chemical-genetic techniques, to test our hypotheses in the following Specific Aims: 1) to delineate the functional organization of the CeA inhibitory circuits; 2) to determine the mechanisms of the fear conditioning-induced synaptic plasticity in CeL; and 3) to determine the role of specific CeL inhibitory circuits in fear conditioning. Findings from this project will have important clinical implications, as dysfunction of fear regulation mechanisms is implicated in a number of psychiatric conditions, including generalized anxiety disorder and post-traumatic stress disorder.

描述（由申请人提供）：杏仁核对于恐惧处理和恐惧调节至关重要。中央杏仁核（CEA）曾经被视为杏仁核综合体和下游恐惧效应者之间的被动继电器，它已成为恐惧学习中的积极参与者。特别是，在CEA（CEL）的侧向细分中，神经元在概念上抑制CEA（CEM）的内侧细分（CEM），从而抑制了大门的恐惧表达，从而编码学到的恐惧。但是，CEL有助于恐惧学习的机制仍然未知。此外，CEL在恐惧学习中的作用与其在恐惧表达中的已知作用之间的联系也不清楚。拟议项目的目的是阐明中央杏仁核有助于恐惧学习的机制，并在帕夫洛夫恐惧条件中策划了恐惧的表达。我们将专注于CEL中不同类别的抑制性神经元。我们的中心假设是，恐惧调节会引起细胞类型特异性的突触修饰，以作为恐惧记忆痕迹的CEL电路。我们进一步提出，这些记忆迹线在恐惧记忆中促进对CEL输出的抑制作用，从而消除CEM并释放恐惧表达。我们设计了一种集成的方法，结合了分子遗传工具，体外和体内电生理学以及光遗传学和化学遗传技术，以在以下特定目的中测试我们的假设：1）划定CEA抑制性通路的功能组织； 2）确定恐惧条件引起的CEL突触可塑性的机制； 3）确定特定CEL抑制回路在恐惧条件中的作用。该项目的发现将具有重要的临床意义，因为恐惧调节机制的功能障碍与许多精神病疾病有关，包括普遍的焦虑症和创伤后应激障碍。