Role of amygdala inhibitory circuit neuromodulation in stress disorders

杏仁核抑制回路神经调节在应激障碍中的作用

• 批准号: 10377973
• 负责人: JEFFREY G TASKER
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377973
• 关键词: Adrenergic Receptor; Amygdaloid structure; Arousal; Behavioral Paradigm; Brain; Cells; Chemosensitization; Cholecystokinin; Cognitive; Complex; Designer Drugs; Development; Emotional; Equilibrium; Excitatory Synapse; Exposure to; Extinction (Psychology); Feeling suicidal; Financial Hardship; Foundations; Fright; Genetically Engineered Mouse; Health; Interneurons; Lead; Learning; Light; Link; Measures; Mediating; Memory; Modeling; Mus; Neuronal Plasticity; Neurons; Norepinephrine; Output; Parvalbumins; Pathologic; Pathology; Pattern; Phase; Play; Post-Traumatic Stress Disorders; Process; Psychopathology; Regulation; Risk Factors; Role; Sensory; Signal Transduction; Slice; Societies; Source; Stream; Stress; Structure; Suicide; Synapses; Testing; Trauma; Viral; alcohol use disorder; base; behavior test; cell type; desensitization; experimental study; fear memory; gamma-Aminobutyric Acid; in vivo; insight; locus ceruleus structure; memory consolidation; memory process; mouse model; nerve supply; neural circuit; neurochemistry; neuroregulation; neurotransmission; noradrenergic; optogenetics; patch clamp; postsynaptic; pre-clinical; preclinical study; presynaptic; receptor; relating to nervous system; response; stress disorder; synaptic inhibition; traumatic stress

Project Title: Role of amygdala inhibitory circuit neuromodulation in stress disorders Project Summary Traumatic stress exposure can lead to long-term stress disorders and represents a considerable risk factor for suicide. Stress disorders such as posttraumatic stress disorder (PTSD) and alcohol use disorder have significant links with suicidality and are characterized by plasticity of neural circuits and neurochemical signaling in the amygdala, particularly in the basolateral complex of the amygdala (BLA). The BLA integrates neural inputs from multiple sources and assigns emotional valence to information by establishing distinct streams of information outflow. BLA circuits process inputs to form emotional memories based on the excitation/inhibition balance set by the relative excitatory and inhibitory synaptic inputs to the principal output neurons of the BLA. While potentiation at excitatory synapses is the foundation of memory formation, inhibitory circuits regulate the excitation/inhibition balance to control synaptic potentiation, and neuromodulatory signals tune the synaptic interactions. Noradrenergic modulation is thought to signal arousal and contribute significantly to the emotional salience of information processed in the amygdala. Our preliminary preclinical findings in mice suggest that norepinephrine (NE) exerts robust regulatory control over GABAergic parvalbumin (PV) and cholecystokinin (CCK) inhibitory inputs to the BLA principal neurons, and that this control is compromised following traumatic stress exposure. We propose to characterize the noradrenergic modulation of PV and CCK synaptic inputs to the BLA principal neurons, and to define the role of noradrenergic modulation of synaptic inhibition in BLA- mediated fear memory formation. We will target the noradrenergic afferent regulation of PV and CCK interneuronal circuits using chemogenetic and optogenetic strategies. We will interrogate local PV and CCK interneuron inhibitory synaptic signaling in the BLA for noradrenergic neuromodulation using patch clamp recordings in slices of amygdala. We will use behavioral paradigms to determine the role of the noradrenergic modulation of BLA inhibitory circuits in fear consolidation and extinction. Finally, we will test for traumatic stress- induced plasticity of the noradrenergic modulation of inhibitory circuits and the PV and CCK circuit regulation of fear learning. These studies together will reveal the mechanisms of the noradrenergic modulation of BLA circuits and provide important insights into the role(s) of distinct perisomatic inhibitory circuits in the control of BLA- dependent fear memory formation, as well as into how these circuits are disrupted by traumatic stress exposure.

项目名称：杏仁核抑制回路神经调节在应激障碍中的作用 项目概要 创伤性应激暴露可导致长期应激障碍，并且是一个相当大的风险因素 自杀。创伤后应激障碍 (PTSD) 和酒精使用障碍等应激障碍对 与自杀有关，其特征是神经回路和神经化学信号传导的可塑性 杏仁核，特别是杏仁核基底外侧复合体（BLA）。 BLA 整合了来自 多个来源并通过建立不同的信息流为信息分配情感价 外流。 BLA 电路处理输入，根据激励/抑制平衡集形成情感记忆 通过 BLA 主要输出神经元的相对兴奋性和抑制性突触输入。尽管 兴奋性突触的增强是记忆形成的基础，抑制性电路调节 兴奋/抑制平衡控制突触增强，神经调节信号调节突触 互动。去甲肾上腺素能调节被认为是唤醒信号并对情绪有显着贡献 杏仁核处理信息的显着性。我们在小鼠身上的初步临床前研究结果表明 去甲肾上腺素 (NE) 对 GABA 能小白蛋白 (PV) 和胆囊收缩素发挥强大的调节控制作用 (CCK) 对 BLA 主要神经元的抑制性输入，并且这种控制在创伤后受到损害 压力暴露。我们建议表征 PV 和 CCK 突触输入的去甲肾上腺素能调节 BLA 主要神经元，并定义去甲肾上腺素能调节突触抑制在 BLA- 介导恐惧记忆的形成。我们将针对 PV 和 CCK 的去甲肾上腺素能传入调节 使用化学遗传学和光遗传学策略的神经元间回路。我们将询问当地PV和CCK BLA 中的中间神经元抑制性突触信号传导用于使用膜片钳进行去甲肾上腺素能神经调节 杏仁核切片中的录音。我们将使用行为范式来确定去甲肾上腺素能的作用 BLA 抑制回路在恐惧巩固和消退过程中的调节。最后，我们将测试创伤性应激—— 抑制性电路去甲肾上腺素能调节的诱导可塑性以及 PV 和 CCK 电路调节 恐惧学习。这些研究将共同​​揭示 BLA 回路去甲肾上腺素能调节的机制 并提供关于不同体周抑制回路在 BLA-控制中的作用的重要见解 依赖恐惧记忆的形成，以及这些回路如何被创伤性应激暴露破坏。