Muscarinic Modulation of the Basolateral Amygdala

基底外侧杏仁核的毒蕈碱调节

• 批准号: 8887946
• 负责人: ALEXANDER JOSEPH MCDONALD
• 金额: $ 49.23万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887946
• 关键词: Acetylcholine; Address; Alzheimer' s Disease; Amygdaloid structure; Anxiety Disorders; BRAIN initiative; Brain; Brain Mapping; Brain region; Cell Nucleus; Cell physiology; Cells; Data; Development; Disease; Drug Addiction; Electron Microscopy; Electrophysiology (science); Emotional; Emotional Disturbance; Event; Extinction (Psychology); Frequencies; Functional disorder; Glutamates; Goals; Hippocampus (Brain); Human; Immunofluorescence Immunologic; Impaired cognition; Impairment; Interneurons; Knowledge; Label; Learning; Long-Term Potentiation; Mammals; Mediating; Memory; Molecular; Muscarinic Acetylcholine Receptor; Muscarinics; Nervous system structure; Neurons; Pathway interactions; Patients; Physiology; Play; Population; Pyramidal Cells; Receptor Activation; Recurrence; Regulation; Reporting; Research; Role; Schizophrenia; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic; Therapeutic Intervention; Work; basal forebrain; base; behavioral study; cell type; cholinergic; density; fear memory; hippocampal pyramidal neuron; interdisciplinary collaboration; memory consolidation; nerve supply; neuronal excitability; neuropsychiatry; novel; optogenetics; presynaptic; prevent; public health relevance; receptor; response; therapy development; tool; transmission process

 DESCRIPTION (provided by applicant): Signaling through muscarinic acetylcholine receptors (mAChRs) in the basolateral (BL) nucleus of the amygdala plays an essential role in the formation and extinction of emotional memory. Accordingly, in all mammals, including humans, the BL receives more robust cholinergic innervation than any other target of the basal forebrain. Behavioral studies have demonstrated that activation of mAChRs in BL enhances fear memories, whereas blockade of these receptors prevents memory consolidation. Moreover, Alzheimer's disease as well as neuropsychiatric disorders such as schizophrenia, which are commonly associated with emotional disturbances, are thought to result, at least in part, from abnormal cholinergic transmission. Indeed, in Alzheimer's patients the extent of degeneration of cholinergic input to BL is correlated with their impairment of emotional event memory. These findings clearly suggest that therapeutic modulation of mAChR-mediated mechanisms in the BL could be important for treating a number of major neuropsychiatric diseases involving impairments in emotional learning. Despite the importance of mAChRs in the physiology and pathophysiology of emotional memory, there have been no studies that have systematically examined the molecular, cellular, and network-level mechanisms by which mAChRs regulate BL function. The studies outlined in this proposal will combine multiple-labeling electron microscopy and multiple-labeling confocal immunofluorescence with state-of-the-art electrophysiology and optogenetics to address this significant knowledge gap. Our long term goal is to understand how muscarinic receptor regulation of the amygdala can be manipulated for therapeutic purposes. The objective here is to determine how synaptically released acetylcholine, acting on mAChRs, regulates neuronal activity in the BL. Our central hypothesis is that distinct mAChRs on different neuronal subpopulations play discrete roles in regulating neuronal oscillations, filtering salient signals and strengthening glutamatergic inputs in the BL. Our hypothesis is based on preliminary data which reveal that mAChRs strongly modulate BL circuits in a manner distinct from that reported in other brain regions. This hypothesis will be tested by pursuing three specific aims: 1) To define muscarinic modulation of neuronal excitability and oscillatory activity at pyramidal cells and interneurons in the BL; 2) To define frequency-dependent gating of glutamatergic and GABAergic transmission by presynaptic mAChRs; and 3) To determine the functional effect of mAChRs on synaptic transmission and plasticity in the BL. This project encompasses several of the priorities/themes of the BRAIN Initiative, including "characterizing cell types in the nervous system", developing tools to "manipulate these precisely defined neurons", creating "structural maps of the brain", and "crossing boundaries in interdisciplinary collaborations. Information about mAChR regulation of BL circuits will be critical for the development of therapies to ameliorate severe neuropsychiatric disorders, treat drug addiction and diminish the emotional deficits produced by Alzheimer's disease.

 描述（由适用提供）：通过毒蕈碱乙酰胆碱接收器（MACHRS）信号传导在杏仁核的基底外侧（BL）核中，在情绪记忆的形成和扩展中起着至关重要的作用。根据包括人类在内的所有哺乳动物的说法，BL接受的胆碱能神经比基础前脑的任何其他靶标更强。行为研究表明，BL中的MACHR的激活增强了恐惧记忆，而对这些受体的封锁则阻止了记忆巩固。此外，阿尔茨海默氏病以及通常与情绪障碍相关的精神分裂症等神经精神疾病，至少部分是由于异常的胆碱能传播所致。的确，在阿尔茨海默氏症患者中，胆碱能输入对BL的变性程度与他们的情绪事件记忆的损害相关。这些发现清楚地表明，BL中MACHR介导的机制的治疗调节对于治疗许多涉及情绪学习障碍的主要神经精神疾病可能很重要。尽管MACHR在情绪记忆的生理学和病理生理学中很重要，但没有研究系统地检查了MACHR调节BL功能的分子，细胞和网络级别机制。该提案中概述的研究将结合多标记的电子显微镜和多标记的共聚焦免疫荧光，并与最先进的电生理学和光遗传学结合使用，以解决这一重要的知识差距。我们的长期目标是了解如何为治疗目的操纵杏仁核的毒蕈碱受体调节。这里的目的是确定突触释放的乙酰胆碱如何作用于MACHR，调节BL中的神经元活性。我们的中心假设是，不同神经元亚群的明显MACHR在调节神经元振荡中起离散的作用，过滤显着信号并加强BL中的谷氨酸能输入。我们的假设基于初步数据，该数据表明MACHR以与其他大脑区域报道的方式强烈调节BL电路。该假设将通过追求三个具体目的来检验：1）定义神经元刺激和振荡活动的毒蕈碱调节 在BL中的锥体细胞和中间神经元中； 2）定义突触前MACHR的谷氨酸能和GABA能传播的频率依赖性门控； 3）确定MACHR对BL中的合成传递和可塑性的功能效应。 This project encompasses several of the priorities/themes of the BRAIN Initiative, including "characterizing cell types in the nervous system", developing tools to "manipulate these precisely defined neurons", creating "structural maps of the brain", and "crossing boundaries in interdisciplinary collaborations. Information about mAChR regulation of BL circuits will be critical for the development of therapies to ameliorate severe neuropsychiatric disorders, treat吸毒成瘾并减少阿尔茨海默氏病产生的情绪缺陷。