Muscarinic Modulation of the Basolateral Amygdala

基底外侧杏仁核的毒蕈碱调节

基本信息

批准号：
9062517
负责人：
ALEXANDER JOSEPH MCDONALD
金额：
$ 44.31万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
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/9062517
关键词：
Acetylcholine Address Alzheimer&apos s Disease Amygdaloid structure Anxiety Disorders BRAIN initiative Brain Brain Mapping Brain region Cell Nucleus Cell physiology Cells Data Development Drug Addiction Electron Microscopy Electrophysiology (science)Emotional Emotional Disturbance Event Extinction (Psychology)Frequencies Functional disorder Glutamates Goals Health 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 neuropsychiatric disorder novel therapeutics optogenetics presynaptic prevent receptor response therapy development tool transmission process

项目摘要

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（由申请人提供）：通过杏仁核基底外侧（BL）核中的毒蕈碱乙酰胆碱受体（mAChR）发出的信号在情绪记忆的形成和消退中起着重要作用。因此，在包括人类在内的所有哺乳动物中，BL接收信号。比任何其他基底前脑目标更强大的胆碱能神经支配行为研究表明，BL 中 mAChR 的激活。增强恐惧记忆，而阻断这些受体会阻止记忆巩固。此外，阿尔茨海默病以及精神分裂症等通常与情绪障碍相关的神经精神疾病被认为至少部分是由异常的胆碱能传递引起的。在阿尔茨海默病患者中，BL 胆碱能输入的退化程度与情绪事件记忆受损相关，这些发现清楚地表明，治疗性调节 mAChR 介导的机制。 BL 对于治疗情绪学习中的许多主要神经精神疾病很重要尽管 mAChR 在情绪记忆的生理学和病理生理学中很重要，但还没有研究系统地研究分子、细胞和网络水平的机制。该提案中概述的研究将多重标记电子显微镜和多重标记共聚焦免疫荧光结合最先进的电生理学和我们的长期目标是了解如何操纵杏仁核的毒蕈碱受体调节以达到治疗目的，以确定突触释放的乙酰胆碱如何作用于 mAChR 来调节 BL 中的神经元活动。我们的中心假设是，不同神经元亚群上的不同 mAChR 在调节神经元振荡、过滤显着信号和增强神经元功能方面发挥着不同的作用。我们的假设基于初步数据，这些数据表明 mAChR 以与其他大脑区域不同的方式强烈调节 BL 回路，该假设将通过追求三个特定目标进行检验：1）定义毒蕈碱调节。神经元兴奋性和振荡活动 BL 中的锥体细胞和中间神经元；2) 定义突触前 mAChR 的谷氨酸和 GABA 能传递的频率依赖性门控；3) 确定 mAChR 对 BL 中突触传递和可塑性的功能影响。 BRAIN Initiative 的优先事项/主题，包括“表征神经系统中的细胞类型”、开发“操纵这些精确定义的细胞类型”的工具神经元”，创建“大脑的结构图”，以及“跨学科合作的跨界信息，对于开发改善严重神经精神疾病、治疗药物成瘾和减少情绪缺陷的疗法至关重要。阿尔茨海默病。