Muscarinic Modulation of the Basolateral Amygdala

 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失中发挥着重要作用。因此，在包括人类在内的所有哺乳动物中，BL 比基底前脑的任何其他目标接受更强大的胆碱能神经支配。行为研究表明，BL 中 mAChR 的激活会增强恐惧记忆，而封锁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神经精神疾病通常与情绪障碍有关，被认为至少部分是由异常的胆碱能传递引起的。事实上，在阿尔茨海默病患者中，BL 胆碱能输入的退化程度与他们的情绪事件记忆受损有关。这些发现清楚地表明，对 BL 中 mAChR 介导的机制进行治疗性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具有重要意义，但目前还没有研究系统地研究 mAChR 调节 BL 功能的分子、细胞和网络水平机制。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与最先进的电生理学和光遗传学相结合，以解决这一重大知识差距。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。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 BL 中的谷氨酸输入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具体目标来检验：1）定义神经元兴奋性和振荡活动的毒蕈碱调节 BL 中的锥体细胞和中间神经元； 2) 定义突触前 mAChR 的谷氨酸能和 GABA 能传递的频率依赖性门控； 3) 确定 mAChR 对 BL 突触传递和可塑性的功能影响。该项目涵盖了 BRAIN Initiative 的几个优先事项/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神经元”的工具、创建“大脑的结构图”以及“跨学科合作的跨界”。有关 BL 回路的 mAChR 调节的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阿尔茨海默病产生的情绪缺陷的疗法至关重要。

 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.