Molecular-Genetic Dissection of Subcortical Circuitry Regulating Arousal

项目摘要 在理解大脑调节的电路、细胞和突触基础方面存在着根本性的差距 并维持神经行为和脑电图（EEG）唤醒。这是一个重要的问题 因为它不仅降低了我们治疗唤醒障碍的能力，包括恢复意识， 昏迷的人，而且也影响治疗和更深入地了解许多神经精神， 神经退行性和神经系统疾病，通常包括严重的唤醒中断，包括阿尔茨海默氏症 和帕金森氏症我们最近发现了基底前脑的一个特别关键和意想不到的作用， GABA能（BFGABA）神经元支持清醒和快速皮质节律。我们进一步确认了那个尾迹- 促进下丘脑乳头体上区（SUMV2）的神经元（VEG2+）是一个主要来源 对BF的兴奋性输入。目前的建议试图通过定义分子， 细胞和突触基础，通过这些基础，皮层下SUMVs2-BFGABA回路有助于唤醒和快速 行为动物的皮质节律在大量初步数据的基础上，我们的目标是下一步 在追求目标过程中，定义和表征：1）皮层下神经元 SUMV12-BFGABA回路调节神经行为和EEG唤醒，2）所有突触前输入来源， SUMVIGF2和BFGABA神经元，并证实了这个皮层下网络内的功能性突触连接， 跨越"输入"的突触后靶点（"输出"）， SUMVs2 → BFGABA激活视前区和外侧下丘脑中驱动唤醒的"输出"回路。我们的长期 我们的目标是了解皮层下SUMVp2BFGABA回路的细胞和突触基础 调节行为和脑电图唤醒。中心假设是SUMV12-BFGABA回路既 这是大脑正常唤醒所必需的拟议研究的理由是， 确定SUMVIGF2-BFGABA回路调节唤醒水平的细胞和突触基础 是操纵它们和减少患有糖尿病的人所经历的功能障碍的关键的第一步。 性唤起障碍在强有力的初步数据的指导下，这一假设将通过追求三个具体的 目标。该方法在智力和技术上都具有创新性，因为它试图通过以下方式揭示机械基础： 这个新发现的皮层下回路调节大脑的唤醒，因为它采用了一种新的组合， 新开发和验证的方法。这项研究具有重要意义，因为它有望垂直 推进和扩大对细胞和突触机制的理解， 皮层下回路调节唤醒。最终，这些知识有可能为发展提供信息， 治疗觉醒障碍患者，包括神经精神疾病患者， 神经退行性疾病和神经系统疾病，伴有严重的唤醒中断，特别是BF 功能障碍也有牵连。

Project Summary There is a fundamental gap in understanding the circuit, cellular and synaptic bases by which the brain regulates and maintains neurobehavioral and electroencephalographic (EEG) arousal. This is an important problem because it not only reduces our ability to treat disorders of arousal, including restoration of consciousness in comatose individuals, but also impacts treatment and deeper understanding of many neuropsychiatric, neurodegenerative and neurological disorders that often include severe arousal disruption, including Alzheimer’s and Parkinson’s disease. We recently uncovered an especially critical and unexpected role for basal forebrain GABAergic (BFGABA) neurons in supporting wake and fast cortical rhythms. We further identified that wake- promoting glutamatergic (Vglut2+) neurons of the supramammillary hypothalamus (SUMVglut2) are a major source of excitatory input to the BF. The current proposal seeks to extend these findings by defining the molecular, cellular and synaptic bases by which the subcortical SUMVglut2  BFGABA circuit contributes to arousal and fast cortical rhythms in behaving animals. Building upon substantive preliminary data, our objective is the next step in pursuit of that goal, to define and characterize: 1) the cellular and synaptic bases by which the subcortical SUMVglut2  BFGABA circuit regulates neurobehavioral and EEG arousal, 2) all sources of presynaptic inputs to SUMVglut2 and BFGABA neurons and confirm functional synaptic connectivity within this subcortical network, spanning “input”SUMVglut2  BFGABA, and 3) the postsynaptic targets (“outputs”) of the SUMVglut2→BFGABA”outputs” circuit in the preoptic and lateral hypothalamus that drive arousal. Our long-term goal is to understand the cellular and synaptic bases by which the subcortical SUMVglut2  BFGABA circuit regulates behavioral and EEG arousal. The central hypothesis is that the SUMVglut2  BFGABA circuit is both necessary and sufficient for normal levels of brain arousal. The rationale for the proposed research is that identifying the cellular and synaptic bases by which the SUMVglut2  BFGABA circuit can modulate arousal levels is a critical first step towards manipulating them and reducing the dysfunction experienced by individuals with disorders of arousal. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims. The approach is intellectually and technically innovative as it seeks to reveal the mechanistic basis by which this newly revealed subcortical circuit regulates brain arousal and because it employs a novel combination of newly developed and validated approaches. The proposed research is significant, as it is expected to vertically advance and expand understanding of the cellular and synaptic mechanisms by which a recently revealed subcortical circuit regulates arousal. Ultimately, such knowledge has the potential to inform the development of treatments for patients with arousal-based disorders, including those suffering neuropsychiatric, neurodegenerative and neurological disorders with severe arousal disruption, particularly those in which BF dysfunction has been implicated.