Molecular-Genetic Dissection of Subcortical Circuitry Regulating Arousal

项目摘要 在理解大脑调节的回路、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(EEG)唤醒。这是一个重要的问题 因为它不仅降低了我们治疗觉醒障碍的能力，包括恢复意识 昏迷的人，但也影响治疗和对许多神经精神疾病的深入了解， 神经退行性和神经性疾病，通常包括严重的觉醒障碍，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)神经元支持觉醒和快速皮质节律。我们进一步确认了那次觉醒- 促进下丘脑乳头状上核的谷氨酸能神经元是其主要来源 对高炉的兴奋性输入。目前的提案试图通过定义分子，来扩展这些发现， 皮层下SUMVher2BFGABA环路参与觉醒和快速反应的细胞和突触基础 动物行为的大脑皮层节律。根据大量的初步数据，我们的目标是下一步 在追求这一目标的过程中，定义和表征：1)大脑皮质下 BFGABA回路调节神经行为和脑电觉醒，2)突触前输入的所有来源 SUMVher2和BFGABA神经元，并确认这个皮质下网络内的功能性突触连接， 跨越“输入”SUMVher2BFGABA，以及3)突触后靶点(“输出”) SUMVher2→BFGABA在驱动觉醒的视前和下丘脑外侧“输出”电路。我们的长期合作 目的是了解皮层下SUMVher2BFGABA回路的细胞和突触基础 调节行为和脑电波的唤醒。中心假设是SUMVher2BFGABA电路既是 对正常水平的大脑唤醒来说是必要的，也是足够的。建议进行这项研究的理由是 识别SUMVher2BFGABA回路调节觉醒水平的细胞和突触基础 是操控它们和减少个人经历的功能障碍的关键第一步 性唤醒障碍。在强劲的初步数据的指导下，这一假说将通过追求三个具体的 目标。这种方法在智力和技术上都是创新的，因为它试图通过以下方式揭示机械基础 这一新发现的皮质下回路调节大脑唤醒，因为它采用了一种新的组合 新开发和验证的方法。这项拟议的研究意义重大，因为预计它将垂直 促进和扩大对细胞和突触机制的理解，最近揭示的 皮质下回路调节觉醒。归根结底，这样的知识有可能为 对以唤醒为基础的障碍患者的治疗，包括那些患有神经精神障碍的患者， 伴有严重觉醒障碍的神经退行性和神经性疾病，尤其是BF 已经牵涉到功能障碍。

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.