Deconstruction of a Hypothalamic Exercise-responsive Circuit for Neuroprotection

解构下丘脑运动反应回路的神经保护作用

• 批准号: 10562283
• 负责人: Erik Bradley Bloss
• 金额: $ 76.71万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562283
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Anatomy; Architecture; Array tomography; Automobile Driving; Brain; Cells; Chemosensitization; Cognition; Cognitive; Data; Development; Disease; Exercise; Exertion; Functional Imaging; Genetic; Genetic Models; Goals; Health; Hypothalamic structure; Image; Imaging Techniques; Impaired cognition; Individual; Intervention; Knowledge; Label; Late Onset Alzheimer Disease; Logic; Maps; Measures; Mediating; Middle Hypothalamus; Mus; Nerve Degeneration; Neuroanatomy; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Output; Pattern; Physical Endurance; Physiological; Population; Recording of previous events; Research Personnel; Resolution; Risk Reduction; SF1; Shapes; Signal Transduction; Structure of paraventricular nucleus of thalamus; Structure of terminal stria nuclei of preoptic region; Synapses; Testing; Therapeutic; Training; Viral; Work; aging brain; behavior measurement; brain circuitry; cell type; cognitive benefits; cognitive performance; early onset; endurance exercise; experience; experimental study; improved; in vivo; in vivo calcium imaging; inflammatory marker; insight; mouse model; neural; neural circuit; neuroinflammation; neurophysiology; neuroprotection; neuroregulation; neurotransmission; new technology; novel therapeutics; pre-clinical; protective effect; reconstruction; response; therapeutic target; tool; transmission process

PROJECT SUMMARY Exercise slows the cognitive declines associated with aging and protects against the development and progression of neurodegenerative diseases such as Alzheimer's disease (AD). At the cellular level, exercise enhances synaptic connectivity and reduces markers of neuroinflammation in aging cortical circuits. Exactly how exercise signals in the brain generate these neuroprotective effects remains unknown. Our preliminary experiments have identified a set of neurons in the mouse ventromedial hypothalamus (VMH) expressing Steroidogenic Factor 1 (SF-1) that robustly increase their activity in response to exercise. We have found that the VMH SF-1 neural activity signal is potentiated severalfold following repeated exercise, suggesting that the exercise signals generated by VMH SF-1 neurons are plastic and shaped by experience. Furthermore, we have found that direct stimulation of SF-1 neurons substantially increases subsequent endurance capacity, suggesting VMH Sf-1 neurons are an important neural node controlling the physiological benefits of exercise. However, several important questions remain unknown. First, which features of VMH SF-1 neurons enables plasticity of activity signals following repeated exercise? Second, which specific sets of VMH SF-1 output neurons transmit exercise-relevant signals? Last, is it possible to stimulate VMH SF-1 neurons and generate the neuroprotective effects of exercise on cognition and neural circuitry in the aging brain or in AD-like states? The proposed experiments will leverage advanced neuroanatomical and neurophysiological tools with preclinical genetic models to gain insights into these questions. In Aim 1, we will pair large-volume, high-resolution, and cell-type specific array tomographic neuroanatomical reconstructions with in vivo calcium imaging and neuronal activity perturbations to determine how exercise shapes the synaptic architecture of VMH SF-1 neurons. These experiments will define how changes in the synaptic inputs to these neurons might physically `store' exercise history within VMH circuitry. In Aim 2, we will use advanced viral mapping and in vivo single-cell functional imaging techniques to identify which neurons are activated by exercise and understand how these exercise signals are transmitted to specific circuits downstream of the VMH. These experiments will define the organization and logic by which exercise-related activity in VMH neurons drives functional changes in the brain. In Aim 3, we will take advantage of advanced preclinical genetic mouse models of early- and late-onset AD to determine whether stimulating activity in VMH neurons might recapitulate the neuroprotective effects of exercise observed in cortical circuits. These experiments will increase our understanding of how signals in the VMH could be harnessed for therapeutic manipulation in disease states. By leveraging the synergistic expertise of the team of investigators assembled to address this problem, insights from these experiments will advance our fundamental understanding of how the beneficial effects of exercise are mediated by specific synapses, cell- types, and circuits, and whether these features are potential therapeutic targets for intervention in disease states.

项目摘要 锻炼可以减缓与衰老相关的认知能力下降， 神经退行性疾病如阿尔茨海默病（AD）的进展。在细胞层面，锻炼 增强突触连接，减少老化皮层回路中的神经炎症标记。如何 大脑中的运动信号产生这些神经保护作用仍然是未知的。我们的初步 实验已经确定了小鼠下丘脑腹内侧（VMH）中的一组神经元表达 类固醇生成因子1（SF-1），在运动时强烈增加其活性。我们发现 VMH SF-1神经活动信号在重复运动后增强数倍，表明 由VMH SF-1神经元产生的运动信号是可塑的，并由经验塑造。此外，我们还 发现SF-1神经元的直接刺激大大增加了随后的耐力，这表明 VMH Sf-1神经元是控制运动生理益处的重要神经节点。然而，在这方面， 有几个重要的问题仍然不明。首先，VMH SF-1神经元的哪些特征使神经元的可塑性成为可能， 重复运动后的活动信号？第二，VMH SF-1输出神经元的哪些特定集合传输 运动相关信号最后，是否有可能刺激VMH SF-1神经元并产生神经保护作用， 运动对大脑老化或AD样状态下认知和神经回路的影响？拟议 实验将利用先进的神经解剖学和神经生理学工具， 模型来深入了解这些问题。在目标1中，我们将对大体积、高分辨率和细胞类型 特异性阵列断层神经解剖重建与体内钙成像和神经元活性 扰动，以确定如何行使形状VMH SF-1神经元的突触结构。这些 实验将确定这些神经元突触输入的变化如何在物理上“储存”运动 VMH电路中的历史。在目标2中，我们将使用先进的病毒作图和体内单细胞功能性免疫分析。 成像技术，以确定哪些神经元被激活的运动，并了解这些运动 信号被发送到VMH下游的特定电路。这些实验将定义 VMH神经元中运动相关活动驱动大脑功能变化的组织和逻辑。 在目标3中，我们将利用先进的早发型和晚发型AD的临床前遗传小鼠模型， 确定VMH神经元的刺激活动是否可能重现运动的神经保护作用 在皮层回路中观察到的。这些实验将增加我们对VMH中的信号如何 被用于疾病状态下的治疗操作。通过利用团队的协同专业知识， 研究人员聚集在一起解决这个问题，这些实验的见解将推动我们的研究。 运动的有益效果是如何通过特定的突触，细胞介导的基本理解， 类型和电路，以及这些特征是否是干预疾病状态的潜在治疗靶点。