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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要锻炼可以减缓与衰老相关的认知能力下降，并防止发育和发育障碍。阿尔茨海默病（AD）等神经退行性疾病的进展。在细胞水平上，运动增强突触连接并减少老化皮质回路中的神经炎症标志物。究竟如何大脑中的运动信号产生这些神经保护作用仍然未知。我们的初步实验已经鉴定出小鼠下丘脑腹内侧（VMH）中的一组神经元表达类固醇生成因子 1 (SF-1) 可大幅增加其对运动的反应活性。我们发现 VMH SF-1 神经活动信号在重复运动后增强数倍，这表明 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，我们还有发现直接刺激 SF-1 神经元可显着提高随后的耐力能力，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，几个重要问题仍然未知。首先，VMH SF-1 神经元的哪些特征能够实现可塑性重复运动后的活动信号？其次，哪些特定的 VMH SF-1 输出神经元组传输运动相关信号？最后，是否有可能刺激VMH SF-1神经元并产生神经保护作用？运动对衰老大脑或类似 AD 状态的认知和神经回路有何影响？拟议的实验将利用先进的神经解剖学和神经生理学工具以及临床前遗传学模型来深入了解这些问题。在目标 1 中，我们将配对大体积、高分辨率和细胞类型通过体内钙成像和神经元活动进行特定阵列断层扫描神经解剖重建扰动以确定运动如何塑造 VMH SF-1 神经元的突触结构。这些实验将定义这些神经元突触输入的变化如何物理上“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图谱和体内单细胞功能分析成像技术可识别运动激活哪些神经元并了解这些神经元如何运动信号被传输到 VMH 下游的特定电路。这些实验将定义 VMH 神经元中与运动相关的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 临床前遗传小鼠模型来确定 VMH 神经元的刺激活动是否可以概括运动的神经保护作用在皮质回路中观察到。这些实验将加深我们对 VMH 中信号如何发挥作用的理解可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聚集在一起解决这个问题的研究人员，这些实验的见解将推动我们的研究基本了解运动的有益效果如何通过特定突触、细胞- 类型和回路，以及这些特征是否是疾病状态干预的潜在治疗目标。