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.

项目摘要运动减慢与衰老相关的认知下降，并防止发展和神经退行性疾病的进展，例如阿尔茨海默氏病（AD）。在细胞级别，运动增强突触连通性并减少衰老皮质回路中神经炎症的标记。确切的方式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一组神经元在表达小鼠腹侧下丘脑（VMH）中类固醇生成因子1（SF-1），可响应于运动而稳健地增加其活性。我们发现反复运动后，VMH SF-1神经活动信号增强了几倍，表明 VMH SF-1神经元产生的运动信号是塑料的，并根据经验形成。此外，我们还有发现直接刺激SF-1神经元大大增加了随后的耐力能力，这表明 VMH SF-1神经元是控制运动生理益处的重要神经淋巴结。然而，几个重要的问题仍然未知。首先，VMH SF-1神经元的特征使可塑性重复运动后的活动信号？第二，哪一组VMH SF-1输出神经元传输与运动相关的信号？最后，是否可以刺激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的影响？提议实验将利用先进的神经解剖学和神经生理学工具和临床前遗传模型以了解这些问题。在AIM 1中，我们将配对大批量，高分辨率和细胞类型特定阵列层析成像神经解剖学重建，具有体内钙成像和神经元活性扰动以确定运动如何塑造VMH SF-1神经元的突触结构。这些实验将定义突触输入中这些神经元的变化如何在物理上“存储”练习 VMH电路中的历史。在AIM 2中，我们将使用先进的病毒映射和体内单细胞功能成像技术以识别通过运动激活哪些神经元并了解这些神经元如何运动信号传输到VMH下游的特定电路。这些实验将定义组织和逻辑，VMH神经元中与运动相关的活动驱动大脑的功能变化。在AIM 3中，我们将利用早期和晚期AD的先进临床前遗传小鼠模型确定VMH神经元中刺激活性是否可能概括运动的神经保护作用在皮质回路中观察到。这些实验将增加我们对VMH中信号的理解可以利用疾病状态的治疗操作。通过利用团队的协同专业知识为解决这个问题而组装的调查人员，这些实验的见解将推动我们的对运动的有益作用如何通过特定突触，细胞 - 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标。