'Run for Your Life: Leveraging Exercise to Protect Against Dementia'

有规律的体育锻炼是最佳健康和长寿的基础。它可以促进认知功能，稳定我们身体的睡眠-觉醒周期和规律，包括食物和饮料的摄入。在阿尔茨海默病、帕金森病和亨廷顿病等神经退行性疾病中，认知能力下降伴随着睡眠、觉醒、食欲、口渴等方面的障碍。目前的证据表明，有规律的体育锻炼可能对神经退行性疾病有保护作用，但运动针对的大脑区域在很大程度上仍然未知。一个可能的目标是下丘脑，大脑的昼夜节律和体内平衡控制中心。由于认知能力下降是神经退行性疾病的特征，该学科的许多研究重点是学习和记忆脑回路，如内侧前额皮质。相比之下，下丘脑参与这些疾病的调查和理解被忽视。侧隔将大脑的主要学习和记忆回路与下丘脑的能量平衡和睡眠控制中心连接起来，并在阿尔茨海默病小鼠模型中受到影响。这种激素的受体胰高血糖素样肽1 （GLP-1）在外侧隔膜中表达，刺激大脑GLP-1受体可增强认知并调节食欲。体育锻炼影响GLP-1水平，在本项目中，学生将评估定期锻炼和GLP-1信号传导对阿尔茨海默病小鼠模型的认知、昼夜节律和稳态下降具有保护作用的假设。该项目将使用J20小鼠系，这是一种经过验证的阿尔茨海默病小鼠模型，它过度表达一种突变形式的APP，并将评估在跑步轮和GLP-1信号中进行的计时体育锻炼如何改变学习和记忆下降的时间过程，大脑活动，以及摄食行为和睡眠的日常节奏。研究人员将小鼠置于不同的跑步轮可用性和/或GLP-1受体刺激物的管理条件下，并在不同的生命阶段评估小鼠的认知表现和摄食行为的昼夜节律稳健性。脑活动将评估使用最先进的多电极阵列记录以及脑电图。免疫组织化学、通道示踪和电生理学将用于确定运动和GLP-1激动剂在生命的不同阶段如何影响下丘脑的外侧隔信号。具体来说，该项目将评估：1)定期在跑步轮上进行自愿运动是否会延缓认知能力下降、昼夜节律和睡眠中断？2) GLP-1急性治疗是否能改善认知和昼夜节律下降？3)外隔与下丘脑的通信是否因计划的随意运动和/或GLP-1而改变？4)计划性自愿运动和GLP-1信号是单独发挥作用还是相互增强作用？

Regular physical exercise is fundamental to optimal health and longevity. It promotes cognitive function and can stabilize sleep-wake cycles and regularity in our body's homeostatic state including food and drink intake. In neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Huntington's Disease, cognitive decline is accompanied by impairments in sleep-wake, appetite, thirst, etc. Current evidence indicates that regular physical exercise could be protective in neurodegenerative conditions, but brain regions targeted by exercise remain largely unknown. A likely target is the hypothalamus, the brain's hub of circadian and homeostatic control. Since cognitive decline characterizes neurodegenerative diseases, the focus of much research in this discipline is on learning and memory brain circuits such as the medial prefrontal cortex. By contrast, investigation and understanding of hypothalamic involvement in these diseases is neglected. The lateral septum connects the brain's main learning and memory circuits with energy balance and sleep control centres in the hypothalamus and is affected in mouse models of Alzheimer's disease. Receptors for the hormone, glucagon-like peptide 1 (GLP-1), are expressed in the lateral septum and stimulation of brain GLP-1 receptors enhances cognition and regulate appetite. Physical exercise influences levels of GLP-1 and in this project, the student will assess the hypothesis that regular exercise and GLP-1 signaling are protective cognitive, circadian, and homeostatic decline in a mouse model of Alzheimer's disease. The project will use the J20 mouse line, a validated mouse model of Alzheimer's disease, which overexpresses a mutant form of APP, and will evaluate how timed physical exercise in a running wheel and GLP-1 signaling alter the time-course in decline in learning and memory, brain activity, and daily rhythms in ingestive behavior and sleep. Mice will be housed under different conditions of runningwheel availability and/or administration of GLP-1 receptor stimulants and assessed at different stages of the lifespan for cognitive performance and robustness in circadian rhythms of ingestive behave. Brain activity will be assessed using state of the art multielectrode array recordings as well as electroencephalography. Immunohistochemistry, tract-tracing, and electrophysiology will be used to determine how the lateral septum signaling to the hypothalamus is affected by exercise and GLP-1 agonists at different stages of the lifespan. Specifically, the project will assess: 1) Does scheduled voluntary exercise in a running wheel delay cognitive decline and disruptions in circadian rhythms and sleep? 2) Does acute treatment with GLP-1 ameliorate cognitive and circadian decline? 3) Is communication by the lateral septum to the hypothalamus altered by scheduled voluntary exercise and/or GLP-1? 4) Do scheduled voluntary exercise and GLP-1 signaling exert their effects independently or can they augment each others actions?