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

定期体育锻炼是最佳健康和长寿的基础。它促进认知功能，可以稳定睡眠-觉醒周期和我们身体的自我平衡状态的规律性，包括食物和饮料的摄入。在神经退行性疾病，如阿尔茨海默氏病，帕金森氏病，和亨廷顿氏病，认知能力下降是伴随着睡眠，觉醒，食欲，口渴等损害目前的证据表明，定期体育锻炼可以在神经退行性疾病的保护，但大脑区域的运动目标仍然在很大程度上是未知的。一个可能的目标是下丘脑，大脑的昼夜节律和自我平衡控制中心。由于认知能力下降是神经退行性疾病的特征，因此这一学科的许多研究都集中在学习和记忆脑回路上，如内侧前额叶皮层。相比之下，下丘脑参与这些疾病的调查和理解被忽视。侧隔连接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，并在阿尔茨海默病小鼠模型中受到影响。胰高血糖素样肽1（GLP-1）的激素受体在外侧隔中表达，刺激大脑GLP-1受体可增强认知能力并调节食欲。体育锻炼影响GLP-1的水平，在这个项目中，学生将评估这一假设，即定期锻炼和GLP-1信号是保护性的认知，昼夜节律和稳态下降在阿尔茨海默病的小鼠模型。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，过度表达APP的突变形式，并将评估跑步轮中的定时体育锻炼和GLP-1信号传导如何改变学习和记忆，大脑活动以及摄食行为和睡眠的日常节奏下降的时间过程。小鼠将在不同的转轮可用性和/或GLP-1受体兴奋剂给药条件下圈养，并在生命周期的不同阶段评估认知性能和摄食行为昼夜节律的稳健性。将使用最先进的多电极阵列记录以及脑电图评估脑活动。将使用免疫组织化学、束追踪和电生理学来确定运动和GLP-1激动剂在寿命的不同阶段如何影响下丘脑的外侧隔信号传导。具体来说，该项目将评估：1）在跑步轮上进行有计划的自愿运动是否会延迟认知能力下降以及昼夜节律和睡眠的中断？2)GLP-1急性治疗是否改善认知和昼夜节律下降？3)定期自主运动和/或GLP-1是否改变了外侧隔与下丘脑的通信？4)有计划的自愿运动和GLP-1信号传导是否独立发挥作用，或者它们是否可以相互增强？

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?