Exercise and TLR: Mechanisms underlying resilience to chronic stress

压力是日常生活中不可避免和正常的一部分，激活压力反应对于 生存然而，慢性压力会对心理健康和幸福产生负面影响，并导致心理健康问题。 易感人群的疾病。我们并不完全了解慢性压力如何影响行为，但有一种方式 调查这个问题的目的是确定促进保护免受慢性应激诱导的机制。 行为。 近年来，慢性应激引起的炎症与精神发育有关， 紊乱炎症因子在患有重度抑郁症、焦虑症、 和神经退行性疾病，这可能是这些疾病进展的基础。类似炎症 介质在炎症和慢性应激的小鼠模型中也被上调。我们发现TLR 1，一种收费蛋白- 与下游炎症反应相关的受体一样，在应激的海马中上调， 然而，小鼠在慢性应激模式期间的自愿运动保护小鼠免受上调的TLR 1， 以及与慢性压力相关的行为变化。在这个建议中，我们将确定TLR 1调节是否 在对慢性压力的行为和炎症反应的恢复中起作用。 长期以来，人们都知道运动对身心健康有积极的影响， 与炎症因子减少有关。我们的初步数据表明， 慢性应激促进了hyponeophagia，回避，空间， 记忆识别和体重减轻。 在本提案中，我们将加强我们对慢性病恢复力机制的认识， 应力我们假设海马TLR 1激活是这种效应的中心机制。我们的目标是 (1)确定自愿锻炼是否可以防止慢性压力的影响，并防止压力引起的 海马TLR 1增加，（2）鉴定受慢性应激影响的下游炎症因子+/- 自愿运动，并确定TLR 1的micro-RNA调节因子是否由于慢性应激而被破坏，（3）和 确定TLR 1缺乏是否是慢性压力恢复力的潜在机制。为了实现这些目标，我们 将进行一项机制分子和行为研究，主要侧重于培养本科生 研究人员根据R15机制的目标，本科生将是所有人的核心。 研究设计、数据收集、分析、解释和数据展示等方面。进行这些 临床前研究的类型对于培养下一代研究人员和 领域

Stress is an inevitable and normal part of daily life, and activation of the stress response is vital for survival. However, chronic stress can have a negative impact on mental health and wellbeing, and lead to mental illness in susceptible individuals. We do not fully understand how chronic stress impacts behavior, but one way of investigating this issue is to determine mechanisms that promote protection from chronic-stress induced behaviors. In recent years, inflammation from chronic stress has been associated with the development of mental disorders. Inflammatory factors are elevated in individuals suffering from Major Depressive Disorder, Anxiety, and Neurodegenerative Disorders, which could underly the progression of these diseases. Similar inflammatory mediators are also upregulated in mouse models of inflammatory and chronic stress. We found that TLR1, a toll- like receptor involved in downstream inflammatory response, was upregulated in the hippocampus of stressed mice, however, voluntary exercise during the chronic stress paradigm protected mice from upregulated TLR1, and behavioral changes associated with chronic stress. In this proposal, we will determine if TLR1 modulation has a role in resilience to the behavioral and inflammatory response to chronic stress. Exercise has long been known to induce positive effects on physical and mental health, and it is also associated with reduced inflammatory factors. Our preliminary data indicates that voluntary exercise during chronic stress promotes a protective phenotype in behavioral tests of hyponeophagia, avoidance, spatial memory recognition, and weight loss in both male and female mice. In this proposal, we will enhance our knowledge of the mechanisms underlying resilience to chronic stress. We hypothesize that hippocampal TLR1 activation is a central mechanism for this effect. Our aims are to (1) determine if voluntary exercise protects from the effects of chronic stress and prevents the stress-induced increase in hippocampal TLR1, (2) identify downstream inflammatory factors affected by chronic stress +/- voluntary exercise and determine if micro-RNA regulators of TLR1 are disrupted due to chronic stress, (3) and determine if TLR1 deficiency is a mechanism underlying resilience to chronic stress. To pursue these aims, we will conduct a mechanistic molecular and behavioral study with a primary focus on training undergraduate researchers. In accordance with the goals of the R15 mechanism, undergraduate students will be central to all aspects of the study design, data collection, analysis, interpretation, and presentation of data. Conducting these types of preclinical studies is essential for training the next generation of researchers and progression of the field.