Exercise and TLR: Mechanisms underlying resilience to chronic stress

应激是日常生活中不可避免和正常的一部分，而应激反应的激活对 生死存亡。然而，慢性压力会对心理健康和幸福感产生负面影响，并导致 易感人群的疾病。我们并不完全了解慢性压力是如何影响行为的，但有一种方式 研究这一问题的目的是确定促进对慢性应激诱导的保护的机制 行为。 近年来，慢性应激引起的炎症与智力的发展有关。 精神错乱。患有严重抑郁障碍、焦虑、 和神经退行性疾病，这可能会低估这些疾病的进展。类似的炎症反应 在炎症和慢性应激的小鼠模型中，介质也被上调。我们发现TLR1，一种通行费- 参与下游炎症反应的样受体，在应激大鼠海马区表达上调 然而，小鼠在慢性应激范例中的自愿运动保护小鼠免受TLR1上调， 以及与慢性压力相关的行为变化。在本提案中，我们将确定TLR1调制是否 在对慢性应激的行为和炎症反应中起到弹性作用。 众所周知，运动对身心健康有积极的影响，而且它也是 与炎性因子减少有关。我们的初步数据显示，在 慢性应激促进低吞咽、回避、空间等行为测试中的保护性表型 雄鼠和雌鼠的记忆识别和体重减轻。 在这项建议中，我们将加强我们对慢性病潜在弹性机制的了解。 压力。我们推测，海马区TLR1的激活是这一效应的中心机制。我们的目标是 (1)确定自愿锻炼是否能保护身体免受慢性压力的影响，并防止由压力引起的 (2)确定慢性应激影响的下游炎症因子/- 自愿运动并确定TLR1的Micro-RNA调节器是否由于慢性应激而被扰乱，(3)和 确定TLR1缺乏是否是对慢性压力的一种潜在恢复机制。为了实现这些目标，我们 将进行机械性的分子和行为研究，主要集中在培养本科生 研究人员。根据R15机制的目标，本科生将是所有人的中心 研究设计、数据收集、分析、解释和数据呈现的各个方面。执行这些操作 临床前研究的类型对于培养下一代研究人员和临床前研究的进展至关重要 菲尔德。

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.