Exercise and TLR: Mechanisms underlying resilience to chronic stress

运动和 TLR：慢性压力恢复能力的机制

• 批准号: 10730416
• 负责人: Melissa Taft Manners
• 金额: $ 45.8万
• 依托单位: ROWAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730416
• 关键词: 3' Untranslated Regions; Academic Research Enhancement Awards; Affect; Antidepressive Agents; Anxiety Disorders; Behavior; Behavioral; Binding; Biological Assay; Body Weight Changes; Body Weight decreased; Chronic; Chronic stress; Cognition; Data; Data Collection; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Exercise; Faculty; Family; Female; Gene Expression; Genes; Goals; Health; Hippocampus; Immunohistochemistry; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Knowledge; Life; Luciferases; Major Depressive Disorder; Measures; Mediating; Mental Health; Mental disorders; MicroRNAs; Modeling; Molecular; Mus; Natural Immunity; Neurodegenerative Disorders; Pathway interactions; Pattern recognition receptor; Personal Satisfaction; Phenotype; Physiological; Play; Predisposition; Proteins; Regulation; Reporter; Reporting; Research Design; Research Personnel; Risk Factors; Role; Running; Signal Transduction; Social Interaction; Stress; System; TLR1 gene; Testing; Therapeutic; Toll-like receptors; Training; Up-Regulation; Wild Type Mouse; Work; associated symptom; behavior test; behavioral response; behavioral study; biological adaptation to stress; depressive symptoms; design; feeding; graduate student; improved; knock-down; male; memory recognition; mental development; mouse model; next generation; novel; object recognition; physical conditioning; preclinical study; prevent; promote resilience; protective effect; resilience; sex; social; spatial memory; stress reduction; undergraduate student

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.

压力是日常生活的必然且正常的一部分，压力反应的激活对于 生存。但是，慢性压力会对心理健康和福祉产生负面影响，并导致心理 易感人士的疾病。我们不完全了解慢性压力如何影响行为，而是一种方式 调查此问题的是确定促进避免长期压力诱导的保护的机制 行为。 近年来，慢性压力引起的炎症与精神的发展有关 疾病。患有严重抑郁症，焦虑症，炎症因素升高 和神经退行性疾病，可能是这些疾病的进展。类似的炎症 在炎症和慢性应激的小鼠模型中，介体也被上调。我们发现TLR1，Tol-tol- 就像参与下游炎症反应的受体一样，在压力的海马中上调 然而，小鼠在慢性应激范式中受保护的小鼠免受上调的TLR1的保护， 和与慢性压力相关的行为变化。在此提案中，我们将确定TLR1是否调制 在对慢性压力的行为和炎症反应中起作用。 众所周知，运动会引起对身心健康的积极影响，这也是 与炎症因子减少有关。我们的初步数据表明在 慢性应激促进了在高肌，回避和空间的行为测试中的保护性表型 男性和雌性小鼠的记忆识别和体重减轻。 在此提案中，我们将增强对慢性韧性的机制的了解 压力。我们假设海马TLR1激活是这种效果的核心机制。我们的目标是 （1）确定自愿运动是否可以保护慢性应激的影响并防止应力引起的 海马TLR1的增加，（2）确定受慢性应激影响+/-影响的下游炎症因子 自愿运动，并确定由于慢性应激，（3）和 确定TLR1缺乏症是否是对慢性应激的韧性的基础机制。追求这些目标，我们 将进行机械性分子和行为研究，主要关注训练本科生 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，解释和数据的各个方面。进行这些 临床前研究的类型对于培训下一代研究人员和进步至关重要 场地。