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.

压力是日常生活中不可避免且正常的一部分，激活压力反应对于 生存。然而，慢性压力会对心理健康和福祉产生负面影响，并导致心理问题。 易感人群患病。我们并不完全了解慢性压力如何影响行为，但有一种方式 研究这个问题的目的是确定促进保护免受慢性压力诱发的机制 行为。 近年来，慢性压力引起的炎症与精神障碍的发展有关。 失调。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 在炎症和慢性应激的小鼠模型中，介质也会上调。我们发现 TLR1，一个收费站 参与下游炎症反应的类似受体在应激的海马体中表达上调 然而，小鼠在慢性应激模式下的自愿锻炼可以保护小鼠免受 TLR1 上调的影响， 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 在对慢性压力的行为和炎症反应的恢复中发挥作用。 长期以来，人们都知道锻炼可以对身心健康产生积极影响，而且 与炎症因子减少有关。我们的初步数据表明，自愿锻炼期间 慢性压力在吞食不足、回避、空间行为等行为测试中促进保护性表型 雄性和雌性小鼠的记忆识别和体重减轻。 在本提案中，我们将增强对慢性病恢复力背后机制的了解。 压力。我们假设海马 TLR1 激活是这种效应的核心机制。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 TLR1 增加，(2) 识别受慢性应激影响的下游炎症因子 +/- 自愿锻炼并确定 TLR1 的 micro-RNA 调节因子是否因慢性压力而受到破坏，(3) 和 确定 TLR1 缺乏是否是慢性压力恢复能力的潜在机制。为了实现这些目标，我们 将进行机械分子和行为研究，主要重点是培养本科生 研究人员。根据R15机制的目标，本科生将成为一切的核心 研究设计、数据收集、分析、解释和数据呈现等方面。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展至关重要 场地。