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Exercise and TLR: Mechanisms underlying resilience to chronic stress

运动和 TLR：慢性压力恢复能力的机制

基本信息

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
项目类别：
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&apos 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

项目摘要

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和正常的一部分，激活压力反应对健康至关重要