Neuroimmune Mechanisms of Depressive-Like Behavior During Aging

衰老过程中抑郁样行为的神经免疫机制

• 批准号: 7986896
• 负责人: Keith W Kelley
• 金额: $ 30.92万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986896
• 关键词: 5-Hydroxytryptophan; Acids; Acute; Adipose tissue; Adult; Aerobic; Affect; Age; Aging; Alzheimer' s Disease; Anhedonia; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Anxiety; Applications Grants; Arthritis; Attenuated; Behavior; Behavioral; Biochemical; Biological Markers; Brain; C-reactive protein; Calmette-Guerin Bacillus; Cardiovascular Diseases; Cardiovascular system; Chronic; Chronic Disease; Clinical; Collaborations; Communication; Communities; Cytokine Signaling; Data; Depressed mood; Diagnosis; Disease; Disease Progression; Educational Intervention; Effectiveness; Elderly; Elderly woman; Encephalitis; Enzymes; Exercise; Exhibits; Fatigue; Funding; Future; General Population; Glutamates; Goals; Grant; Growth Factor; Hippocampus (Brain); Image; Individual; Inflammation; Inflammatory; Insulin; Intervention; Kynurenine; Laboratories; Lead; Lexapro; Lipopolysaccharides; Longitudinal Studies; Measurement; Measures; Mediating; Medical Societies; Mental Depression; Metabolism; Modeling; Moderate Exercise; Molecular; Mood Disorders; Moods; Mus; Nerve; Neuroimmunomodulation; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pathway interactions; Peripheral; Persons; Pharmaceutical Preparations; Physical activity; Plasma; Play; Population; Prevalence; Prozac; Regimen; Research; Research Support; Risk; Role; Sensory; Serotonin; Social Interaction; Stimulus; Symptoms; Testing; Tissues; Training; Tryptophan; Tryptophan 2,3 Dioxygenase; Ursidae Family; Visceral; Wood material; Work; aged; aging brain; attenuation; clinically relevant; cytokine; depressive symptoms; design; disability; disturbance in affect; evidence base; fitness; immune activation; immune function; improved; influenzavirus; mRNA Expression; monoamine; neurotransmission; novel; parent grant; pre-clinical; public health relevance; research study; response; restoration

DESCRIPTION (provided by applicant): The broad goal of this revision supplement to AG 029573 "Neuroimmune Mechanisms of Depressive-Like Behavior during Aging" is to determine the efficacy of a moderate exercise training intervention in attenuating exaggerated behavioral disturbances induced by inflammation in aged mice. This proposed work adds significant translational aims to the prior funded grant and is novel and exciting because we will be testing a defined mechanism whereby exercise may be exerting its behavioral effects. Our preliminary data support our hypothesis that exercise will act in an anti-inflammatory capacity, specifically within visceral adipose tissue, resulting in a reduction in inflammation within brains of aged mice. This, in turn, will result in an attenuation of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in the brain and leading to a decrease in behavioral disturbances including depressive-like and anhedonic behavior, fatigue, and fatigability. Our three objectives include examination of exercise efficacy in response to (1) an acute inflammatory stimuli (lipopolysaccharide; LPS), (2) a chronic inflammatory stimuli (Bacille Calmette-Guerin; BCG), and (3) intracerebroventricular LPS. In addition to behavior, we will also examine whether exercise reduces brain cytokines, IDO expression and activity and the kynurenine/tryptophan ratio in response to inflammation. We are making excellent progress on the original aims, and the proposed research fits well with the stated objectives of the parent grant because all of the behavioral and biochemical measurements outlined in the parent grant will be utilized in the proposed studies. There is very little technical risk in conducting these experiments, but there is real potential for these experiments to bear a high yield. We have initiated a collaboration with Dr. Jeffrey Woods who will assist in the design and conduct of the exercise intervention. If the hypotheses of this research are supported, these preclinical data will be used as support for future grant applications aimed at determining the effectiveness of regular exercise and the role of IDO in behavioral disturbances in aged persons with chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE: The relevance of this proposed research lies in its potential to identify a safe, effective strategy to attenuate inflammation-induced behavioral disturbances (depression, mood disorders, fatigue) in older adults.

描述（由申请人提供）：AG 029573“衰老期间抑郁样行为的神经免疫机制”修订补充的广泛目标是确定适度运动训练干预在减轻老年小鼠炎症诱导的过度行为障碍方面的有效性。这项拟议的工作增加了重要的翻译目标，以先前资助的赠款，是新颖和令人兴奋的，因为我们将测试一个明确的机制，使运动可能发挥其行为的影响。我们的初步数据支持我们的假设，即运动将发挥抗炎作用，特别是在内脏脂肪组织中，从而减少老年小鼠大脑中的炎症。这反过来又会导致大脑中色氨酸分解代谢酶吲哚胺2，3-双加氧酶（IDO）的减弱，并导致行为障碍的减少，包括抑郁样和缺乏乐趣的行为、疲劳和易疲劳性。我们的三个目标包括检测运动对以下刺激的反应：（1）急性炎症刺激（脂多糖; LPS），（2）慢性炎症刺激（卡介苗; BCG），和（3）脑室内LPS。除了行为，我们还将研究运动是否会减少大脑细胞因子，IDO表达和活性以及犬尿氨酸/色氨酸比率对炎症的反应。我们在最初的目标上取得了很大的进展，拟议的研究与父母补助金的既定目标非常吻合，因为父母补助金中概述的所有行为和生化测量都将用于拟议的研究。进行这些实验的技术风险很小，但这些实验有真实的潜力产生高产。我们已经开始与杰弗里·伍兹博士合作，他将协助设计和进行运动干预。如果这项研究的假设得到支持，这些临床前数据将用于支持未来的拨款申请，旨在确定定期运动的有效性和IDO在慢性炎症性疾病老年人行为障碍中的作用。 公共卫生相关性：这项拟议研究的相关性在于它有可能确定一种安全有效的策略，以减轻老年人炎症引起的行为障碍（抑郁症，情绪障碍，疲劳）。