Neuroimmune Mechanisms of Depressive-Like Behavior During Aging

描述（由申请人提供）：本修订补充AG 029573“衰老过程中抑郁样行为的神经免疫机制”的总体目标是确定适度运动训练干预在减轻衰老小鼠炎症引起的夸大行为障碍方面的功效。这项提议的工作为之前的资助增加了重要的转化目标，并且是新颖和令人兴奋的，因为我们将测试一种明确的机制，通过这种机制，运动可能会发挥其行为效应。我们的初步数据支持我们的假设，即运动具有抗炎能力，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。反过来，这将导致大脑中色氨酸分解代谢酶吲哚胺2,3-双加氧酶（IDO）的衰减，并导致行为障碍的减少，包括抑郁样和快感缺乏行为，疲劳和疲劳。我们的三个目标包括检查运动对(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的反应效果。除行为外，我们还将研究运动是否会降低脑细胞因子、IDO表达和活性以及对炎症反应的犬尿氨酸/色氨酸比率。我们在最初的目标上取得了良好的进展，并且拟议的研究与母基金的既定目标非常吻合，因为母基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，但这些实验确实有获得高产量的潜力。我们已经开始与杰弗里·伍兹博士合作他将协助设计和实施运动干预。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。

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.