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）：对AG 029573的修订补充的广泛目标“衰老期间的抑郁症行为的神经免疫机制”是确定适度运动训练干预措施在衰减衰老的夸张行为扰动炎症引起的夸张的行为干扰方面的疗效。这项拟议的工作为先前的资助赠款增添了重大的翻译目标，并且令人兴奋，因为我们将测试一种定义的机制，从而使锻炼可能发挥其行为影响。我们的初步数据支持我们的假设，即运动将以抗炎能力，特别是内脏脂肪组织内的作用，从而导致老年小鼠大脑内炎症的减少。反过来，这将导致色氨酸分解代谢酶吲哚胺2,3-二氧酶（IDO）的衰减，并导致行为障碍的降低，包括抑郁症状和抗衰变的行为，疲劳，疲劳和疲劳。我们的三个目标包括响应（1）急性炎症刺激（脂多糖； LPS），（2）慢性炎症刺激（Bacille Calmette-guerin; BCG）和（3）脑内脑室内LPS，检查了运动功效。除行为外，我们还将检查运动是否会减少脑细胞因子，IDO表达和活性以及响应炎症的Kynurenine/Throptophan比率。我们在最初的目标上取得了出色的进步，拟议的研究非常符合父母赠款的既定目标，因为在拟议的研究中将使用父母赠款中概述的所有行为和生化测量值。进行这些实验几乎没有技术风险，但是这些实验具有很高的产量。我们已经与杰弗里·伍兹（Jeffrey Woods）博士进行了合作，该公司将协助设计和进行运动干预。如果支持这项研究的假设，这些临床前数据将用作旨在确定常规运动有效性以及IDO在慢性炎症性疾病老年人行为障碍中的作用的支持。 公共卫生相关性：这项拟议的研究的相关性在于其潜力是确定一种安全，有效的策略，以减轻老年人的炎症引起的行为障碍（抑郁症，情绪障碍，疲劳）。