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

基本信息

批准号：
7391645
负责人：
Keith W Kelley
金额：
$ 30.74万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
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/7391645
关键词：
Acute Adult Affect Age Aging Aging-Related Process Anhedonia Anxiety Attenuated Behavior Behavioral Biological Availability Brain C-reactive protein Calmette-Guerin Bacillus Cancer Patient Cardiovascular Diseases Cells Chronic Clinical Condition Data Depressed mood Depressive disorder Desire for food Development Dioxygenases Disease Elderly Elevation Encephalitis Enzymes Event Experimental Models Fatigue Feeling suicidal General Population Goals Health Heart Diseases Hepatitis C Human Immune Immune response Immune system Immunity Immunocompetence Immunotherapy Individual Infection Inflammation Inflammatory Injection of therapeutic agent Insulin Resistance Interferons Interleukin-1 Interleukin-2 Kynurenine Laboratories Lead Life Malignant Neoplasms Malignant neoplasm of kidney Mediating Mediator of activation protein Mental Depression Metabolic syndrome Metabolism Metastatic Melanoma Microglia Molecular Mood Disorders Mus Neuroglia Neuroimmunomodulation Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Patients Pattern Peripheral Plasma Play Population Prevalence Process Protein Overexpression Psychopathology Recording of previous events Renal carcinoma Research Research Personnel Rheumatoid Arthritis Role Serotonin Serum Signal Transduction Sleep Staging Symptoms T-Lymphocyte Testing Tryptophan Tryptophan Metabolism Pathway Tumor Necrosis Factor-alpha Tumor Necrosis Factors age related aged aging brain aging population base cytokine depressive symptoms falls healthy aging human TNF protein hypomania indoleamine innovation macrophage microbial mood regulation neurobiological mechanism neuroinflammation neuropathology neurotransmission normal aging novel novel therapeutics older patient prevent programs psychologic research study response

项目摘要

DESCRIPTION (provided by applicant): Inflammation is now recognized to be responsible for major health problems of the aging population, contributing to costly diseases such as obesity, the metabolic syndrome, heart disease and insulin resistance in type-2 diabetes. The chronic process of even healthy aging is also associated with development of low grade inflammation. However, age-related changes in inflammation have mainly been considered in relation to systemic disorders. We and others have now collected substantial evidence to show that this inflammation status, as defined by the overexpression of proinflammatory cytokines, is not restricted to the periphery but is also found in the brain. Brain inflammation causes symptoms of sickness that are usually associated with microbial infections, which is likely to make an important contribution to the comorbid behavioral and psychological disturbances that occur in the elderly. Indeed, one in five individuals over the age of 65 suffer from depressive disorders, which is more than twice the prevalence found in the general population. A likely mechanism for the increased prevalence of depressive disorders during aging is a reduction in the synthesis of serotonin, a key neurotransmitter in the regulation of mood, caused by proinflammatory cytokines acting in the brain. This action is mediated by immune-induced activation of the tryptophan-degrading enzyme, indoleamine 2,3 dioxygenase (IDO). This process decreases the bioavailability of tryptophan for the synthesis of serotonin. Our preliminary data indicate that peripheral immune activation activates IDO and induces depressive-like behavioral alterations, and these effects are exacerbated in aged compared to adult mice. Based on this evidence, we propose that peripheral immune activation precipitates the occurrence of mood disorders in aged individuals. We propose to test this hypothesis in aged mice exposed to both acute and chronic peripheral immune activation, two events that we have already shown to increase brain IDO activity. In the first objective, we will determine whether the depressive-like behavioral alterations that develop in response to both acute and chronic peripheral immune activation are exacerbated in aged mice. In the second objective, we will assess the role of increases in peripheral and brain IDO, as well as brain tryptophan and serotonin, in these behavioral changes, whereas the third objective will determine the contribution of brain glial cells to the age-associated increase in brain IDO. We will then use novel pharmacological approaches to determine if targeting brain inflammation (Objective 4) or brain IDO (Objective 5) attenuates the functional consequences of aging on development of depressive like behavior. These exciting experiments will be the first to use integrative neuroimmune approaches to evaluate IDO as the critical mediator between the age-related increase in peripheral and brain inflammation and the increased prevalence of mood disorders in aged individuals.

描述（由申请人提供）：现在人们认识到炎症是造成老龄化人口主要健康问题的原因，导致肥胖、代谢综合征、心脏病和 2 型糖尿病中的胰岛素抵抗等代价高昂的疾病。即使是健康衰老的慢性过程也与低度炎症的发展有关。然而，与年龄相关的炎症变化主要被认为与全身性疾病有关。我们和其他人现在已经收集了大量证据，表明这种由促炎细胞因子过度表达定义的炎症状态不仅限于外周，而且也存在于大脑中。脑部炎症引起的疾病症状通常与微生物感染有关，这可能是导致老年人出现共病行为和心理障碍的重要原因。事实上，65 岁以上的人中有五分之一患有抑郁症，这一比例是普通人群患病率的两倍多。衰老过程中抑郁症患病率增加的一个可能机制是血清素合成减少，血清素是调节情绪的关键神经递质，由大脑中作用的促炎细胞因子引起。该作用是由色氨酸降解酶吲哚胺 2,3 双加氧酶 (IDO) 的免疫诱导激活介导的。这个过程降低了色氨酸合成血清素的生物利用度。我们的初步数据表明，外周免疫激活会激活 IDO 并诱导抑郁样行为改变，与成年小鼠相比，这些影响在老年小鼠中更为严重。基于这一证据，我们提出外周免疫激活会促进老年人情绪障碍的发生。我们建议在暴露于急性和慢性外周免疫激活的老年小鼠中测试这一假设，我们已经证明这两种事件会增加大脑 IDO 活性。在第一个目标中，我们将确定老年小鼠中因急性和慢性外周免疫激活而发生的抑郁样行为改变是否会加剧。在第二个目标中，我们将评估外周和大脑 IDO 以及大脑色氨酸和血清素增加在这些行为变化中的作用，而第三个目标将确定大脑胶质细胞对与年龄相关的 IDO 增加的贡献。大脑IDO。然后，我们将使用新的药理学方法来确定针对大脑炎症（目标 4）或大脑 IDO（目标 5）是否可以减轻衰老对抑郁样行为发展的功能影响。这些令人兴奋的实验将首次使用综合神经免疫方法来评估 IDO 作为与年龄相关的外周和大脑炎症增加与老年人情绪障碍患病率增加之间的关键介质。