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: 8049171
• 负责人: Keith W Kelley
• 金额: $ 59.78万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049171
• 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; Data; Depressed mood; Depressive disorder; Desire for food; Development; Dioxygenases; Disease; Disease Resistance; Elderly; 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; 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; 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; age related; aged; aging brain; aging population; base; cytokine; depressive symptoms; falls; healthy aging; hypomania; immune activation; indoleamine; innovation; macrophage; microbial; mood regulation; neurobiological mechanism; neuroinflammation; neuropathology; neurotransmission; normal aging; novel; novel therapeutics; older patient; overexpression; prevent; programs; psychologic; research study; response

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）：现在被认为炎症是造成衰老人口的重大健康问题的原因，这导致了2型糖尿病中肥胖，代谢综合征，心脏病和胰岛素抵抗等昂贵的疾病。即使健康衰老的慢性过程也与低年级炎症的发展有关。但是，与全身性疾病有关的炎症与年龄相关的变化已被考虑。我们和其他人现在已经收集了大量证据表明，这种炎症状态（由促炎细胞因子的过表达所定义）不限于周围，而是在大脑中发现。脑部炎症会引起疾病的症状，通常与微生物感染有关，这可能会对老年人发生的合并性行为和心理障碍做出重要贡献。实际上，有65岁以上的五分之一的人患有抑郁症，这是普通人群中患病率的两倍以上。衰老期间抑郁症患病率增加的可能机制是降低了5-羟色胺的合成，羟色胺是由脑在大脑中作用的促炎细胞因子引起的关键神经递质。该作用是由免疫诱导的色氨酸降解酶，吲哚胺2,3二加氧酶（IDO）激活的介导的。这个过程降低了色氨酸对5-羟色胺的合成的生物利用度。我们的初步数据表明，外周免疫激活激活IDO并引起抑郁样的行为改变，并且与成年小鼠相比，这些作用在老年人中加剧了。基于这一证据，我们建议外周免疫激活会导致老年人的情绪障碍发生。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检验这一假设，这是我们已经证明增加了大脑IDO活性的两个事件。在第一个目标中，我们将确定在老年小鼠中是否会导致急性和慢性外周免疫激活产生的抑郁样行为改变会加剧。在第二个目标中，我们将评估这些行为变化中周围和脑IDO以及脑色氨酸和5-羟色胺的增加的作用，而第三个目标将决定脑胶质神经胶质细胞对与年龄相关的脑IDO增加的贡献。然后，我们将使用新颖的药理学方法来确定靶向脑部炎症（目标4）还是脑IDO（目标5）会减轻衰老对抑郁类似行为发展的功能后果。这些令人兴奋的实验将是第一个使用综合神经免疫性方法评估IDO作为与年龄相关的周围和脑部炎症增加与老年人情绪障碍患病率增加之间的关键中介者的评估。

项目成果

Voluntary wheel running does not affect lipopolysaccharide-induced depressive-like behavior in young adult and aged mice.

• DOI: 10.1159/000356144
• 发表时间: 2014
• 期刊: Neuroimmunomodulation
• 影响因子: 2.4
• 作者: Martin SA;Dantzer R;Kelley KW;Woods JA
• 通讯作者: Woods JA

Effects of voluntary wheel running on LPS-induced sickness behavior in aged mice.

• DOI: 10.1016/j.bbi.2012.12.014
• 发表时间: 2013-03
• 期刊: Brain, behavior, and immunity
• 作者: Martin SA;Pence BD;Greene RM;Johnson SJ;Dantzer R;Kelley KW;Woods JA
• 通讯作者: Woods JA

HIV-1 Tat activates indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures in a p38 mitogen-activated protein kinase-dependent manner.

• DOI: 10.1186/1742-2094-8-88
• 发表时间: 2011-08-02
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Fu X;Lawson MA;Kelley KW;Dantzer R
• 通讯作者: Dantzer R

Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis.

• DOI: 10.1016/j.bbi.2013.05.005
• 发表时间: 2013-10
• 期刊: Brain, behavior, and immunity
• 作者: Cook MD;Martin SA;Williams C;Whitlock K;Wallig MA;Pence BD;Woods JA
• 通讯作者: Woods JA

Ten years of Nature Reviews Neuroscience: insights from the highly cited.

• DOI: 10.1038/nrn2912
• 发表时间: 2010-10
• 期刊: NATURE REVIEWS NEUROSCIENCE
• 影响因子: 34.7
• 作者: Luo, Liqun;Rodriguez, Eugenio;Jerbi, Karim;Lachaux, Jean-Philippe;Martinerie, Jacques;Corbetta, Maurizio;Shulman, Gordon L.;Piomelli, Daniele;Turrigiano, Gina G.;Nelson, Sacha B.;Joels, Marian;de Kloet, E. Ronald;Holsboer, Florian;Amodio, David M.;Frith, Chris D.;Block, Michelle L.;Zecca, Luigi;Hong, Jau-Shyong;Dantzer, Robert;Kelley, Keith W.;Craig, A. D. (Bud)
• 通讯作者: Craig, A. D. (Bud)