Neuroimmune Mechanisms of Depressive-Like Behavior During Aging

描述(申请人提供)：炎症现在被认为是老龄化人口的主要健康问题，导致了昂贵的疾病，如肥胖症、代谢综合征、心脏病和2型糖尿病的胰岛素抵抗。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系统性疾病有关。我们和其他人现在已经收集了大量证据表明，这种炎症状态，如促炎细胞因子的过度表达所定义的，不仅限于外周，而且在大脑中也存在。脑部炎症引起的疾病症状通常与微生物感染有关，这可能是老年人并发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，这是普通人群患病率的两倍多。衰老过程中抑郁障碍患病率增加的一个可能机制是5-羟色胺的合成减少，5-羟色胺是调节情绪的关键神经递质，由大脑中的促炎细胞因子引起。这一作用是由免疫诱导的色氨酸降解酶吲哚-2，3-双加氧酶(IDO)的激活所介导的。这一过程降低了色氨酸合成5-羟色胺的生物利用度。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加剧。基于这一证据，我们认为外周免疫激活加速了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说，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，我们将确定因急性和慢性外周免疫激活而产生的类似抑郁的行为改变是否会在老年小鼠中加剧。在第二个目标中，我们将评估外周和大脑IDO的增加，以及大脑色氨酸和5-羟色胺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脑IDO增加的贡献。然后，我们将使用新的药理学方法来确定靶向脑炎症(目标4)或脑IDO(目标5)是否可以减轻衰老对抑郁样行为发展的功能后果。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发病率增加之间的关键中介。

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.