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. ? ? ?
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