A major advance in the neurobiological basis of behavior is the discovery that proinflammatory cytokines produced by activated innate immune cells not only organize the host response to infection but also can induce symptoms of depression. In cancer patients treated with cytokines, depression is associated with a drop in circulating levels of tryptophan, the amino-acid precursor of serotonin (5-hydroxytryptamine or 5-HT). Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that is potently induced in monocytes and macrophages by cytokines. Induction of this enzyme greatly reduces the bioavailability of tryptophan for 5-HT synthesis. We have exciting new evidence showing that cytokines activate IDO not only in peripheral tissues but also in the brain. The broad objective of this application is to test the hypothesis that cytokine-induced activation of IDO can lead to behavioral disorders eventually culminating in depression. We have established two experimental murine models of IDO activation in vivo, an acute model based on peripheral injection of lipopolysaccharide and a chronic model based on inoculation of attenuated Mycobacterium boris. In Objective 1, we will use immunohistochemistry to identify the brain regions and types of cells where activation of IDO occurs. In Objective 2, cytokine-induced alterations in tryptophan and serotonin metabolism that are associated with IDO activation will be determined by measuring metabolism of tryptophan and serotonin by HPLC. We will also measure the potential compensatory changes that result from these neurochemical alterations, including the 5-HT transporter and 5-HT1A receptors, and their functional consequences on behavior. Since interferon-gamma is the main inducer of IDO in peripheral tissues, we will determine in Objective 3 if this cytokine is also able to act in the brain via the JAK-STAT signaling pathway to activate IDO. In Objective 4, we will confirm that direct pharmacological blockade of IDO by a selective inhibitor or by blockade of the action of interferon-gamma in the brain will abrogate both neurochemical and behavioral alterations. In Objective 5, we will take advantage of the redox sensitivity of IDO to determine whether antioxidant supplementation attenuates the effects of proinflammatory cytokines on IDO expression and action in the brain. These innovative experiments are needed to understand how functional interactions between the immune system and brain regulate behavior and mood .
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