Stress and inflammation regulate the kynurenine pathway dioxygenases in a glia‐ and tissue‐specific manner

The inflammation and stress responses are intimately related adaptive responses to pathogens or other stressors upsetting our body’s homeostasis. However, when infections or other stressors persist-or are sufficiently traumatic-our normally adaptive responses become maladaptive compromising our immune system and mental wellbeing. Depression accounts for ~33% of debilitating mental illness worldwide. Recently, studies have outlined mechanisms by which stressors inducing proinflammatory cytokines or glucocorticoids precipitate symptoms of depression. Central to this hypothesis are the glucocorticoid- and cytokine-inducible enzymes tryptophan and indoleamine 2,3-dioxygenases (DOs: Tdo2, Ido1 and Ido2). The DOs are rate-limiting for tryptophan metabolism by the Kynurenine Pathway. While accumulating evidence supports an interconnection between symptoms of depression and increased Kynurenine Pathway activity, the cellular specificity underpinning DO regulation by stress and inflammation remain poorly defined. Thus, (Chapter 1) after a review of the relevant literature, this thesis probes the regulation of DO expression (Chapter 2) by acute stress, and (Chapter 3) by peripheral inflammation and glucocorticoids, within the mouse brain, astrocytes, microglia, and peripheral tissues. We identify a unique role for astrocytes in the DO response to stress, and describe unique regulation patterns for astrocytes and microglia in the DO response to inflammation and glucocorticoids. Finally, using Cre-lox mediated cell-specific knockdown of Ido1 in mice, we probe the contributions of myeloid- and neuron-derived Ido1 to inflammation-induced anhedonia-like behavior reveling that myeloid-derived Ido1 contributes to inflammation-induced anhedonia. Together, the data highlight glia- and tissue-specific DO regulation by stress and inflammation, and cell-specific contributions of Ido1 to inflammation-induced anhedonia-like behaviors in mice