Glial and tissue-specific regulation of Kynurenine Pathway dioxygenases by acute stress of mice

• Published in: Neurobiology of stress Vol. 7; pp. 1 - 15
• Main Authors: Dostal, Carlos R., Carson Sulzer, Megan, Kelley, Keith W., Freund, Gregory G., McCusker, Robert H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2017; Elsevier
• Subjects: Astrocyte; Ido; Kynurenine; Liver; Original; Stress; Tdo; Kynurenine; Astrocyte; Ido; Liver; Stress; Tdo
• ISSN: 2352-2895; 2352-2895
• DOI: 10.1016/j.ynstr.2017.02.002

Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3-dioxygenases (DOs: Ido1, Ido2, Tdo2). Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent. Thus, C57BL/6J mice were used to characterize DO expression in brain-regions, astrocytes and microglia to characterize restraint-stress-induced DO expression. Stress increased kynurenine in brain and plasma, demonstrating increased DO activity. Of three Ido1 transcripts, only Ido1-v1 expression was increased by stress and within astrocytes, not microglia, indicating transcript- and glial-specificity. Stress increased Ido1-v1 only in frontal cortex and hypothalamus, indicating brain-region specificity. Of eight Ido2 transcripts, Ido2-v3 expression was increased by stress, again only within astrocytes. Likewise, stress increased Tdo2-FL expression in astrocytes, not microglia. Interestingly, Ido2 and Tdo2 transcripts were not correspondingly induced in Ido1-knockout (Ido1KO) mice, suggesting that Ido1 is necessary for the central DO response to acute stress. Unlike acute inflammatory models resulting in DO induction within microglia, only astrocyte DO expression was increased by acute restraint-stress, defining their unique role during stress-dependent activation of the Kynurenine Pathway. •Acute stress increased tryptophan metabolism to kynurenine.•Stress increased Ido1, Ido2 and Tdo2 expression by astrocytes.•Stress did not increase Ido2 in astrocytes from Ido1KO mice.•Stress did not increase Tdo2 in brains fromIdo1KO mice.•Brain and hepatic Ido1, Ido2 and Tdo2 are differentially regulated by stress.