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oai:www.ideals.illinois.edu:2142/99101 2023-07-11 col_2142_5131 col_2142_13007 com_2142_5130 com_2142_13006

Tdo2 McCusker, Robert H. McCusker, Robert H. Kelley, Keith W. Freund, Gregory G. Llano, Daniel A. Dostal, Carlos Rene 2018-03-02T19:59:38Z 2018-03-02T19:59:38Z 2020-03-03T10:15:35Z 2017-07-14 2017-08 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. Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2019-08-01 The student, Carlos Dostal, accepted the attached license on 2017-07-13 at 00:17. The student, Carlos Dostal, submitted this Dissertation for approval on 2017-07-13 at 00:48. This Dissertation was approved for publication on 2017-07-14 at 09:20. DSpace SAF Submission Ingestion Package generated from Vireo submission #11444 on 2018-03-02 at 13:02:07 Made available in DSpace on 2018-03-02T19:59:38Z (GMT). No. of bitstreams: 3 DOSTAL-DISSERTATION-2017.pdf: 6916964 bytes, checksum: c314a41144ef9d836d4222fbfafb9b12 (MD5) LICENSE.txt: 4210 bytes, checksum: 7b6f6ebea8d911da2958b91321b06c35 (MD5) PROQUEST_LICENSE.txt: 4556 bytes, checksum: 49772cde7cf2f363093f87a840471b20 (MD5) Previous issue date: 2017-07-14 Embargo set by: Seth Robbins for item 105055 Lift date: 2020-03-02T19:59:52Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 105055 Lift date: 2020-03-02T20:02:46Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system U of I Only Restriction Lifted for Item 105055 on 2020-03-03T10:15:35Z. application/pdf http://hdl.handle.net/2142/99101 en Copyright 2017 Carlos Dostal Brain Astrocyte Microglia Neuron Inflammation Stress Kynurenine Ido1 Ido2 Depression Anhedonia Schizophrenia Stress and inflammation regulate the kynurenine pathway dioxygenases in a glia‐ and tissue‐specific manner text text Neuroscience Program Neuroscience University of Illinois at Urbana-Champaign Dissertation Ph.D.