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Autophagy, an intracellular degradation, and recycling process is essential in maintaining cellular homeostasis. Dysregulated autophagy is linked to the pathogenesis of various diseases, including inflammatory bowel disease (IBD) which consists of Crohn’s disease and ulcerative colitis. In IBD, enterochromaffin cell numbers and one of its main product serotonin (5-hydroxytryptamine; 5-HT) levels are elevated. Previously, we had shown that tryptophan hydroxylase 1 deficient (Tph1-/-) mice, with reduced gut 5-HT had decreased severity of colitis. Here, we showed that gut 5-HT plays a vital role in modulating autophagy and thus regulating gut microbial composition and susceptibility to intestinal inflammation. Tph1-/- mice, had upregulated colonic autophagy via the mammalian target of rapamycin pathway (mTOR), and decreased colitis severity. Tph1-/- mice after 5-HT replenishment, and serotonin reuptake transporter deficient (SERT-/-) mice, which have increased 5-HT levels, showed converse results. Deletion of intestinal epithelial cell-specific autophagy gene, Atg7, in Tph1-/- mice (DKO mice) abolished the protective effect of Tph1 deficiency in colitis, decreased the production of antimicrobial peptide, β-defensin 1 and promoted colitogenic microbiota. Furthermore, using cecal microbial transplantation, we found that the colitic microbiota of the DKO mice contributed to the increased severity of colitis. Supporting this pathway's translational importance, we uncovered that 5-HT treatment of peripheral blood mononuclear cells from both healthy volunteers and patients with Crohn’s disease inhibited autophagy via the mTOR pathway. Our results in this thesis emphasize the role of 5-HT-autophagymicrobiota axis in intestinal inflammation. Moreover, these findings suggest 5-HT as a novel therapeutic target in intestinal inflammatory disorders such as IBD that exhibit dysregulated autophagy. / Thesis / Doctor of Philosophy (PhD) / Approximately 0.7% of Canadians are currently affected with inflammatory bowel disease (IBD). The gut hormone serotonin, which regulates many normal functions, is elevated in gut inflammation. Reduced serotonin levels decrease the severity of inflammation. IBD pathology has been linked to a unique cell self-eating process called autophagy. Using cell lines, mice, and samples from IBD patients, we assessed the interactions between serotonin signaling and autophagy during gut inflammation. I found that an increase in serotonin levels enhances the severity of gut inflammation by inhibiting autophagy. We also established the connection between serotonin and autophagy in the intestinal epithelial cells, and how this modulates epithelial cell function. Furthermore, we demonstrated the establishment of an altered gut microbiota upon disruption of the serotonin-autophagy axis in the epithelial cells, which subsequently influenced gut inflammation severity. Thus, we identified one of the key triggers related to the pathogenesis and severity of IBD.

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Syrian hamsters are a useful model for offensive aggression because males and females spontaneously engage in agonistic bouts. In hamsters, there is a large sex difference on aggression in the serotonin (5-HT) pathways. Male aggression is inhibited and female aggression increases with injections of a 5-HT agonist into the anterior hypothalamus (AH), but little is known if similar effects are seen in adult hamsters with repeated systemic administration of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (FLX), which is one of the few approved pharmacological treatments for mood disorders in children and adolescents. The goal of this study is to determine if repeated intraperitoneal injections of FLX over 30 days in adolescent male and female hamsters has an effect on offensive aggression similar to site specific alterations of the 5-HT system in the AH. Our data suggest that systemic administration of FLX as adolescents over 30 days does not affect offensive aggression in males or females as adults.

The structure and function of brain show sexual dimorphism in vertebrates. Brain sexual differentiation is resulted from the neural development. The neural development of brain is determined by genetic regulation and also influenced by external environmental factors(ex: temperature¡B neurotransmitter ). Serotonin (5-hydroxytrptamine, 5-HT) function as a neurotransmitter and/or neuromodulator in the central nervous system. Serotonin plays a important role in the development of the central nervous system via serotonin receptor¡CAstrocyte has the role of neural supporting and neural protection in CNS. Astrocyte has the important role of brain development. In the present study, the influence of temperature on the proliferation of astrocyte was investigated.These results show that the proliferation of astrocyte are varied with the temperature. Serotonin is not involved in the proliferation of astrocyte .Wherease,but has an effect on the ratio 5-HT+-cell in the astrocyte culture via the 5-HT1A receptor.