Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Hassan, A.
Behavioral Characterization of Experimental Colitis in Mice: Role of Psychological Stress, Peptide YY, and Glucagon-like Peptide-1
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp.
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- Autor*innen der Med Uni Graz:
- Hassan Ahmed
- Betreuer*innen:
- Gemes Geza
- Holzer Peter
- Schicho Rudolf
- Altmetrics:
- Abstract:
- Background: Inflammatory bowel disease (IBD) is associated with an increased risk of anxiety and depression disorders, and psychological stress can lead to exacerbation of IBD. This work aimed at exploring endocrine signaling pathways between the gut and brain in order to advance the understanding of gut-brain communication in IBD. The work involved three sets of experiments performed in male mice. In the first set of experiments, the behavioral consequences of experimental colitis, psychological stress, and their combination were investigated. In the second set of experiments, the status and the role of peptide YY (PYY) and glucagon like peptide 1 (GLP-1) in experimental colitis were assessed. Visceral pain is one of the chief complaints in IBD, and the third set of experiments explored the role of PYY in visceral pain. Methods: Seven-day treatment with dextran sulfate sodium (DSS; 2% in drinking water) was used to induce colitis, and 1-hour sessions of water avoidance stress (WAS) for 7 days were used as a model of psychological stress. The behavioral battery included the open field (OF) test, the social interaction (SI) test, the tail suspension test (TST) and the forced swim test (FST). To assess the role of PYY and GLP-1 in colitis, colitis severity, food and water intake as well as OF and SI behavior were assessed in mice treated with the Y2 receptor antagonist BII0246 combined with the GLP-1 receptor antagonist exendin (9-39). The effect of PYY knockout (PYY(-/-)), PYY (3-36) and BII0246 on visceral pain sensitivity were evaluated by measuring pain-related behaviors after rectal administration of 2% allyl isothiocyanate (AITC). In PYY(-/-) mice, visceral pain sensitivity was additionally evaluated by referred hyperalgesia and the mouse grimace scale. Key findings: (1) DSS treatment decreased locomotion and enhanced anxiety-like behavior in the OF and reduced SI. (2) DSS treatment also increased circulating neuropeptide Y (NPY) and hypothalamic expression of cyclooxygenase-2 (COX 2) mRNA and decreased hippocampal expression of NPY mRNA, brain-derived neurotrophic factor (BDNF) mRNA and mineralocorticoid receptor mRNA. (3) Repeated WAS for 7 days had little influence on behavior but prevented the DSS-induced behavioral disturbances in the OF and SI tests. In contrast, repeated WAS did not modify colon length, colonic myeloperoxidase (MPO) content and circulating proinflammatory cytokines, parameters used to assess colitis severity. (4) Repeated WAS significantly decreased the expression of corticotropin-releasing factor (CRF) mRNA in the hippocampus. The effect of repeated WAS to blunt the DSS-evoked behavioral disturbances was associated with a rise of circulating corticosterone and an increase in the expression of hypothalamic NPY mRNA. (5) DSS treatment increased colonic PYY and preproglucagon mRNA and circulating PYY and active GLP-1. (6) BII0246 + exendin (9-39) increased the colonic MPO content independently of DSS treatment. Additionally, the treatment of DSS-treated mice with BII0246 + exendin (9-39) reduced food intake and led to behavioral impairment in the OF. (7) PYY(-/-) mice showed enhanced pain-related behaviors and increased referred hyperalgesia in response to intrarectal treatment. (8) BII0246 increased pain-related behaviors in response to intrarectal treatment with AITC while PYY (3-36) was without effect. Conclusions: Reduced hippocampal NPY and BDNF and increased hypothalamic COX-2 are likely to contribute to colitis-induced behavioral impairment. Repeated predictable stress causes resilience against behavioral impairment induced by colitis. The resilience induced by repeated predictable stress is related to increased hypothalamic NPY and increased circulating corticosterone. PYY and GLP-1 have a protective role against colitis and colitis-induced behavioral impairment. Endogenous PYY has a hypoalgesic effect which seems to be mediated by peripheral Y2 receptors.