Altered Brain Excitability and Increased Anxiety in Mice With Experimental Colitis: Consideration of Hyperalgesia and Sex Differences

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC) are incurable lifelong inflammatory bowel diseases (IBD) with a rising worldwide incidence. IBD is characterized by diarrhea, rectal bleeding, severe cramping and weight loss. However, there is a growing evidence that IBD is also associated with anxiety- and depression-related disorders, which further increase the societal burden of these diseases. Given the limited knowledge of central nervous system (CNS) changes in IBD, we investigated CNS-related comorbidities in a mouse model of experimental colitis induced by dextran sulfate sodium (DSS) administration in drinking water for 5 days. In male and female C57BL6J mice, DSS treatment caused increased brain excitability, revealed by a decrease in seizure onset times after intraperitoneal administration of kainic acid. Moreover, both sexes showed increased anxiety-related behavior in the elevated plus-maze (EPM) and open field (OF) paradigms. We assessed somatic pain levels, because they may influence behavioral responses. Only male mice were hyperalgesic when tested with calibrated von Frey hairs and on the hotplate for mechanical and thermal pain sensitivity respectively. Administration of diazepam (DZP; ip, 1 mg/kg) 30 min before EPM rescued the anxious phenotype and improved locomotion, even though it significantly increased thermal sensitivity in both sexes. This indicates that the altered behavioral response is unlikely attributable to an interference with movement due to somatic pain in females. We show that experimental colitis increases CNS excitability in response to administration of kainic acid, and increases anxiety-related behavior as revealed using the EPM and OF tests.

Anxiolytic effects of the flavonoid luteolin in a mouse model of acute colitis

“…This also reinforces our previous findings showing that there are no differences in the ambulatory behavior of mice treated with luteolin as assessed in the open field test [7]. Altogether, our data indicate that DSS induces anxiety like behaviors that are consistent with previous findings in both male and female mice [5] and which can be attenuated by luteolin treatment.…”

“…Peripheral inflammation is recognized as an important contributor to anxiety [1] and major depressive disorder [2], with such symptoms observed particularly among patients with inflammatory bowel disease (IBD) [3, 4]. Recent rodent studies using the dextran sodium sulfate (DSS) model demonstrated that the activation of the immune system contributes to the development of anxiety- and depression-related behaviors as consequence of colitis [5–7]. In our previous work, we showed that long-term behavioral abnormalities related to anxiety and depression arise in mice of either sex as a consequence of acute colonic inflammation, in parallel with a marked elevation of interleukin 1beta in the hippocampus, increased infiltration of leukocytes into the brain microvasculature and significant changes of the firing properties of hippocampal pyramidal cells.…”

EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury

“…Individual mice were placed in the EPM center and allowed to move freely for 5 min. The test was video recorded and later analyzed for time spent in the open versus closed arms, as previously described (Acharjee et al, 2013, Nyuyki et al, 2018, Pellow et al, 1985).…”

Fluid supplementation accelerates epithelial repair during chemical colitis

“…Acute colitis by DSS impairs cognitive [20] and locomotive behavior [21], and has been shown to induce hyperalgesia [9, 22], which can further modify mouse behavior. To determine whether fluid supplementation reduces mouse stress during acute colitis, DSS-treated control and fluid-supplemented mice underwent the TST, NOR, and open field activity tests on the indicated days (Fig 1A).…”