CENTRAL AUTONOMIC ACTIVATION IN TNBS-INDUCED COLITIS

L Assen, I Ran, QJ Pittman, KA Sharkey

Gastrointestinal and Neuroscience Research Groups, University of Calgary, Calgary, Alberta

The involvement of the CNS in inflammatory bowel disease (IBD) is increasingly being recognized. We investigated the effect of TNBS-colitis, an experimental form of IBD, on neuronal and glial activation in the rat brain. We examined autonomic centres that are involved in the control of the gastrointestinal tract including the dorsal vagal complex and paraventricular nucleus of the hypothalamus (PVN). We used the expression of Fos as a marker of neuronal activation, glial fibrillary acid protein (GFAP) as a marker of astrocyte activation and MHCII to assess activation of microglia/dendritic cells. The expression of Fos markedly increased in the area postrema (AP), nucleus of the solitary tract (nTS) and PVN 6-24h after induction of colitis. This increase persisted until 7d in the AP and nTS, but not beyond 24h in the PVN. Fos expression at 12h was not altered by subdiaphragmatic vagotomy. Further evidence for hypothalamic activation came from measurements of plasma corticosterone. At 12h after the induction of TNBS colitis we detected high levels of corticosterone in TNBS-treated rats (271±45ng/ml control, n=10; 707±51ng/ml TNBS, n=10; p<0.05). Ablation of vagal afferents with capsaicin did not alter the effect of colitis on corticosterone levels (934±66ng/ml control+TNBS, n=5; 787±48ng/ml capsaicin+TNBS, n=5; ns). The expression of GFAP did not change in response to inflammation throughout the dorsal vagal complex at all times studied. In contrast, GFAP expression significantly increased in the PVN beginning at 12h and persisting for 7d in the TNBS-treated rats. MHCII expression remained unaltered in most nuclei. However, marked changes in the morphology of the MHCII expressing cells in the AP indicated microglial activation over the first 24h of colitis. These data demonstrate that TNBS colitis involves the activation of central autonomic nuclei. Our observations suggest an alteration in CNS function during peripheral inflammatory responses, like colitis, by direct activation of neurons, glia and CNS immune cells.