Differential activation of the prefrontal cortex and amygdala following psychological stress and colorectal distension in the maternally separated rat.

Visceral hypersensitivity is a hallmark of many clinical conditions and remains an ongoing medical challenge. Although the central neural mechanisms that regulate visceral hypersensitivity are incompletely understood, it has been suggested that stress and anxiety often act as initiating or exacerbating factors. Dysfunctional corticolimbic structures have been implicated in disorders of visceral hypersensitivity such as irritable bowel syndrome (IBS). Moreover, the pattern of altered physiological responses to psychological and visceral stressors reported in IBS patients is also observed in the maternally separated (MS) rat model of IBS. However, the relative contribution of various divisions within the cortex to the altered stress responsivity of MS rats remains unknown. The aim of this study was to analyze the cellular activation pattern of the prefrontal cortex and amygdala in response to an acute psychological stressor (open field) and colorectal distension (CRD) using c-fos immunohistochemistry. Several corticoamygdalar structures were analyzed for the presence of c-fos-positive immunoreactivity including the prelimbic cortex, infralimbic cortex, the anterior cingulate cortex (both rostral and caudal) and the amygdala. Our data demonstrate distinct activation patterns within these corticoamygdalar regions including differential activation in basolateral versus central amygdala following exposure to CRD but not the open field stress. The identification of this neuronal activation pattern may provide further insight into the neurochemical pathways through which therapeutic strategies for IBS could be derived.

Colorectal distension-induced prefrontal cortex activation in the Wistar-Kyoto rat: implications for irritable bowel syndrome.

The prefrontal cortex plays a key role in the perception of painful stimuli, including those emerging from the viscera. Colorectal distension is a non-invasive stimulus used to study visceral pain processing in the nervous system. Visceral hypersensitivity is one of the main characteristics of the functional bowel disorder irritable bowel syndrome (IBS). Moreover, recent human neuroimaging studies have emphasized the importance of altered brain activity and circuitry in the manifestation of IBS symptom severity and reaction to visceral stimuli. It is unclear whether animal models of visceral hypersensitivity display a similar response. Therefore, in the present study, we have used c-Fos protein immunoreactivity as an indicator of cell activation, to compare the response of the viscerally hypersensitive Wistar-Kyoto (WKY) rat and control Sprague-Dawley (SD) rat strains to colorectal distension (CRD), a noxious visceral stimulus. Several corticolimbic structures were analysed including the prelimbic cortex, infralimbic cortex and the rostral and caudal anterior cingulate cortices. Moreover, visceral hypersensitivity was also assessed behaviourally in both strains. As previously described WKY rats had a lower pain threshold than SD controls in response to CRD. In all brain regions analysed, exposure to CRD induced an increase in c-Fos activation in both the WKY and SD rats. However, an exaggerated cell activation was found in the prelimbic, infralimbic and rostral anterior cingulate cortices of the WKY rat compared to SD animals. No significant difference was found in caudal anterior cingulate cortex activation when the strains were compared. These results demonstrate, to our knowledge, for the first time an augmented colorectal distension-induced prefrontal cortex activity in WKY rats similar to that seen in IBS patients, further supporting the use of this strain as a model in which to study brain-gut axis dysregulation observed in IBS.

Differential stress-induced alterations of colonic corticotropin-releasing factor receptors in the Wistar Kyoto rat.

BACKGROUND A growing body of data implicates increased life stresses with the initiation, persistence and severity of symptoms associated with functional gut disorders such as irritable bowel syndrome (IBS). Activation of central and peripheral corticotropin-releasing factor (CRF) receptors is key to stress-induced changes in gastrointestinal (GI) function. METHODS This study utilised immunofluorescent and Western blotting techniques to investigate colonic expression of CRF receptors in stress-sensitive Wistar Kyoto (WKY) and control Sprague Dawley (SD) rats. KEY RESULTS No intra-strain differences were observed in the numbers of colonic CRFR1 and CRFR2 positive cells. Protein expression of functional CRFR1 was found to be comparable in control proximal and distal colon samples. Sham levels of CRFR1 were also similar in the proximal colon but significantly higher in WKY distal colons (SD: 0.38 +/- 0.14, WKY: 2.06 +/- 0.52, P < 0.01). Control levels of functional CRFR2 were similar between strains but sham WKYs samples had increased CRFR2 in both the proximal (SD: 0.88 +/- 0.21, WKY: 1.8 +/- 0.18, P < 0.001) and distal (SD: 0.18 +/- 0.08, WKY: 0.94 +/- 0.32, P < 0.05) regions. Exposure to open field (OF) and colorectal distension (CRD) stressors induced decreased protein expression of CRFR1 in SD proximal colons, an effect that was blunted in WKYs. CRD stimulated decreased expression of CRFR2 in WKY rats alone. Distally, CRFR1 is decreased in WKY rats following CRD but not OF stress without any apparent changes in SD rats. CONCLUSIONS & INFERENCES This study demonstrates that psychological and physical stressors alter colonic CRF receptor expression and further support a role for local colonic CRF signalling in stress-induced changes in GI function.