Neonatal maternal separation in the rat impacts on the stress responsivity of central corticotropin-releasing factor receptors in adulthood
Early-life stress is a key predisposing factor to the development of functional gastrointestinal (GI) disorders. Thus, changes in stress-related molecular substrates which influence colonic function may be important in understanding the pathophysiology of such disorders. Activation of peripheral corticotropin-releasing factor (CRF) receptors is thought to be important in the maintenance of GI function homeostasis. Therefore, immunofluorescent and Western blotting techniques were utilized to investigate colonic expression of CRF receptors in the maternal separation (MS) model as compared to non-separated (NS) rats. Receptor expression was also assessed following exposure to two different acute stressors, the open field (OF) and colorectal distension (CRD). Immunofluorescent dual-labeling demonstrated increased activation of both CRFR1 (MS: 79.6+/-4.4% vs. NS: 43.8+/-6.8%, p<0.001) and CRFR2 (MS: 65.9+/-3.2% vs. NS: 51.6+/-5.8%, p<0.05) positive cells in MS rats. Protein expression of CRFR1 and CRFR2 in the proximal colon was similar under baseline conditions and not affected by exposure to an OF stressor in either cohort. In contrast, distal CRFR1 and CRFR2 levels were higher in MS rats but were significantly reduced post OF stress. Moreover, decreases in expression of CRFR1 in the proximal and distal colon of NS rats following exposure to CRD were blunted in MS rats. CRD also caused an increase in the functional isoform of CRFR2 in the distal colon of MS rats with no effect in NS colons. This study demonstrates that acute stressors alter colonic CRF receptor expression in a manner that is determined by the underlying stress sensitivity of the subject.