Cingulothalamic neurons develop topographic patterns of cue-elicited neuronal activity during discrimination learning. These patterns are context-related and are degraded by hippocampal lesions, suggesting that hippocampal modulation of cingulothalamic activity results in the expression of the patterns, which could promote the retrieval of context-appropriate responses and memories. This hypothesis was tested by training rabbits (Oryctolagus cuniculus) with fornix lesions concurrently on two discrimination tasks (approach and avoidance) in different contexts. Because the same conditioned stimuli were used for both tasks, contextual information was critical for overcoming intertask interference during concurrent task acquisition. The lesions degraded the topographic patterns and significantly impaired concurrent learning, suggesting that hippocampal-cingulothalamic interactions and the resulting topographic patterns are critical for processing contextual information needed to defeat interference.

Purpose In animal models, the small intestine responds to massive small bowel resection (SBR) through a compensatory process termed adaptation, characterized by increases in both villus height and crypt depth. This study seeks to determine whether similar morphologic alterations occur in humans following SBR. Methods Clinical data and pathologic specimens of infants who had both a SBR for necrotizing enterocolitis (NEC) and an ostomy takedown from 1999–2009 were reviewed. Small intestine mucosal morphology was compared in the same patients at the time of SBR and the time of ostomy takedown. Results For all samples, there was greater villus height (453.6±20.4 vs. 341.2±12.4 μm, p<0.0001) and crypt depth (178.6±7.2 vs. 152.6±6 μm, p<0.01) in the ostomy specimens compared to the SBR specimens. In infants with paired specimens, there was an increase of 31.7±8.3% and 22.1±10.0% in villus height and crypt depth, respectively. There was a significant correlation between the amount of intestine resected and the percent change in villus height (r=0.36, p<0.05). Conclusion Mucosal adaptation after SBR in human infants is similar to what is observed in animal models. These findings validate the use of animal models of SBR utilized to understand the molecular mechanisms of this important response.

The structural and functional changes during intestinal adaptation are necessary to compensate for the sudden loss of digestive and absorptive capacity after massive intestinal resection. When the adaptive response is inadequate, short bowel syndrome (SBS) ensues and patients are left with the requirement for parenteral nutrition and its associated morbidities. Several hormones have been studied as potential enhancers of the adaptation process. The effects of growth hormone (GH), insulin-like growth factor-1, epidermal growth factor and glucagon-like peptide-2 (GLP-2) on adaptation have been studied extensively in animal models. In addition, GH and GLP-2 have shown promise for the treatment of short bowel syndrome in clinical trials in humans. Several lesser studied hormones, including leptin, corticosteroids, thyroxine, testosterone and estradiol, are also discussed.

No abstract

Increased apoptosis in crypt enterocytes is a key feature of intestinal adaptation following massive small bowel resection (SBR). Expression of the proapoptotic factor Bax has been shown to be required for resection-induced apoptosis. It has also been demonstrated that p38-α MAPK (p38) is necessary for Bax activation and apoptosis in vitro. The present studies were designed to test the hypothesis that p38 is a key regulator of Bax activation during adaptation after SBR in vivo. Enterocyte expression of p38 was deleted by tamoxifen administration to activate villin-Cre in adult mice with a floxed Mapk14 (p38-α) gene. Proximal 50% SBR or sham operations were performed on wild-type (WT) and p38 intestinal knockout (p38-IKO) mice under isoflurane anesthesia. Mice were killed 3 or 7 days after operation, and adaptation was analyzed by measuring intestinal morphology, proliferation, and apoptosis. Bax activity was quantified by immunoprecipitation, followed by Western blotting. After SBR, p38-IKO mice had deeper crypts, longer villi, and accelerated proliferation compared with WT controls. Rates of crypt apoptosis were significantly lower in p38-IKO mice, both at baseline and after SBR. Levels of activated Bax were twofold higher in WT mice after SBR relative to sham. In contrast, activated Bax levels were reduced by 67% in mice after p38 MAPK deletion. Deleted p38 expression within the intestinal epithelium leads to enhanced adaptation and reduced levels of enterocyte apoptosis after massive intestinal resection. p38-regulated Bax activation appears to be an important mechanism underlying resection-induced apoptosis.