Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress

Abstract

. Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol 283: G1257-G1263, 2002. First published August 28, 2002 10.1152/ajpgi.00314.2002Intestinal dysfunction is related to stress and early life events, but the mechanisms are largely unknown. Our aim was to determine whether early trauma predisposes adult rats to intestinal mucosal dysfunction in response to stress. Neonatal Sprague-Dawley rats were individually separated from their mothers for 3 h/day at 4-21 days of age. Between days 80 and 90, separated and control rats were subjected to mild acute stress (30-min water avoidance) or sham stress. Mucosal barrier function and ion transport were assessed in colonic tissues mounted in Ussing chambers. Mild stress increased short-circuit current, conductance, and transepithelial transport of macromolecules in separated rats, while having minimal effects in controls. Pretreatment of the separated rats with a corticotropin-releasing hormone (CRH) antagonist, the peptide ␣-helical CRH(9-41) injected intraperitoneally 20 min before stress, abolished the stress-induced mucosal changes. Our results indicate that neonatal trauma can induce phenotypic changes in adulthood, including enhanced vulnerability of the gut mucosa to stress via mechanisms involving peripherally located CRH receptors.behavior; corticotropin-releasing hormone; electron microscopy; ion transport; intestinal permeability HUMANS EXPERIENCE STRESS OF various types during daily life, and adequate responses to these stressors are necessary for survival. If the severity or the chronicity of the stressful experience exceeds the adaptive capacity, the individual will be predisposed to illness and disease in multiple organ systems (21). A large number of studies have shown that early-life experience plays an important role in stress responsiveness throughout life (8). In animal models, neonatal adversity can result in permanent functional changes in the stress-mediating systems of the central nervous system (15). For example, newborn rats subjected to maternal separation demonstrate increased release of corticotropinreleasing hormone (CRH), altered expression of glucocorticoid receptors, as well as changes in the norepinephrine and GABA systems (3, 4). Recently, it was also shown in humans that adverse early-life events are associated with hyperresponsiveness to stress and alterations in the hypothalamic-pituitaryadrenal (HPA) axis (10).There is evidence that early-life trauma and ongoing psychological stress can affect the clinical course of intestinal disorders (16,17,20,26) and also reactivate inflammation in experimental colitis (6,9,22,25). The mechanisms underlying stress-induced exacerbations of intestinal diseases are, however, largely unknown. One possible link between intestinal disease and stress is a change in mucosal function. Our previous studies have shown that acute stress in rats induces enhanced intestinal epithelial permeability to macromolecu...

Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability

“…Enhanced uptake of antigens during this period might result in sensitization and/or priming for activation of immune cells upon reencounter with these antigens in later life. In our study, the MS-induced defects persisted past the period of separation and appeared to be maintained by the activation of peripheral CRF receptors (CRF-Rs) (11,37). Another recent study (10) also implicated cholinergic pathways in MS-induced epithelial abnormalities.…”

“…It has been shown to modulate gastrointestinal activity by acting at both central (19) and peripheral sites (20,37,42). A single intraperitoneal injection of CRF in adult rats resulted in similar gut pathophysiology, including increased ion secretion and permeability, to that observed in rats exposed to acute restraint stress (32).…”

“…stress; colonic; barrier THE NEONATAL PERIOD is an important developmental period in humans and rodents, and stress during this time can have long-lasting effects on behavior and physiology. Maternal separation (MS) is a well-characterized model of early life stress used in the study of anxiety and depression (17, 31) as well as intestinal dysfunction (1,2,7,28,37). The physiological response to stress is controlled by the hypothalamicpituitary adrenal (HPA) axis, which develops during the neonatal period.…”

“…Maternal separation (MS) is a well-characterized model of early life stress used in the study of anxiety and depression (17,31) as well as intestinal dysfunction (1,2,7,28,37). The physiological response to stress is controlled by the hypothalamicpituitary adrenal (HPA) axis, which develops during the neonatal period.…”

“…Adult rats that are not genetically susceptible to stress can also develop similar abnormalities following exposure to a mild acute stressor if they have been subjected to neonatal MS (7,37). We (11) previously reported that neonatal rats subjected to MS had impaired epithelial barrier function even at the time of separation.…”