title: Differential neuroendocrine responses to chronic variable stress in adult Long Evans rats exposed to handling-maternal separation as neonates.
abstract: Burgeoning evidence supports a preeminent role for early- and late-life stressors in the development of physio- and psychopathology. Handling-maternal separation (HMS) in neonatal Long Evans hooded rats leads to stable phenotypes ranging from resilient to vulnerable to later stressor exposure. Handling with 180 min of maternal separation yields a phenotype of stress hyper-responsiveness associated with facilitation of regional CRF neurocircuits and glucocorticoid resistance. This study assessed whether or not prolonged HMS (180 min/day, HMS180) on post-natal days 2-14 sensitizes the adult limbic hypothalamo-pituitary-adrenal (LHPA) axis to chronic variable stress (CS) compared to brief HMS (15 min/day, HMS15). We examined regional mRNA densities of corticotropin-releasing factor (CRF), its receptor CRF1, glucocorticoid receptor (GR), and mineralocorticoid receptor (MR); regional CRF1 and CRF2alpha binding, and pituitary-adrenal responses to an acute air-puff startle (APS) stressor in four groups: HMS15, nonstressed; HMS15, stressed; HMS180, nonstressed; HMS180, stressed. As expected we observed exaggerated pituitary-adrenal responses to APS, increased regional CRF mRNA density, decreased regional CRF1 binding, and decreased cortical GR mRNA density in nonstressed HMS180 vs. HMS15 animals. However, in contrast to our hypothesis, CS decreased pituitary-adrenal reactivity and central amygdala CRF mRNA density in HMS180 rats, while increasing cortical GR mRNA density and CRF1 binding. CS had no effect on the pituitary-adrenal response to APS in HMS15 rats, despite tripling hypothalamic paraventricular CRF mRNA density. The data suggest that many effects of prolonged HMS are reversible in adulthood by CS, while the neuroendocrine adaptations imbued by brief HMS are sufficiently stable to restrain pituitary-adrenal stress responses even following CS.
authors.affiliation: Stress Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Drive, Ste 4105, Atlanta, GA 30322, USA.
authors.forename: Charlotte O
authors.initials: CO
authors.lastname: Ladd
authors.forename: K V
authors.initials: KV
authors.lastname: Thrivikraman
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Huot
authors.forename: Paul M
authors.initials: PM
authors.lastname: Plotsky
mesh_terms: D000222:Adaptation, Physiological; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn / Q000523:psychology; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006234:Handling, Psychological; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008426:Maternal Deprivation; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D013216:Reflex, Startle / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology; D014018:Tissue Distribution; D000099052:CRF Receptor, Type 1
chemical_list: D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone