title: Differential and age-dependent effects of maternal deprivation on the hypothalamic-pituitary-adrenal axis of brown norway rats from youth to senescence.
abstract: In this study, the hypothesis was tested that infants deprived from maternal care show persistent changes in hypothalamic-pituitary-adrenal activity. For this purpose, we studied the effect of maternal deprivation in one cohort of the healthy ageing Brown Norway rat strain showing still more than 80% survival rate at 32 months of age. Three-day-old male Brown Norway rats were either maternally deprived for 24 h or remained with the dam. In 3, 12 and 30-32 months (young, adult, senescent) deprived rats and their nondeprived littermates (controls), we determined basal resting and stress-induced plasma adrenocorticotropic hormone (ACTH) and corticosterone as well as corticotropin releasing hormone (CRH) mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus. Mineralocorticoid (MR) and glucocorticoid receptors (GR) in hippocampus and PVN were also assessed using in vitro cytosol binding and in situ hybridization. The effect of ageing per se showed that in the control nondeprived Brown Norway rats, basal corticosterone and ACTH concentrations did not change during life. However, with age, the corticosterone response to novelty stress became progressively attenuated, but prolonged, while there was an age-related increase in the ACTH response. CRH mRNA expression in PVN decreased with age. Hippocampal MR binding and MR mRNA expression in the dentate gyrus were reduced at senescence, as were the GR binding capacities in hippocampus and hypothalamus. Maternal deprivation did not affect survival rate, body weight, nor adrenal weight of the ageing Brown Norway rats. Basal corticosterone and ACTH levels were not affected by deprivation, except for a rise in basal corticosterone concentrations at 3 months. At this age, the corticosterone output in response to novelty was attenuated in the deprived rats. In contrast, a striking surge in novelty stress-induced corticosterone output occurred at midlife while, at senescence, the corticosterone and ACTH responses were attenuated again in the deprived animals, particularly after the more severe restraint stressor. CRH mRNA expression was reduced only during adulthood in the deprived animals. After maternal deprivation, the MR mRNA in dentate gyrus showed a transient midlife rise. GR binding in hypothalamus and hippocampus GR binding was reduced in young rats while, in the senescent deprived animals, a reduced GRmRNA expression was observed in PVN and hippocampal CA1. In conclusion, in the Brown Norway rat, ageing causes a progressive decline in corticosterone output after stress, which is paralleled at senescence by decreased MR and GR mRNA expression in hippocampus and hypothalamus. The long-term effects of maternal deprivation become manifest differently at different ages and depend on test conditions. The deprivation effect culminates in a midlife corticosterone surge and results at senescence in a strongly reduced corticosterone output.
authors.affiliation: Leiden/Amsterdam Center for Drug Research and Leiden University Medical Center, Division of Medical Pharmacology, University of Leiden, Leiden, The Netherlands.
authors.forename: J O
authors.initials: JO
authors.lastname: Workel
authors.forename: M S
authors.initials: MS
authors.lastname: Oitzl
authors.forename: M
authors.initials: M
authors.lastname: Fluttert
authors.forename: H
authors.initials: H
authors.lastname: Lesscher
authors.forename: A
authors.initials: A
authors.lastname: Karssen
authors.forename: E R
authors.initials: ER
authors.lastname: de Kloet
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D021983:Cyclophilins / Q000235:genetics; D003600:Cytosol / Q000378:metabolism; D005106:Exploratory Behavior / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D008426:Maternal Deprivation; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D012016:Reference Values; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000209:etiology / Q000503:physiopathology; D013315:Stress, Psychological / Q000503:physiopathology
chemical_list: D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D021983:Cyclophilins; D003345:Corticosterone