THE HYPOTHALAMUS-PITUITARY-ADRENOCORTICAL AXIS - EPIGENETIC DETERMINANTS, CHANGES WITH AGING, INVOLVEMENT OF NGF

In order to study the hypothesis that maternal corticosterone (B) influences the hippocampus/hypothalamus-pituitary-adrenocortical axis system in the adult rat, we induced a moderate increase in maternal plasma level of B by adding the hormone to the drinking water of the darns (200 mu g/ml) from the day of delivery to weaning. B-nursed male rats had, at 3 months of age, a lower basal concentration of ACTH and B, as well as a lower stress (2 min restraint) induced increase. The reduced stress response was also present at 12 months. These endocrine differences were parallel to behavioural modifications. In the adult offspring of mothers that were hypercorticosteronemic during lactation, an improved spatial learning ability, a reduced emotional performance in a conflict procedure and a better performance in a conditioned active avoidance rest was observed. Finally, the analysis of hippocampal adrenocorticoid receptors revealed that the postnatal endocrine manipulation induced an increase in the Type I receptor density in the adult offspring. Our findings point to an epigenetic effect of maternal B on the maturational process of the hypothalamus-pituitary-adrenocortical (HPA) axis and the hippocampus with endocrine and behavioural consequences in adulthood. The aging process has been shown to alter the normal Functioning of the HPA axis. This alteration might arise from a reduced hippocampal negative feedback control, as suggested by the age-dependent loss of hippocampal adrenocorticoid receptors. Among the hypothalamic factors endowed with corticotropin secretagogue activity, corticotropin-releasing hormone (CRH) and vasopressin are considered the major physiological mediators of hypothalamic control of ACTH release, We have investigated the effect produced by the aging process on the dynamics of adrenocortical response to CRH and VP in freely-moving jugular catheterized male Sprague-Dawley rats (3- and 24-month-old). The results have indicated that with aging the response to ACTH secretagogues is dampened but prolonged. In the aged rat, the adrenocortical response to nerve growth factor (NGF) is also reduced. This might be due to the loss of NGF receptors in the aged brain. Concerning the blain structure(s) involved in the accomplishment of the adrenocortical activation induced by NGF, here we show that following intravenous NGF administration, the concentrations of the trophic factor are increased in the hippocampus. This gives further support to a possible regulatory role of the hippocampus on the activity of the HPA axis.