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Correlations between Hypothalamus-Pituitary-Adrenal Axis Parameters Depend on Age and Learning Capacity

Division of Medical Pharmacology (O.C.M., P.J.S., M.S.O.), LACDR and Leiden University Medical Center, 2300 RA Leiden, The Netherlands; and Institute of Physiological Psychology (B.T., G.J., J.P.H.), University of Düsseldorf, 40225 Düsseldorf, Germany

Address all correspondence and requests for reprints to: O. C. Meijer, Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research and Leiden University Medical Center, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail: o.meijer{at}lacdr.leidenuniv.nl.

Glucocorticoid hormones are released after activation of the hypothalamus-pituitary-adrenal (HPA) axis and in the brain can modulate synaptic plasticity and memory formation. Clear individual differences in spatial learning and memory in the water maze allowed classification of groups of young (3 months) and aged (24 months) male Wistar rats as superior and inferior learners. We tested 1) whether measures of HPA activity are associated with cognitive functions and aging and 2) whether correlations of these measures depend on age and learning performance. Basal ACTH, but not corticosterone, was increased in aged rats, with the stress-induced ACTH response exaggerated in aged-inferior learners. Aged-superior learners had lower expression of glucocorticoid receptor and CRH mRNA in the parvocellular paraventricular nucleus of the hypothalamus compared with all other groups. Hippocampal mineralocorticoid receptor and glucocorticoid receptor mRNAs differed modestly between groups, but steroid receptor coactivator and heat-shock-protein 90 mRNAs were not different. Strikingly, correlations between HPA axis markers were dependent on grouping animals according to learning performance or age. CRH mRNA correlated with ACTH only in aged animals. Parvocellular arginine vasopressin mRNA was negatively correlated to basal corticosterone, except in aged-inferior learners. Corticosteroid receptor mRNA expression showed a number of correlations with other HPA axis regulators specifically in superior learners. In summary, the relationships between HPA axis markers differ for subgroups of animals. These distinct interdependencies may reflect adjusted set-points of the HPA axis, resulting in adaptation (or maladaptation) to the environment and, possibly, an age-independent determination of learning ability.