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Enduring, Handling-Evoked Enhancement of Hippocampal Memory Function and Glucocorticoid Receptor Expression Involves Activation of the Corticotropin-Releasing Factor Type 1 Receptor

Departments of Anatomy/Neurobiology (K.A.F., K.L.B., S.A.-E., B.A.S., B.J.K., T.Z.B.) and Pediatrics (T.Z.B.), University of California, Irvine, California 92697-4475; and Hebrew University, Jerusalem and Kaplan Medical Center (S.A.-E.), Rehovoth, Israel

Address all correspondence and requests for reprints to: Dr. Tallie Z. Baram, Med Sci I, Zot: 4475, University of California, Irvine, California 92697-4475. E-mail: tallie{at}uci.edu.

Early-life experience, including maternal care, influences hippocampus-dependent learning and memory throughout life. Handling of pups during postnatal d 2–9 (P2–9) stimulates maternal care and leads to improved memory function and stress-coping. The underlying molecular mechanisms may involve early (by P9) and enduring reduction of hypothalamic corticotropin-releasing factor (CRF) expression and subsequent (by P45) increase in hippocampal glucocorticoid receptor (GR) expression. However, whether hypothalamic CRF levels influence changes in hippocampal GR expression (and memory function), via reduced CRF receptor activation and consequent lower plasma glucocorticoid levels, is unclear. In this study we administered selective antagonist for the type 1 CRF receptor, NBI 30775, to nonhandled rats post hoc from P10–17 and examined hippocampus-dependent learning and memory later (on P50–70), using two independent paradigms, compared with naive and vehicle-treated nonhandled, and naive and antagonist-treated handled rats. Hippocampal GR and hypothalamic CRF mRNA levels and stress-induced plasma corticosterone levels were also examined. Transient, partial selective blockade of CRF₁ in nonhandled rats improved memory functions on both the Morris watermaze and object recognition tests to levels significantly better than in naive and vehicle-treated controls and were indistinguishable from those in handled (naive, vehicle-treated, and antagonist-treated) rats. GR mRNA expression was increased in hippocampal CA1 and the dentate gyrus of CRF₁-antagonist treated nonhandled rats to levels commensurate with those in handled cohorts. Thus, the extent of CRF₁ activation, probably involving changes in hypothalamic CRF levels and release, contributes to the changes in hippocampal GR expression and learning and memory functions.

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