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

Abstract

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.

Hippocampal neuroplasticity induced by early-life stress: Functional and molecular aspects

“…For example, short daily periods (15 min) of separation from the mother have been used to model mild stress and may have positive effects on hippocampal function. These positive effects are likely mediated by the nurturing input from the mother upon return of the pups to the cage [89,8,48,49]. In contrast, repeated prolonged (3 h) separation from the mother [113] or a single 24 h separation [46] have been considered models of more severe acute/subacute stress.…”

“…The effects of psychological stress early in life may be considered a 'double-edged sword,' in that the nature and magnitude of the stressor determines whether its long-term consequences will enhance or impair hippocampal function [27]. Mild stress early in life results in beneficial long-term consequences: Hippocampusmediated memory function is facilitated in adult rodents and non-human primates reared with enhanced maternal care [89,121,49] or in enriched environments [75,149].…”

“…(2) Importantly, full manifestation of stress-induced hippocampal changes occurs later, and may be reversible during the 2nd and 3rd postnatal week [49]. Thus, recent studies demonstrate that the long-term deleterious hippocampal effects of sub-optimal neonatal experience can be prevented by later intervention, including environmental enrichment [23] or pharmacological treatment [49].…”

“…The effects of psychological stress early in life may be considered a 'double-edged sword,' in that the nature and magnitude of the stressor determines whether its long-term consequences will enhance or impair hippocampal function [27]. Mild stress early in life results in beneficial long-term consequences: Hippocampusmediated memory function is facilitated in adult rodents and non-human primates reared with enhanced maternal care [89,121,49] or in enriched environments [75,149].In contrast, chronic or severe stress early in life can have long-term adverse effects on hippocampal integrity and performance in humans (reviewed in [120,147]) and experimental animals [120,31]. These effects may manifest in impaired, or progressively deteriorating cognitive performance [98,18].…”

“…In summary, chronic stress during a critical developmental period (around P2-P9 in rat) may set in motion long-lasting hippocampal changes. These may not manifest until later, and seem to be preventable by interventions during the 2nd-3rd postnatal weeks [23,49]. …”