Normal brain development requires coordinated regulation of several processes including proliferation, differentiation, and cell death. Multiple factors from endogenous and exogenous sources interact to elicit positive as well as negative regulation of these processes. In particular, the perinatal rat brain is highly vulnerable to specific developmental insults that produce later cognitive abnormalities. We used this model to examine the developmental effects of an exogenous factor of great concern, methylmercury (MeHg). Seven-day-old rats received a single injection of MeHg (5 lg/gbw). MeHg inhibited DNA synthesis by 44% and reduced levels of cyclins D1, D3, and E at 24 h in the hippocampus, but not the cerebellum. Toxicity was associated acutely with caspase-dependent programmed cell death. MeHg exposure led to reductions in hippocampal size (21%) and cell numbers 2 weeks later, especially in the granule cell layer (16%) and hilus (50%) of the dentate gyrus defined stereologically, suggesting that neurons might be particularly vulnerable. Consistent with this, perinatal exposure led to profound deficits in juvenile hippocampal-dependent learning during training on a spatial navigation task. In aggregate, these studies indicate that exposure to one dose of MeHg during the perinatal period acutely induces apoptotic cell death, which results in later deficits in hippocampal structure and function.
Information that is spaced over time is better remembered than the same amount of information massed together. This phenomenon, known as the spacing effect, was explored with respect to its effect on learning and neurogenesis in the adult dentate gyrus of the hippocampal formation. Because the cells are generated over time and because learning enhances their survival, we hypothesized that training with spaced trials would rescue more new neurons from death than the same number of massed trials. In the first experiment, animals trained with spaced trials in the Morris water maze outperformed animals trained with massed trials, but there was not a direct effect of trial spacing on cell survival. Rather, animals that learned well retained more cells than animals that did not learn or learned poorly. Moreover, performance during acquisition correlated with the number of cells remaining in the dentate gyrus after training. In the second experiment, the time between blocks of trials was increased. Consequently, animals trained with spaced trials performed as well as those trained with massed, but remembered the location better two weeks later. The strength of that memory correlated with the number of new cells remaining in the hippocampus. Together, these data indicate that learning, and not mere exposure to training, enhances the survival of cells that are generated 1 wk before training. They also indicate that learning over an extended period of time induces a more persistent memory, which then relates to the number of cells that reside in the hippocampus.
The quality of maternal care during early life has a dramatic impact on later stress reactivity and anxiety. Two inbred mouse strains, C57BL/6J and BALB/cJ, differ in levels of maternal care, stress reactivity, and anxiety-like behavior in adulthood. However, the relative contribution of early environmental factors and genetic predisposition to differences in these strains is not known. Maternal care, plasma corticosterone levels, emotionality, and hippocampal and paraventricular nucleus (PVN) glucocorticoid receptor mRNA levels were measured in adult C57BL/6J and BALB/cJ mice. Litters were then cross-fostered and anxiety-like behavior and stress reactivity was assessed in adulthood. Significantly less maternal care and elevated stress-induced corticosterone and emotionality was observed in BALB/cJ compared to C57BL/6J mice. Yet, no strain differences were found in hippocampal or paraventricular nucleus glucocorticoid receptor mRNA levels. Cross-fostering did alter anxiety-like behavior and basal corticosterone levels, which suggests that while genetic differences account for some of the variations between these two strains early rearing conditions also contribute.
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