Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus

Abstract

Early experiences such as prenatal stress significantly influence the development of the brain and the organization of behavior. In particular, prenatal stress impairs memory processes but the mechanism for this effect is not known. Hippocampal granule neurons are generated throughout life and are involved in hippocampaldependent learning. Here, we report that prenatal stress in rats induced lifespan reduction of neurogenesis in the dentate gyrus and produced impairment in hippocampal-related spatial tasks. Prenatal stress blocked the increase of learning-induced neurogenesis. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for psychopathological vulnerabilities in aging. It is well documented from animal studies that during the perinatal period, the development of an organism is subjected to complex environmental influences. Deleterious life events during pregnancy induce neurobiological and behavioral defects in offspring, some of them involving the hippocampal formation (1-5). Indeed, prenatal stress results in an enhanced production of stress hormones by the mother during critical periods of fetal brain development and provokes a definitively longer corticosterone response to stress in the offspring associated with a reduction in the number of hippocampal corticosteroid receptors (1,3,5). Behaviorally, the progeny, from adulthood to senescence, exhibit memory deficits in a hippocampal-dependent task (2, 4, 5).Recently, it has been hypothesized that hippocampal-mediated learning (6) may be related to the generation of new neurons in the adult dentate gyrus (7,8,9). These newborn cells migrate in the granule cell layer, and differentiate in granule neurons whose projections, the mossy fibers, extend to the CA3 hippocampal region (10, 11). Furthermore, the size of the mossy fibers' projections correlates with variations in performances in spatial memory tests (12, 13). Finally, glucocorticoid levels regulate de novo cell proliferation in the dentate gyrus. Indeed, adrenalectomy performed in young or aged rats increases neurogenesis, an effect that is prevented by glucocorticoid treatment (14,15,16). These results raised the critical question as to whether prenatal stress can impair neurogenesis and, if so, whether it is related to learning ability.To test this hypothesis, we first examined cell proliferation in the progeny of stressed mothers with 5-bromo-2Ј-deoxyuridine (BrdUrd), a thymidine analogue incorporated into genetic material during synthetic DNA phase (S phase) of mitotic division. Cellspecific markers were used to phenotype the newly born neurons after longer survival times. We next examined whether the structural hippocampal defects resulting from prenatal stress had functional consequences on learning abilities. Finally, we examined whether the reduction in cell proliferation in the dentate gyrus had an impact on spatial memory, a hypothesis supported by others (17). MethodsHousing Conditions. Adult virgin Sprague-Dawley female rats (Iffa Credo) ...

A reward increases running-wheel performance without changing cell proliferation, neuronal differentiation or cell death in the dentate gyrus of C57BL/6 mice

“…Changes in the extent of adult hippocampal neurogenesis are associated with changes in the performance of animals in hippocampus-dependent behavioral tasks [7][8][9][10][11], and a recent study of conditional TLX knockout mice, a gene expressed by adult neural stem cells, suggest a causal link between the performance in specific aspects of behavioral tasks and neurogenesis [12]. Voluntary physical exercise is a consistent and strong modulator of adult hippocampal neurogenesis.…”

DOHaD : conséquences à long terme de la pathologie périnatale

“…anomalies à la fois du développement mais aussi des capacités cognitives [26]. Le placenta possède un méca-nisme de protection du foetus vis-à-vis d'un excès de cortisol maternel, qui repose sur sa transformation par la 11 -hydroxystéroïde déshydrogénase.…”

SC35 promotes sustainable stress-induced alternative splicing of neuronal acetylcholinesterase mRNA

“…Transient SC35 overexpression coincides with AChE-R/AChE-S dominance in the developing brain Maternal stress during pregnancy was reported to cause long-lasting deleterious effects in the offspring, 6 suggesting that stress affects brain development. Also, we have recently shown that neuronal progenitor cells express both AChE-S and AChE-R, which exert distinct effects on cortical development.…”

“…5 In rats, both adult and prenatal stress reduce learning performance, 6 suggesting, among other possibilities, parallel stress-induced changes in alternative splicing. However, the molecular mechanisms leading to such changes are still largely obscure.…”