Impact of binge-like alcohol exposure during the third trimester equivalent on cell cycle kinetics of progenitor cells in the dentate gyrus of PD10 rats

Criss, Kerry
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University of Delaware
The subgranular zone (SGZ) of the dentate gyrus (DG) is one of two areas of the brain where neurons are generated into adulthood; the other is the subventricular zone. This unique cell population undergoes significant growth during the brain growth spurt (a postnatal event in rodents) and continues to develop throughout the lifespan. Several studies have examined the impact of neonatal alcohol exposure (AE) on postnatal neurogenesis in the developing DG. For example, a significant decrease in the number of granule cells was observed on PD10 in rats that received a daily binge-like dose of alcohol during the third trimester equivalent (PD4-9) or the equivalent of entire human gestation (G1-20 + PD4-9) (1). Furthermore, the impact of developmental AE on these precursors and their progeny is long lasting. Previous work in our lab demonstrated that binge-like AE on PD4-9 did not affect cell proliferation on PD42 or PD50 (2; 3) but decreased the number of adult-born granule cells that matured and survived for 30 days (3). Observed changes in postnatal neurogenesis could possibly reflect an enduring impact of neonatal AE on the progenitors' cell cycle. Indeed, several studies have demonstrated that alcohol alters cell cycle kinetics. For example, a high dose of alcohol in vitro (400 mg/dl) lengthened the cell cycle and increased the incidence of cell death in neocortical cell cultures obtained from rodent fetuses on G16 (4). Prenatal AE lengthened the cell cycle of proliferating cells in the ventricular zone due to an elongation of the G1 phase, while exposure did not impact cell cycle length of cells proliferating in the subventricular zone (5). The current study examined the impact of binge-like AE during the third trimester equivalent on the cell cycle kinetics of neural precursors (NPCs) in the SGZ of DG of the rodent hippocampus. Rat pups were randomly assigned to three groups on PD4: intubated with alcohol (5.25 g/kg/day; AE), shamintubated (SI), or suckle control (SC). Following sacrifice on PD10, cumulative labeling with bromodeoxyuridine (BrdU) was performed. Future work will examine the impact of developmental alcohol exposure on two other cell populations, Sox2+ and Ki67+ cells. Then, the total length of the cell cycle and the S phase can be calculated. This study was undertaken to establish if a change in duration of granule cell precursors' cell cycle at PD10 could be a cellular mechanism leading to alterations in new neuron survival.