Episodic Prenatal Exposure To Ethanol Affects Postnatal Neurogenesis In The Macaque Dentate Gyrus And Visual Recognition Memory.

Fetal alcohol syndrome (FAS) is a prime cause of cognitive dysfunction. The present study tested the hypotheses (a) that gestational ethanol exposure results in deficits in hippocampal-related behaviors and associated neurogenesis and (b) that the period of gastrulation is a time of vulnerability. Pregnant macaques were intubated with ethanol or saline once per week for 3, 6, or 24 weeks. Exposures included or omitted the period of gastrulation. Offspring were given behavioral tests including a Visual-Paired Comparison (VPC), a hippocampal-associated memory task, and euthanized as adolescents. Their dentate gyri were processed for immunohistochemical identification of cells passing through the cell cycle (Ki-67 and proliferating cell nuclear antigen), exiting the cell cycle (p21), or passing through early stages of neuronal morphogenesis (Tuj1). Performance in neurobehavioral tasks was unaffected by ethanol exposure, the notable exception being performance in the VPC that was poorer for macaques exposed to ethanol including gastrulation. Anatomical studies show that the expression of Ki-67 was greater and ratio of p21-positive cells to the ratio of Ki-67-expressing cells was lower in animals in which the ethanol exposure included gastrulation. On the other hand, no ethanol-induced differences in TuJ1 expression were detected. Thus, the dentate gyrus is a bellwether of long-term consequences of gestational ethanol exposure. Targeted effects of ethanol on early neural generation (cell cycle and cycle exit) correlate with the timing-dependent degradation in VPC performance and exposure during gastrulation results in notable deficits. These changes evidence a pattern of fetal programming underlying FAS.