Ms. No.: NSC-12-1582: Periadolescent ethanol vapor exposure persistently reduces measures of hippocampal neurogenesis that are associated with behavioral outcomes in adulthood

摘要

Excessive alcohol consumption is prevalent among adolescents and may result in lasting neurobehavioral consequences. The use of animal models to study adolescent alcohol exposure has the advantage of allowing for the control necessary in order to evaluate the effects of ethanol on the brain and separate such effects from genetic background and other environmental insults. In the present study the effects of moderate ethanol vapor exposure, during adolescence, on measures of neurogenesis and behavioral measures were evaluated at two different times following ethanol withdrawal, in adulthood. The two groups of Wistar rats were both exposed to intermittent ethanol vapor (14 hrs on/10 hrs off/day) for 35–36 days from PD 23-PD 58 (average blood ethanol concentration (BEC): 163 mg%). In the first group, after rats were withdrawal from vapor they were subsequently assessed for locomotor activity, conflict behavior in the open field, and behaviors in the forced swim test and then sacrificed at 72 days of age. The second group of rats were withdrawn from vapor and injected for 5 days with Bromo-deoxy-Uridine (BrdU). Over the next 8 weeks they were also assessed for locomotor activity, conflict behavior in the open field, and behaviors in the forced swim test and then sacrificed at 113/114 days of age. All rats were perfused for histochemical analyses. Ethanol vapor exposed rats displayed hypoactivity in tests of locomotion and less anxiety-like and/or more “disinhibitory” behavior in the open field conflict. Quantitative analyses of immunoreactivity revealed a significant reduction in measures of neurogenesis, progenitor proliferation, as indexed by doublecortin (DCX), Ki67, and increased markers of cell death as indexed by cleaved caspase-3, and Fluoro-Jade at 72 days, and decreases in doublecortin (DCX), and increases in cleaved caspase-3 at 114 days in the ethanol vapor exposed rats. Progenitor survival, as assessed by BrdU+, was reduced in the vapor exposed animals that were sacrificed at 114 days. The reduction seen in DCX labeled in cell counts was significantly correlated with hypoactivity at 24 hours after withdrawal as well as less anxiety-like and/or more “disinhibitory” behavior in the open field conflict test at 2 and 8 weeks following termination of vapor exposure. These studies demonstrate that behavioral measures of disinhibitory behavior correlated with decreases in neurogenesis are all significantly and persistently impacted by periadolescent ethanol exposure and withdrawal in Wistar rats.