Abstract

Excessive alcohol consumption during adolescence remains a significant health concern as alcohol drinking during adolescence increases the likelihood of an alcohol use disorder in adulthood by fourfold. Binge drinking in adolescence is a particular problem as binge-pattern consumption is the biggest predictor of neurodegeneration from alcohol and adolescents are particularly susceptible to the damaging effects of alcohol. The adolescent hippocampus, in particular, is highly susceptible to alcohol-induced structural and functional effects, including volume and neuron loss. However, hippocampal structure and function may recover with abstinence and, like in adults, a reactive burst in hippocampal neurogenesis in abstinence may contribute to that recovery. As the mechanism of this reactive neurogenesis is not known, the current study investigated potential mechanisms of reactive neurogenesis in binge alcohol exposure in adolescent, male rats. In a screen for cell cycle perturbation, a dramatic increase in the number of cells in all phases of the cycle was observed at 7 days following binge ethanol exposure as compared to controls. However, the proportion of cells in each phase was not different between ethanol-exposed rats and controls, indicating that cell cycle dynamics are not responsible for the reactive burst in neurogenesis. Instead, the marked increase in hippocampal proliferation was shown to be due to a twofold increase in proliferating progenitor cells, specifically an increase in cells colabeled with the progenitor cell marker Sox2 and S-phase (proliferation) marker, BrdU, in ethanol-exposed rats. To further characterize the individual subtypes of neural progenitor cells (NPCs) affected by adolescent binge ethanol exposure, a fluorescent quadruple labeling technique was utilized to differentiate type 1, 2a, 2b, and 3 progenitor cells simultaneously. At one week into abstinence, animals in the ethanol exposure groups had an increase in proliferating type 2 (intermediate progenitors) and type 3 (neuroblast) progenitors but not type 1 neural stem cells. These results together suggest that activation of type 2 NPCs out of quiescence is likely the primary mechanism for reactive hippocampal neurogenesis following adolescent alcohol exposure.

Highlights

  • Alcohol use disorders (AUDs) remain a significant public health problem

  • The results show that 7 days after binge alcohol exposure there were no changes in the proportion of hippocampal neural progenitor cells (NPCs) in each cell cycle phase in adolescent rats (Figure 2I), which suggests that the cell cycle was not altered by prior ethanol exposure at this time point (T7), similar to that observed in adult rats

  • We demonstrate that adolescent rats exhibit reactive hippocampal neurogenesis after 4-day binge ethanol exposure, confirmed by the enhanced expression of the immature neuronal marker, NeuroD1, 14 days after ethanol exposure (Figure 1)

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Summary

INTRODUCTION

Alcohol use disorders (AUDs) remain a significant public health problem. Nearly 14% of the USA population meet the DSM-V diagnostic criteria for an AUD in any given year which translates into a life-time prevalence of 29% [1]. Within the first several days of abstinence there is a striking burst in cell proliferation along the SGZ that results in a significant increase in newborn neurons in both adult and adolescent models of AUDs [64, 66,67,68,69] This reactive neurogenesis has been observed in other acutely damaging events such as traumatic brain injury [70], ischemia [71,72,73], and seizure [74, 75]. An increase in the number of neural progenitor cells (NPCs) and proliferating NPCs was observed, suggesting an expansion of the stem cell pool (see text footnote 1) This expansion appears to be due, in part, to more type 1 NSCs recruited out of quiescence at 7 days of abstinence to help drive this reactive neurogenesis effect in adult rats (see text footnote 1). As the mechanism of increased proliferation would be either a shortened (accelerated) cell cycle or activation of a larger number of NPCs out of quiescence, we screened for cell cycle effects and examined which subtype of progenitor cells were proliferating at 7 days of abstinence

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