Abstract:

Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system, particularly aberrant hippocampal neurogenesis. In this study, we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells (NSCs) and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus. We found abnormal orientation of tamoxifen-induced tdTomato+ (tdTom+) NSCs in adult mice 2 months after treatment with EtOH (5.0 g/kg, i.p.) for 7 consecutive days. EtOH markedly inhibited tdTom+ NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood. EtOH (100 mM) also significantly inhibited the proliferation to 39.2% and differentiation of primary NSCs in vitro. Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus, which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycin-enhancer of zeste homolog 2 pathway. In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+ NSCs and spatial misposition defects of newborn neurons, thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice. 

Key words: adolescence, adulthood, ethanol, dentate gyrus, EZH2, in vivo tracing, lineage progression, mTOR, neural stem cell, newborn dendritic spine, newborn neurons