Abstract
Hippocampal neurodegeneration is a consequence of excessive alcohol drinking in alcohol use disorders (AUDs), however, recent studies suggest that females may be more susceptible to alcohol-induced brain damage. Adult hippocampal neurogenesis is now well accepted to contribute to hippocampal integrity and is known to be affected by alcohol in humans as well as in animal models of AUDs. In male rats, a reactive increase in adult hippocampal neurogenesis has been observed during abstinence from alcohol dependence, a phenomenon that may underlie recovery of hippocampal structure and function. It is unknown whether reactive neurogenesis occurs in females. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by 7 or 14 days of abstinence. Immunohistochemistry (IHC) was used to assess neural progenitor cell (NPC) proliferation (BrdU and Ki67), the percentage of increased NPC activation (Sox2+/Ki67+), the number of immature neurons (NeuroD1), and ectopic dentate gyrus granule cells (Prox1). On day seven of abstinence, ethanol-treated females showed a significant increase in BrdU+ and Ki67+ cells in the subgranular zone of the dentate gyrus (SGZ), as well as greater activation of NPCs (Sox2+/Ki67+) into active cycling. At day 14 of abstinence, there was a significant increase in the number of immature neurons (NeuroD1+) though no evidence of ectopic neurogenesis according to either NeuroD1 or Prox1 immunoreactivity. Altogether, these data suggest that alcohol dependence produces similar reactive increases in NPC proliferation and adult neurogenesis. Thus, reactive, adult neurogenesis may be a means of recovery for the hippocampus after alcohol dependence in females.
Highlights
Alcohol misuse is a leading cause of preventable death due to its toxic consequences across multiple organs of the body (Centers for Disease Control and Prevention [CDC], 2021)
We investigated the effects of alcohol dependence on neural progenitor cell (NPC) in the dentate gyrus of the hippocampus and its impact on cell cycle activation during recovery in abstinence
14 days after the binge ethanol exposure, we investigated the expression of immature neurons as well as potentially aberrant, ectopic newborn neurons utilizing NeuroD1 IHC, a transcription factor that is transiently expressed in progenitors that have committed to a neuronal fate (Gao et al, 2009; McClain et al, 2014; Hayes et al, 2018)
Summary
Alcohol misuse is a leading cause of preventable death due to its toxic consequences across multiple organs of the body (Centers for Disease Control and Prevention [CDC], 2021). Women appear to be more vulnerable to the damaging effects of alcohol in various organ systems when compared to men, even when accounting for fewer years of harmful consumption or dependence (Nixon et al, 2014; Fama et al, 2020). Many studies show that women develop alcohol-induced brain damage faster than males despite decreased use and misuse (Crawford and Ryder, 1986; Jacobson, 1986; Nixon et al, 1995, 2014; Flannery et al, 2007; Fama et al, 2020; White, 2020) though a few fail to find a difference between males and females in hippocampal volume loss (Demirakca et al, 2011; Grace et al, 2021). Females may exhibit quicker structural brain recovery and withdrawal symptom cessation (Jacobson, 1986; Deshmukh et al, 2003), but they may suffer from more prolonged cognitive impairment compared to males (Luquiens et al, 2019)
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