Baker Jessica A, Mulligan Megan K, Hamre Kristin M
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, United States.
Center for Behavioral Teratology, San Diego State University, San Diego, CA, United States.
Front Neurosci. 2023 Jul 26;17:1197292. doi: 10.3389/fnins.2023.1197292. eCollection 2023.
Fetal alcohol spectrum disorders (FASD) are the leading preventable neurodevelopmental disorders and two hallmark symptoms of FASD are abnormal behavior, and cognitive and learning deficits. The severity of alcohol's teratogenic effects on the developing brain is influenced by genetics and sex. We previously identified recombinant inbred BXD mouse strains that show differential vulnerability to ethanol-induced cell death in the developing hippocampus, a brain region important in learning and memory. The present study aimed to test the hypothesis that strains with increased vulnerability to ethanol-induced cell death in the hippocampus have concomitant deficits in multiple hippocampal-related behaviors during adolescence.
The current study evaluated the effects of developmental ethanol exposure on adolescent behavior in two BXD strains that show high cell death (BXD48a, BXD100), two that show low cell death (BXD60, BXD71), and the two parental strains (C57BL/6 J (B6), DBA/2 J (D2)). On postnatal day 7, male and female neonatal pups were treated with ethanol (5.0 g/kg) or saline given in two equal doses 2 h apart. Adolescent behavior was assessed across multiple behavioral paradigms including the elevated plus maze, open field, Y-maze, and T-maze.
Our results demonstrate that the effects of developmental ethanol exposure on adolescent behavioral responses are highly dependent on strain. The low cell death strains, BXD60 and BXD71, showed minimal effect of ethanol exposure on all behavioral measures but did present sex differences. The parental -B6 and D2-strains and high cell death strains, BXD48a and BXD100, showed ethanol-induced effects on activity-related or anxiety-like behaviors. Interestingly, the high cell death strains were the only strains that showed a significant effect of postnatal ethanol exposure on hippocampal-dependent spatial learning and memory behaviors.
Overall, we identified effects of ethanol exposure, strain, and/or sex on multiple behavioral measures. Interestingly, the strains that showed the most effects of postnatal ethanol exposure on adolescent behavior were the BXD strains that show high ethanol-induced cell death in the neonatal hippocampus, consistent with our hypothesis. Additionally, we found evidence for interactions among strain and sex, demonstrating that these factors have a complex effect on alcohol responses and that both are important considerations.
胎儿酒精谱系障碍（FASD）是最主要的可预防的神经发育障碍，FASD的两个标志性症状是行为异常以及认知和学习缺陷。酒精对发育中大脑的致畸作用严重程度受遗传因素和性别影响。我们之前鉴定出重组近交BXD小鼠品系，这些品系在发育中的海马体（对学习和记忆很重要的脑区）对乙醇诱导的细胞死亡表现出不同的易感性。本研究旨在验证以下假设：在海马体中对乙醇诱导的细胞死亡易感性增加的品系在青春期会伴随多种与海马体相关行为的缺陷。
本研究评估了发育过程中乙醇暴露对两个显示高细胞死亡的BXD品系（BXD48a、BXD100）、两个显示低细胞死亡的品系（BXD60、BXD71）以及两个亲本品系（C57BL/6J（B6）、DBA/2J（D2））青春期行为的影响。在出生后第7天，雄性和雌性新生幼崽接受乙醇（5.0g/kg）或生理盐水处理，分两次等剂量给药，间隔2小时。通过多种行为范式评估青春期行为，包括高架十字迷宫、旷场试验、Y迷宫和T迷宫。
我们的结果表明，发育过程中乙醇暴露对青春期行为反应的影响高度依赖于品系。低细胞死亡品系BXD60和BXD71在所有行为指标上显示乙醇暴露的影响最小，但确实存在性别差异。亲本品系B6和D2以及高细胞死亡品系BXD48a和BXD100显示出乙醇对与活动相关或类似焦虑行为的影响。有趣的是，高细胞死亡品系是仅有的显示出生后乙醇暴露对海马体依赖的空间学习和记忆行为有显著影响的品系。
总体而言，我们确定了乙醇暴露、品系和/或性别对多种行为指标的影响。有趣的是，在青春期行为上显示出出生后乙醇暴露影响最大的品系是在新生海马体中显示高乙醇诱导细胞死亡的BXD品系，这与我们的假设一致。此外，我们发现了品系和性别之间相互作用的证据，表明这些因素对酒精反应有复杂影响，且两者都是重要的考虑因素。
