Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Department of Pharmacology, Medical College of Wisconsin, Milwaukee, 53226, WI, USA.
Transl Psychiatry. 2024 Jan 22;14(1):51. doi: 10.1038/s41398-024-02748-8.
Alcohol consumption during pregnancy can significantly impact the brain development of the fetus, leading to long-term cognitive and behavioral problems. However, the underlying mechanisms are not well understood. In this study, we investigated the acute and chronic effects of binge-like alcohol exposure during the third trimester equivalent in postnatal day 7 (P7) mice on brain cell viability, synapse activity, cognitive and behavioral performance, and gene expression profiles at P60. Our results showed that alcohol exposure caused neuroapoptosis in P7 mouse brains immediately after a 6-hour exposure. In addition, P60 mice exposed to alcohol during P7 displayed impaired learning and memory abilities and anxiety-like behaviors. Electrophysiological analysis of hippocampal neurons revealed an excitatory/inhibitory imbalance in alcohol-treated P60 mice compared to controls, with decreased excitation and increased inhibition. Furthermore, our bioinformatic analysis of 376 dysregulated genes in P60 mouse brains following alcohol exposure identified 50 synapse-related and 23 mitochondria-related genes. These genes encoded proteins located in various parts of the synapse, synaptic cleft, extra-synaptic space, synaptic membranes, or mitochondria, and were associated with different biological processes and functions, including the regulation of synaptic transmission, transport, synaptic vesicle cycle, metabolism, synaptogenesis, mitochondrial activity, cognition, and behavior. The dysregulated synapse and mitochondrial genes were predicted to interact in overlapping networks. Our findings suggest that altered synaptic activities and signaling networks may contribute to alcohol-induced long-term cognitive and behavioral impairments in mice, providing new insights into the underlying synaptic and mitochondrial molecular mechanisms and potential neuroprotective strategies.
怀孕期间饮酒会对胎儿的大脑发育产生重大影响，导致长期的认知和行为问题。然而，其潜在机制尚不清楚。在这项研究中，我们研究了在产后第 7 天（P7）的小鼠中，相当于妊娠晚期的 binge-like 酒精暴露对大脑细胞活力、突触活动、认知和行为表现以及 P60 时的基因表达谱的急性和慢性影响。我们的结果表明，酒精暴露在 6 小时暴露后立即导致 P7 小鼠大脑中的神经细胞凋亡。此外，在 P7 期间暴露于酒精的 P60 小鼠表现出学习和记忆能力受损以及焦虑样行为。对海马神经元的电生理分析显示，与对照组相比，酒精处理的 P60 小鼠中存在兴奋性/抑制性失衡，表现为兴奋减少和抑制增加。此外，我们对 P60 小鼠大脑中酒精暴露后 376 个失调基因的生物信息学分析确定了 50 个与突触相关和 23 个与线粒体相关的基因。这些基因编码位于突触的不同部位、突触小泡、突触外空间、突触膜或线粒体的蛋白质，与不同的生物学过程和功能有关，包括突触传递、运输、突触小泡循环、代谢、突触发生、线粒体活性、认知和行为的调节。失调的突触和线粒体基因被预测在重叠网络中相互作用。我们的发现表明，改变的突触活动和信号网络可能导致酒精引起的小鼠长期认知和行为损伤，为潜在的突触和线粒体分子机制以及潜在的神经保护策略提供了新的见解。
