Barney Thaddeus M, Vore Andrew S, Deak Terrence
Developmental Exposure Alcohol Research Center, Behavioral Neuroscience Program, Department of Psychology, Binghamton, NY, United States.
Front Neurosci. 2022 May 30;16:884197. doi: 10.3389/fnins.2022.884197. eCollection 2022.
Acute ethanol exposure produces rapid alterations in neuroimmune gene expression that are both time- and cytokine-dependent. Interestingly, adolescent rats, who often consume binge-like quantities of alcohol, displayed reduced neuroimmune responses to acute ethanol challenge. However, it is not known whether growth factors, a related group of signaling factors, respond to ethanol similarly in adults and adolescents. Therefore, Experiment 1 aimed to assess the growth factor response to ethanol in both adolescents and adults. To test this, adolescent (P29-P34) and adult (P70-P80) Sprague Dawley rats of both sexes were injected with either ethanol (3.5 g/kg) or saline, and brains were harvested 3 h post-injection for assessment of growth factor, cytokine, or miRNA expression. As expected, acute ethanol challenge significantly increased IL-6 and IκBα expression in the hippocampus and amygdala, replicating our prior findings. Acute ethanol significantly decreased BDNF and increased FGF2 regardless of age condition. PDGF was unresponsive to ethanol, but showed heightened expression among adolescent males. Because recent work has focused on the PDE4 inhibitor ibudilast for treatment in alcohol use disorder, Experiment 2 tested whether ibudilast would alter ethanol-evoked gene expression changes in cytokines and growth factors in the CNS. Ibudilast (9.0 mg/kg s.c.) administration 1 h prior to ethanol had no effect on ethanol-induced changes in cytokine or growth factor changes in the hippocampus or amygdala. To further explore molecular alterations evoked by acute ethanol challenge in the adult rat hippocampus, Experiment 3 tested whether acute ethanol would change the miRNA expression profile of the dorsal hippocampus using RNASeq, which revealed a rapid suppression of 12 miRNA species 3 h after acute ethanol challenge. Of the miRNA affected by ethanol, the majority were related to inflammation or cell survival and proliferation factors, including FGF2, MAPK, NFκB, and VEGF. Overall, these findings suggest that ethanol-induced, rapid alterations in neuroimmune gene expression were (i) muted among adolescents; (ii) independent of PDE4 signaling; and (iii) accompanied by changes in several growth factors (increased FGF2, decreased BDNF). In addition, ethanol decreased expression of multiple miRNA species, suggesting a dynamic molecular profile of changes in the hippocampus within a few short hours after acute ethanol challenge. Together, these findings may provide important insight into the molecular consequences of heavy drinking in humans.
急性乙醇暴露会迅速改变神经免疫基因表达，这种改变既依赖时间，也依赖细胞因子。有趣的是，经常大量饮酒的青春期大鼠对急性乙醇刺激的神经免疫反应有所降低。然而，尚不清楚生长因子（一类相关的信号因子）在成年和青春期个体中对乙醇的反应是否相似。因此，实验1旨在评估青春期和成年个体对乙醇的生长因子反应。为了验证这一点，对青春期（出生后第29 - 34天）和成年（出生后第70 - 80天）的雌雄Sprague Dawley大鼠注射乙醇（3.5 g/kg）或生理盐水，并在注射后3小时采集大脑，以评估生长因子、细胞因子或miRNA的表达。正如预期的那样，急性乙醇刺激显著增加了海马体和杏仁核中IL - 6和IκBα的表达，重复了我们之前的研究结果。无论年龄状况如何，急性乙醇显著降低了BDNF并增加了FGF2。PDGF对乙醇无反应，但在青春期雄性大鼠中表达升高。由于最近的研究集中在磷酸二酯酶4（PDE4）抑制剂异丁司特用于治疗酒精使用障碍，实验2测试了异丁司特是否会改变乙醇诱发的中枢神经系统中细胞因子和生长因子的基因表达变化。在乙醇注射前1小时给予异丁司特（9.0 mg/kg皮下注射）对海马体或杏仁核中乙醇诱导的细胞因子或生长因子变化没有影响。为了进一步探索成年大鼠海马体中急性乙醇刺激引起的分子改变，实验3使用RNA测序测试急性乙醇是否会改变背侧海马体的miRNA表达谱，结果显示急性乙醇刺激3小时后12种miRNA种类迅速受到抑制。在受乙醇影响的miRNA中，大多数与炎症或细胞存活及增殖因子有关，包括FGF2、丝裂原活化蛋白激酶（MAPK）、核因子κB（NFκB）和血管内皮生长因子（VEGF）。总体而言，这些发现表明，乙醇诱导的神经免疫基因表达的快速改变：（i）在青春期个体中减弱；（ii）独立于PDE4信号传导；（iii）伴随着几种生长因子的变化（FGF2增加，BDNF减少）。此外，乙醇降低了多种miRNA种类的表达，表明急性乙醇刺激后短短几小时内海马体中存在动态的分子变化谱。总之，这些发现可能为人类大量饮酒的分子后果提供重要见解。
