Lloret Torres Mario E, Rivas Jiménez Arelys, Tosado Rodríguez Eduardo L, Cardona Jordan Kiara, Lay Rivera Xiany X, Peña Señeriz Yaren L, Capella Muñiz Joseph L, Dieppa Rodríguez Marieliz, Ruiz Bolívar Daniel F, González Del Toro Jovangelis, Florian Alsina John A, Colón Rivera Paola A, Garcia Colon Jose O, Roche-Lima Abiel, Velázquez-Marrero Cristina
Institute of Neurobiology, UPR-Medical Sciences Campus, 201 Blvd del Valle, San Juan, Puerto Rico.
Integrated Informatics Services Facility RCMI-RIC-IIS University of Puerto Rico Medical Science Campus, San Juan, Puerto Rico.
PLoS One. 2025 Jun 25;20(6):e0322576. doi: 10.1371/journal.pone.0322576. eCollection 2025.
Stressor-related disorders frequently co-occur with alcohol use disorder (AUD). This necessitates an understanding of the physiological and genetic factors contributing to this relationship. Binge drinking is the most common method of alcohol consumption among adolescent males and significantly increases the risk of developing comorbid stressor-related disorders and AUD. In experiments modeling the effects of a single binge-like alcohol exposure in male adolescent mice, we observed a clear deficit in context extinction learning. This exposure led to a significant initial increase in subsequent voluntary drinking on day one, as measured by the every-other-day (EOD) two-bottle choice drinking assay, which normalized thereafter.
For this study we performed an mRNASeq analysis of mice nucleus accumbens (NAc), a region intricately involved in regulating both aversive contextual fear responses and reward, after EOD to profile the differential expression of mRNAs within this region. We also used immunohistochemistry of coronal brain slices to characterize expression of proteins associated with stress-related disorders and molecular alcohol tolerance, such as FKBP5, GSK3ß, and ß-catenin, within the striatum, nucleus accumbens (NAc), hippocampus, and basolateral amygdala (BLA).
Comparative mRNA profile analysis reveals significant long-term changes in gene expression induced by binge-like alcohol exposure, even 30 days after the initial exposure. Immunohistochemistry showed a full recovery of previously observed altered levels of target proteins prior to EOD.
These findings suggest that the temporal activation of specific gene subsets plays a crucial role in the comorbidity of AUD and stressor-related diseases. Understanding these mechanisms can help develop more effective, integrated treatment approaches to improve outcomes for affected individuals.
应激源相关障碍常与酒精使用障碍（AUD）共病。这就需要了解促成这种关系的生理和遗传因素。暴饮是青少年男性最常见的饮酒方式，会显著增加患共病应激源相关障碍和AUD的风险。在模拟单次暴饮样酒精暴露对雄性青少年小鼠影响的实验中，我们观察到情境消退学习明显受损。这种暴露导致在第1天通过隔日（EOD）双瓶选择饮水试验测量的后续自愿饮水量最初显著增加，此后恢复正常。
在本研究中，我们在EOD后对小鼠伏隔核（NAc）进行了mRNA测序分析，该区域复杂地参与调节厌恶情境恐惧反应和奖赏，以描绘该区域内mRNA的差异表达。我们还使用冠状脑片免疫组织化学来表征与应激相关障碍和分子酒精耐受性相关的蛋白质表达，如FKBP5、GSK3β和β-连环蛋白，在纹状体、伏隔核（NAc）、海马体和基底外侧杏仁核（BLA）中的表达。
比较mRNA谱分析显示，即使在初次暴露30天后，暴饮样酒精暴露也会诱导基因表达发生显著的长期变化。免疫组织化学显示，在EOD之前观察到的靶蛋白水平改变完全恢复。
这些发现表明，特定基因亚群的时间性激活在AUD与应激源相关疾病的共病中起关键作用。了解这些机制有助于开发更有效的综合治疗方法，以改善受影响个体的治疗效果。
