Chan Amy E, Anderson Justin Q, Grigsby Kolter B, Jensen Bryan E, Ryabinin Andrey E, Ozburn Angela R
Dept. of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA.
Veterans Affairs Portland Health Care System, Research and Development Service, Portland, OR, 97239, USA.
Psychopharmacology (Berl). 2025 Aug 22. doi: 10.1007/s00213-025-06875-y.
Women tend to progress from initial alcohol use to Alcohol Use Disorder (AUD) more quickly than men, highlighting the need to study sex differences in models of early-stage alcohol use. In humans and rodents, the nucleus accumbens (NAc) regulates alcohol binge drinking, a risk factor for developing AUD. However, it is unknown whether similar brain regions and NAc inputs are engaged in males and females during binge-like drinking.
We labeled NAc inputs with a viral retrograde tracer (GFP) and quantified whole-brain c-Fos to determine the regions and NAc inputs differentially engaged in male and female mice during binge-like drinking. Mice underwent a 4-day Drinking-in-the-Dark task for either ethanol or water. Immediately following drinking on day 4, periorbital blood samples were collected for determination of blood ethanol concentration, and brains were collected. c-Fos expression and c-Fos + GFP colocalization was quantified for 426 brain areas using SmartAnalytics. We employed several data and network analysis approaches to identify NAc circuits and regions engaged, and network dynamics altered by binge-like drinking.
We found that ethanol engaged significantly more NAc inputs in binge-like ethanol drinking females, as compared to males, including various GABAergic and glutamatergic regions. Moreover, we found that binge-like drinking females had 129 brain areas with greater c-Fos than males. Relative to water controls, ethanol increased network modularity and decreased connectivity in both sexes and did so more dramatically in males.
Our results support that early-stage binge-like ethanol drinking engages brain regions and NAc inputs and alters network dynamics in a sex-specific manner, which may help to explain the faster transition from initial alcohol use to AUD in women.
女性从最初饮酒发展为酒精使用障碍（AUD）的速度往往比男性更快，这凸显了研究早期饮酒模型中性别差异的必要性。在人类和啮齿动物中，伏隔核（NAc）调节酒精暴饮，这是发展为AUD的一个风险因素。然而，在类似暴饮的饮酒过程中，男性和女性是否涉及相似的脑区和NAc输入尚不清楚。
我们用病毒逆行示踪剂（绿色荧光蛋白，GFP）标记NAc输入，并对全脑c-Fos进行定量，以确定在类似暴饮的饮酒过程中，雄性和雌性小鼠中差异涉及的脑区和NAc输入。小鼠接受为期4天的暗箱饮酒任务，饮用乙醇或水。在第4天饮酒后立即采集眶周血样以测定血液乙醇浓度，并收集大脑。使用SmartAnalytics对426个脑区的c-Fos表达和c-Fos+GFP共定位进行定量。我们采用了几种数据和网络分析方法来识别涉及的NAc回路和脑区，以及类似暴饮的饮酒所改变的网络动力学。
我们发现，与雄性相比，在类似暴饮的乙醇饮用过程中，雌性小鼠的乙醇涉及的NAc输入明显更多，包括各种γ-氨基丁酸能和谷氨酸能区域。此外，我们发现类似暴饮的饮酒雌性小鼠有129个脑区的c-Fos比雄性更多。相对于水对照组，乙醇增加了两性的网络模块性并降低了连通性，且在雄性中更为显著。
我们的结果支持，早期类似暴饮的乙醇饮用涉及脑区和NAc输入，并以性别特异性方式改变网络动力学，这可能有助于解释女性从最初饮酒到发展为AUD的更快转变。
