ACSS2 drives drinking indulgence in male mice by coordinating a gene expression program in the ventral striatum

We recently established ACSS2 as a potential candidate for therapeutic interventions in alcohol use disorders (AUD), in which memory of alcohol-associated environmental cues is a primary driver of craving and relapse. Prior research, however, has been limited to passive exposure to ethanol and the importance of this pathway in models of voluntary drinking that better approximate human alcohol consumption remains unknown. Therefore, we assessed the effect of genetic ACSS2 inhibition on voluntary alcohol intake and simultaneously assayed the epigenetic and transcriptional changes that accompany alcohol consumption. This study tests the effect of knocking out ACSS2 (an enzyme involved in alcohol metabolism in the brain) on alcohol drinking behavior in rodents. This series contains RNA-seq from WT or ACSS2 KO mice, including both males and females, who were subjected to the "drinking in the dark" experimental model for chronic alcohol use (see treatment protocol, below). Samples are from seven dissected portions of the brain: amygdala, cortex, dorsal & ventral hippocampus, prefrontal cortex, and dorsal & ventral striatum. The replicate structure is as follows. For female mice, there are three ACSS2 KO biological replicates each for all brain regions, while the number of WT biological replicates is either two or three depending on the brain region (amygdala, cortex, and prefrontal cortex have two replicates each while dorsal and ventral hippcampus and dorsal and ventral striatum have three replicates each). For male mice, there are three biological replicates each of ACSS2 KO and WT for all tissues except prefrontal cortex, which has one ACSS2 KO and two WT.

我们近期确认ACSS2可作为酒精使用障碍（Alcohol Use Disorders, AUD）治疗干预的潜在靶点，而酒精相关环境线索的记忆是引发渴求与复吸的核心驱动因素。然而此前的相关研究仅局限于被动暴露于乙醇的实验模型，对于该通路在更贴近人类饮酒行为的自愿饮酒模型中的作用仍不明晰。因此，本研究探究了基因层面抑制ACSS2对自愿饮酒量的影响，并同时检测了饮酒过程中伴随的表观遗传与转录组变化。本研究旨在验证敲除ACSS2——一种参与大脑乙醇代谢的酶——对啮齿类动物饮酒行为的影响。本数据集包含野生型（Wild Type, WT）及ACSS2敲除（Knock Out, KO）小鼠的RNA-seq数据，实验对象涵盖雌雄个体，均采用“夜间饮酒”实验模型进行慢性乙醇暴露（具体处理方案见下文）。样本取自7个大脑解剖区域：杏仁核、大脑皮层、背侧与腹侧海马、前额叶皮层，以及背侧与腹侧纹状体。重复实验设计如下：对于雌性小鼠，所有大脑区域的ACSS2 KO组均设置3次生物学重复；而野生型（WT）组的生物学重复数则因脑区而异：杏仁核、大脑皮层及前额叶皮层各设置2次重复，背侧海马、腹侧海马、背侧纹状体与腹侧纹状体各设置3次重复。对于雄性小鼠，除前额叶皮层外，其余所有脑区的ACSS2 KO组与WT组均各设置3次生物学重复；前额叶皮层的ACSS2 KO组仅设置1次生物学重复，WT组设置2次。