Genetic differences in estrous cycle effects on the rat brain transcriptome

Males and females often differ on propensity for a substance use disorder (SUD), etiology and clinical manifestation of SUD, and response to SUD treatment strategies (Riley et al 2018). The fluctuation of sex-related hormones in the brain and/or circulation may contribute to some of these differences. For example, estradiol activity has been associated with sensitivity to drugs of abuse (Tonn Eisinger et al 2018) and vulnerability to SUD (Anker and Carroll 2011). In particular, estrogen can affect the dopamine system in brain and this may contribute to differences in the etiology and the clinical manifestation of SUD (Bobzean et al 2014). Without direct association with SUD, others have shown that stage of the estrous cycle influences RNA transcription levels and splicing in particular brain regions (Duclot and Kabbaj 2015; DiCarlo et al 2017). What has not been thoroughly explored is whether genetic factors can modify the effect of estrous cycle on RNA transcript and ultimately, whether the interaction of these two factors can influence the sex-related differences in SUD vulnerability.男性与女性在物质使用障碍（substance use disorder, SUD）的易感性、疾病病因与临床表现，以及对SUD治疗方案的应答水平上往往存在显著差异（Riley等人，2018）。脑内或循环系统中与性别相关的激素波动，或许是造成上述部分差异的诱因之一。例如，雌二醇（estradiol）活性与成瘾药物敏感性（Tonn Eisinger等人，2018）以及SUD易感性（Anker与Carroll，2011）均存在关联。尤为关键的是，雌激素（estrogen）可对脑内多巴胺系统产生调控作用，这或许也是导致SUD在病因与临床表现上存在性别差异的原因之一（Bobzean等人，2014）。另有研究表明，尽管与SUD无直接关联，但发情周期（estrous cycle）阶段会对特定脑区的RNA转录水平及剪接过程产生影响（Duclot与Kabbaj，2015；DiCarlo等人，2017）。目前尚未被充分探究的问题是：遗传因素是否能够调控发情周期对RNA转录本的影响，以及最终，这两类因素的交互作用是否会影响SUD易感性的性别差异。