Sex specific gene expression patterns in cortico-limbic structures associate with psychiatric disorders

In humans there are sex-specific differences in the prevalence and symptomology of psychiatric disorders. However, preclinical animal models have primarily used males. As such, the molecular mechanisms underlying sex-specific differences in mental illness are not well established. In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala. We found a considerable number of differentially expressed genes (DEGs) between males and females across all brain regions. However, 84.9% of all DEGs were found in the NAcS (> 5000 genes; p < 0.01, FDR < 0.01). Relating these DEGs to genome wide association studies (GWAS) revealed an enrichment for loci associated with major depressive disorder (Psychiatric Genomics Consortium 2019). We compared the DEGs in the NAcS to an analgous human dataset (Labonte, 2017), and found 587 common DEGs which were enriched for genes associated with both anxiety (neuro genetics study, 2016) and broad depression (UK biobank, 2018). Our data provide comprehensive evidence of sex molecular profiles in the NAcS. Importantly these differences associate with anxiety and depression, suggesting an intrinsic molecular basis for sex-based differences in disease prevalence and presentation.精神疾病的患病率及症状学特征存在性别特异性差异，该现象在人类中普遍存在。然而，临床前动物模型大多仅使用雄性实验动物，因此精神疾病性别特异性差异背后的分子机制尚未得到充分阐明。本研究针对雄性与雌性大鼠的皮层边缘系统开展全转录组基因表达谱对比分析，所涉脑区包括扣带回皮层、伏隔核内侧壳区（NAcS）、腹侧齿状回以及基底外侧杏仁核。我们在所有受试脑区中均发现了大量雌雄大鼠间的差异表达基因（DEGs），但全部差异表达基因中的84.9%均富集于NAcS区域（基因数逾5000；p<0.01，错误发现率FDR<0.01）。将这些差异表达基因与全基因组关联研究（GWAS）数据进行关联分析后发现，其显著富集于与重度抑郁症相关的基因位点（精神疾病基因组联盟，2019年）。我们将NAcS区域的差异表达基因与一组类似的人类数据集（Labonte等，2017年）进行比对，共发现587个共有差异表达基因，这些基因显著富集于与焦虑症（神经遗传学研究，2016年）及广泛性抑郁（英国生物样本库，2018年）相关的基因集。本研究数据为NAcS区域存在性别特异性分子特征提供了全面的实验证据。尤为关键的是，这些性别差异与焦虑症及抑郁症存在显著关联，这提示精神疾病患病率及临床表现的性别差异存在内在的分子基础。