性染色体组成调控与情绪相关的基因表达。
Sex chromosome complement regulates expression of mood-related genes.
机构信息
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
出版信息
Biol Sex Differ. 2013 Nov 7;4(1):20. doi: 10.1186/2042-6410-4-20.
BACKGROUND
Studies on major depressive and anxiety disorders suggest dysfunctions in brain corticolimbic circuits, including altered gamma-aminobutyric acid (GABA) and modulatory (serotonin and dopamine) neurotransmission. Interestingly, sexual dimorphisms in GABA, serotonin, and dopamine systems are also reported. Understanding the mechanisms behind these sexual dimorphisms may help unravel the biological bases of the heightened female vulnerability to mood disorders. Here, we investigate the contribution of sex-related factors (sex chromosome complement, developmental gonadal sex, or adult circulating hormones) to frontal cortex expression of selected GABA-, serotonin-, and dopamine-related genes.
METHODS
As gonadal sex is determined by sex chromosome complement, the role of sex chromosomes cannot be investigated individually in humans. Therefore, we used the Four Core Genotypes (FCG) mouse model, in which sex chromosome complement and gonadal sex are artificially decoupled, to examine the expression of 13 GABA-related genes, 6 serotonin- and dopamine-related genes, and 8 associated signal transduction genes under chronic stress conditions. Results were analyzed by three-way ANOVA (sex chromosome complement × gonadal sex × circulating testosterone). A global perspective of gene expression changes was provided by heatmap representation and gene co-expression networks to identify patterns of transcriptional activities related to each main factor.
RESULTS
We show that under chronic stress conditions, sex chromosome complement influenced GABA/serotonin/dopamine-related gene expression in the frontal cortex, with XY mice consistently having lower gene expression compared to XX mice. Gonadal sex and circulating testosterone exhibited less pronounced, more complex, and variable control over gene expression. Across factors, male conditions were associated with a tightly co-expressed set of signal transduction genes.
CONCLUSIONS
Under chronic stress conditions, sex-related factors differentially influence expression of genes linked to mood regulation in the frontal cortex. The main factor influencing expression of GABA-, serotonin-, and dopamine-related genes was sex chromosome complement, with an unexpected pro-disease effect in XY mice relative to XX mice. This effect was partially opposed by gonadal sex and circulating testosterone, although all three factors influenced signal transduction pathways in males. Since GABA, serotonin, and dopamine changes are also observed in other psychiatric and neurodegenerative disorders, these findings have broader implications for the understanding of sexual dimorphism in adult psychopathology.
背景
研究表明，重度抑郁和焦虑障碍与大脑皮质边缘回路功能障碍有关，包括γ-氨基丁酸（GABA）和调节（血清素和多巴胺）神经递质的改变。有趣的是，GABA、血清素和多巴胺系统也存在性别二态性。了解这些性别二态性背后的机制可能有助于揭示女性对情绪障碍易感性增强的生物学基础。在这里，我们研究了与性别相关的因素（性染色体组成、发育性腺性别或成年循环激素）对前额皮质中选定的 GABA、血清素和多巴胺相关基因表达的贡献。
方法
由于性腺性别由性染色体组成决定，因此不能在人类中单独研究性染色体的作用。因此，我们使用了 Four Core Genotypes (FCG) 小鼠模型，该模型人为地分离了性染色体组成和性腺性别，以研究慢性应激条件下 13 个 GABA 相关基因、6 个血清素和多巴胺相关基因以及 8 个相关信号转导基因的表达。结果通过三因素方差分析（性染色体组成×性腺性别×循环睾丸酮）进行分析。通过热图表示和基因共表达网络提供了基因表达变化的整体视角，以识别与每个主要因素相关的转录活性模式。
结果
我们表明，在慢性应激条件下，性染色体组成影响前额皮质中的 GABA/血清素/多巴胺相关基因表达，与 XX 小鼠相比，XY 小鼠的基因表达始终较低。性腺性别和循环睾丸酮对基因表达的控制作用较小，更复杂，变化更大。在所有因素中，雄性条件与一组紧密共表达的信号转导基因相关。
结论
在慢性应激条件下，与性别相关的因素会对前额皮质中与情绪调节相关的基因表达产生不同的影响。影响 GABA、血清素和多巴胺相关基因表达的主要因素是性染色体组成，与 XX 小鼠相比，XY 小鼠具有出乎意料的促病作用。这种作用部分被性腺性别和循环睾丸酮所抵消，尽管所有三个因素都影响了雄性的信号转导途径。由于在其他精神疾病和神经退行性疾病中也观察到 GABA、血清素和多巴胺的变化，因此这些发现对理解成年精神病理学中的性别二态性具有更广泛的意义。
Zotero 插件