Karssen A M, Her S, Li J Z, Patel P D, Meng F, Bunney W E, Jones E G, Watson S J, Akil H, Myers R M, Schatzberg A F, Lyons D M
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305-5485, USA.
Mol Psychiatry. 2007 Dec;12(12):1089-102. doi: 10.1038/sj.mp.4002095. Epub 2007 Sep 25.
Stressful experiences that consistently increase cortisol levels appear to alter the expression of hundreds of genes in prefrontal limbic brain regions. Here, we investigate this hypothesis in monkeys exposed to intermittent social stress-induced episodes of hypercortisolism or a no-stress control condition. Prefrontal profiles of gene expression compiled from Affymetrix microarray data for monkeys randomized to the no-stress condition were consistent with microarray results published for healthy humans. In monkeys exposed to intermittent social stress, more genes than expected by chance appeared to be differentially expressed in ventromedial prefrontal cortex compared to monkeys not exposed to adult social stress. Most of these stress responsive candidate genes were modestly downregulated, including ubiquitin conjugation enzymes and ligases involved in synaptic plasticity, cell cycle progression and nuclear receptor signaling. Social stress did not affect gene expression beyond that expected by chance in dorsolateral prefrontal cortex or prefrontal white matter. Thirty four of 48 comparisons chosen for verification by quantitative real-time polymerase chain reaction (qPCR) were consistent with the microarray-predicted result. Furthermore, qPCR and microarray data were highly correlated. These results provide new insights on the regulation of gene expression in a prefrontal corticolimbic region involved in the pathophysiology of stress and major depression. Comparisons between these data from monkeys and those for ventromedial prefrontal cortex in humans with a history of major depression may help to distinguish the molecular signature of stress from other confounding factors in human postmortem brain research.
持续增加皮质醇水平的应激经历似乎会改变前额叶边缘脑区数百个基因的表达。在此，我们在暴露于间歇性社会应激诱导的高皮质醇血症发作的猴子或无应激对照条件下的猴子中研究这一假设。从随机分配到无应激条件的猴子的Affymetrix微阵列数据汇编的前额叶基因表达谱与已发表的健康人类的微阵列结果一致。在暴露于间歇性社会应激的猴子中，与未暴露于成年社会应激的猴子相比，腹内侧前额叶皮质中似乎有比偶然预期更多的基因差异表达。这些应激反应候选基因中的大多数被适度下调，包括参与突触可塑性、细胞周期进程和核受体信号传导的泛素缀合酶和连接酶。社会应激对背外侧前额叶皮质或前额叶白质中基因表达的影响不超过偶然预期。通过定量实时聚合酶链反应（qPCR）选择用于验证的48项比较中有34项与微阵列预测结果一致。此外，qPCR和微阵列数据高度相关。这些结果为参与应激和重度抑郁症病理生理学的前额叶皮质边缘区域的基因表达调控提供了新的见解。将这些来自猴子的数据与有重度抑郁症病史的人类腹内侧前额叶皮质的数据进行比较，可能有助于在人类死后大脑研究中区分应激的分子特征与其他混杂因素。
