Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
Neuroscience. 2011 Nov 24;196:66-79. doi: 10.1016/j.neuroscience.2011.08.024. Epub 2011 Aug 27.
The aim of the present study was to identify potential biomarkers for depression in the search for novel disease targets and treatment regimens. Furthermore, the study includes a search for biomarkers involved in treatment resistance and stress resilience in order to investigate mechanisms underlying antidepressant drug refraction and stress-coping strategies. Depression-related transcriptomic changes in gene expression profiles were investigated in laser-captured microdissected (LCM) rat hippocampal granular cell layers (GCL) using the chronic mild stress (CMS) rat model of depression and chronic administration of two selective serotonin reuptake inhibitors (SSRIs), escitalopram and sertraline. CMS rats were segregated into diverging groups according to behavioral readouts, and under stringent constraints, the associated differential gene regulations were analyzed. Accordingly, we identified four genes associated with recovery, two genes implicated in treatment resistance, and three genes involved in stress resilience. The identified genes associated with mechanisms of cellular plasticity, including signal transduction, cell proliferation, cell differentiation, and synaptic release. Hierarchical clustering analysis confirmed the subgroup segregation pattern in the CMS model. Thus antidepressant treatment refractors cluster with anhedonic-like rats, and, interestingly, stress-resilient rats cluster with rats undergoing antidepressant-mediated recovery from anhedonia, suggesting antidepressant mechanisms of action to emulate endogenous stress-coping strategies.
本研究旨在寻找抑郁症的潜在生物标志物，以期发现新的疾病靶点和治疗方案。此外，本研究还寻找与治疗抵抗和应激弹性相关的生物标志物，以探究抗抑郁药物失效和应激应对策略的潜在机制。我们利用慢性轻度应激（CMS）大鼠模型和两种选择性 5-羟色胺再摄取抑制剂（SSRIs），即依地普仑和舍曲林，对激光捕获微切割（LCM）大鼠海马颗粒细胞层（GCL）的基因表达谱进行了与抑郁相关的转录组变化研究。根据行为结果，CMS 大鼠被分为不同的组，然后在严格的约束条件下，对相关的差异基因调控进行了分析。因此，我们鉴定出了四个与细胞可塑性机制相关的基因，包括信号转导、细胞增殖、细胞分化和突触释放。层次聚类分析证实了 CMS 模型中的亚组分离模式。因此，抗抑郁治疗抵抗者与快感缺失样大鼠聚集在一起，而有趣的是，应激弹性大鼠与经历抗抑郁药物介导的快感缺失恢复的大鼠聚集在一起，这表明抗抑郁药物的作用机制可以模拟内源性应激应对策略。
