Despite studies providing insight into the neurobiology of chronic stress, depression and anxiety, long noncoding RNA (lncRNA)-mediated mechanisms underlying the common and distinct pathophysiology of these stress-induced disorders remain nonconclusive. In a previous study, we used the chronic mild stress paradigm to separate depression-susceptible, anxiety-susceptible and insusceptible rat subpopulations. In the current study, lncRNA and messenger RNA (mRNA) expression was comparatively profiled in the hippocampus of the three stress groups using microarray technology. Groupwise comparisons identified distinct sets of lncRNAs and mRNAs associated with the three different behavioral phenotypes of the stressed rats. To investigate the regulatory roles of the dysregulated lncRNAs upon mRNA expression, correlations between the differential lncRNAs and mRNAs were first analyzed by combined use of weighted gene coexpression network analysis and ceRNA theory-based methods. Subsequent functional analysis of strongly correlated mRNAs indicated that the dysregulated lncRNAs were involved in various biological pathways and processes to specifically induce rat susceptibility or resiliency to depression or anxiety. Further intersectional analysis of phenotype-associated and drug-associated lncRNA-mRNA networks and subnetworks assisted in identifying 16 hub lncRNAs as potential targets of anti-depression/anxiety drugs. Collectively, our study established the molecular basis for understanding the similarities and differences in pathophysiological mechanisms underlying stress-induced depression or anxiety and stress resiliency, revealing several important lncRNAs that represent potentially new therapeutic drug targets for depression and anxiety disorders.

尽管研究提供了对慢性压力、抑郁和焦虑的神经生物学的洞察，但长非编码 RNA (lncRNA) 介导的这些压力诱发疾病的常见和独特病理生理学机制仍然没有定论。在先前的研究中，我们使用慢性轻度应激范例来分离易感抑郁，易感焦虑和不易感的大鼠亚群。在目前的研究中，lncRNA 和信使 RNA (mRNA) 表达在三个压力组的海马中使用微阵列技术进行了比较分析。分组比较确定了与应激大鼠的三种不同行为表型相关的lncRNA和mRNA的不同集合。为了研究失调的 lncRNA 对 mRNA 表达的调节作用，首先通过结合使用加权基因共表达网络分析和基于 ceRNA 理论的方法分析差异 lncRNA 和 mRNA 之间的相关性。随后对强相关 mRNA 的功能分析表明，失调的 lncRNA 参与各种生物学途径和过程，以特异性诱导大鼠对抑郁或焦虑的易感性或弹性。对表型相关和药物相关的 lncRNA-mRNA 网络和子网络的进一步交叉分析有助于确定 16 个中枢 lncRNA 作为抗抑郁/焦虑药物的潜在靶点。总的来说，我们的研究为理解压力引起的抑郁或焦虑和压力弹性的病理生理机制的异同奠定了分子基础，