Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression.

重度抑郁症 (MDD) 是全球残疾的主要原因。迫切需要客观的生物标志物来诊断这种高度异质性的综合征、分配治疗以及评估治疗反应和预后。微小 RNA (miRNA) 是短链非编码 RNA，可在体液中检测到，已成为许多疾病的潜在生物标志物。本研究探讨了 miRNA 作为 MDD 及其治疗生物标志物的潜在用途。我们分析了在暴露于慢性社交失败压力 (CSDS) 之前和之后收集的小鼠循环血液 miRNA 的表达水平，CSDS 是一种经过广泛验证的小鼠模型，用于研究抑郁症，以及重复丙咪嗪或单剂量氯胺酮治疗后. 我们在潜伏期后观察到抗压小鼠和抗压小鼠之间血液 miRNA 特征的显着差异，但不是在暴露于压力后立即。此外，氯胺酮治疗在重建基线 miRNA 表达水平方面比丙咪嗪更有效，但仅限于对药物有行为反应的小鼠。我们将红细胞特异性 miR-144-3p 确定为候选生物标志物，以帮助抑郁症诊断和预测压力敏感小鼠和 MDD 患者的氯胺酮治疗反应。最后，我们证明，通过皮下注射特定的拮抗剂，系统性敲低 miR-144-3p 足以减少应激敏感小鼠的抑郁相关表型。在这种 miR-144-3p 敲低后对血液进行的 RNA 测序分析也揭示了一种减弱的转录应激特征。这些发现将 miR-144-3p 确定为 MDD 诊断和抗抑郁治疗的新靶点，并增强了我们对与抑郁症相关的表观遗传过程的理解。