Department of Psychology, Sapienza University, Via Dei Marsi, 78, 00184, Rome, Italy.
IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
Mol Neurobiol. 2020 Feb;57(2):823-836. doi: 10.1007/s12035-019-01750-2. Epub 2019 Sep 3.
Chronic stress exposure is known to increase vulnerability to the expression of psychiatric disorders, such as depression. Clinical and preclinical evidences support the involvement of the microRNA-34 family in stress-related psychiatric conditions and in the regulation of stress responses. However, the mechanism and the multiple targets by which the microRNA-34 family can affect the stress response and stress-related behavioral alteration are not fully known. Here, with the aid of constitutive and conditional genetic strategy, we examined the role of microRNA-34 family in the expression of depression-like phenotype in mice induced by chronic stress exposure, and we identified their "in vivo" targets during the stressful challenge. We found that microRNA-34a, under chronic stress, is significantly up-regulated in the mouse raphe nuclei, where its recruitment is necessary to induce depression-like behavioral alterations and impact the function of the serotonergic system. Moreover, by next-generation RNA-seq of Ago-2-bound mRNAs, we identified genes that are targeted by microRNA-34a in response to chronic stress and that are likely to mediate its effects.
慢性应激暴露会增加出现精神障碍（如抑郁症）的易感性。临床和临床前证据支持 microRNA-34 家族参与应激相关精神疾病和应激反应的调节。然而，microRNA-34 家族影响应激反应和应激相关行为改变的机制以及多个靶点尚未完全阐明。在这里，我们借助组成性和条件性遗传策略，研究了 microRNA-34 家族在慢性应激暴露诱导的小鼠抑郁样表型表达中的作用，并在应激挑战期间鉴定了它们的“体内”靶标。我们发现，microRNA-34a 在慢性应激下，在小鼠中缝核中显著上调，其募集对于诱导抑郁样行为改变和影响 5-羟色胺能系统的功能是必需的。此外，通过 Ago-2 结合 mRNA 的下一代 RNA-seq，我们鉴定了 microRNA-34a 在慢性应激下靶向的基因，这些基因可能介导其作用。
