Hypofunction of the serotonergic (5-HT) system has close relationship with the symptoms in major depressive disorders (MDD), however, the underlying neural circuitry mechanisms are not fully understood. Lateral habenula (LHb) plays a crucial role in aversive behaviors and is activated in conditions of depression. It has been reported that 5-HT inhibits the excitability of LHb neurons, leading to the hypothesis that decreased transmission of 5-HT would elevate the activity of LHb and therefore mediates depressive symptoms. Using retrograde tract tracing with cholera toxin subunit B, we find that dorsal raphe nucleus (DRN) sends primary 5-HT projection to the LHb. In vitro slice patch-clamp recording reveals that opto-stimulation of DRN inputs to the LHb suppresses the frequency of miniature excitatory postsynaptic current, while increases paired pulse ratio in LHb neurons, indicating 5-HT projection presynaptically suppresses the excitability of LHb neurons. In chronic unpredictable mild stress (CUMS) rat model of depression, optogenetic stimulation of DRN-LHb projection alleviates the depressive symptoms in CUMS models. Meanwhile, opto-inhibition of this circuit results in elevated c-fos expression in LHb and induces depression-like behaviors. This study demonstrates that the 5-HT projection from DRN to LHb suppresses the excitability of LHb neurons, and hypofunction of 5-HT transmission induces depressive behavior via the activation of LHb. Our results reveal the functional connectivity of DRN-LHb circuit and its antidepressant action, which may provide a novel target for the treatment of depression.

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β-Catenin has been implicated in major depressive disorder (MDD), which is associated with synaptic plasticity and dendritic arborization. MicroRNAs (miRNA) are small noncoding RNAs containing about 22 nucleotides and involved in a variety of physiological and pathophysiological process, but their roles in MDD remain largely unknown. Here, we investigated the expression and function of miRNAs in the mouse model of chronic social defeat stress (CSDS). The regulation of β-catenin by selected miRNA was validated by silico prediction, target gene luciferase reporter assay, and transfection experiment in neurons. We demonstrated that the levels of miR-214-3p, which targets β-catenin transcripts were significantly increased in the medial prefrontal cortex (mPFC) of CSDS mice. Antagomir-214-3p, a neutralizing inhibitor of miR-214-3p, increased the levels of β-catenin and reversed the depressive-like behavior in CSDS mice. Meanwhile, antagomir-214-3p increased the amplitude of miniature excitatory postsynaptic current (mEPSC) and the number of dendritic spines in mPFC of CSDS mice, which may be related to the elevated expression of cldn1. Furthermore, intranasal administered antagomir-214-3p also significantly increased the level of β-catenin and reversed the depressive-like behaviors in CSDS mice. These results may represent a new therapeutic target for MDD.

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Background: miR-126-5p plays an important role in promoting endothelial cell (EC) proliferation. We thus explored whether miR-126-5p can promote EC proliferation and angiogenesis in chronically ischemic brains (CIBs). Results: Improved revascularization in moyamoya patients was correlated with upregulated miR-126-5p expression in the TM and DM. In vitro experiments showed that miR-126-5p promoted EC proliferation through the PI3K/Akt pathway. CIBs from the agomir group exhibited significantly higher p-Akt, VEGF, CD31 and eNOS expression compared with the control CIBs. The ICBP and the RCF were significantly better in the agomir compared with the control group. Conclusion: Increasing miR-126-5p expression in the TM can promote EC proliferation and angiogenesis in CIBs of 2VO+EMS rats through the PI3K/Akt pathway. Methods: We assessed the correlation between revascularization and miR-126-5p expression in the temporal muscle (TM) and dura mater (DM) of moyamoya patients. The effect of miR-126-5p on EC proliferation and downstream signaling pathways was explored in vitro. We established an animal model of two-vessel occlusion plus encephalo-myo-synangiosis (2VO+EMS), transfected the TM with miR-126-5p agomir/antagomir, compared the expression of miR-126-5p and relevant downstream cytokines in brain tissue among different groups, and investigated the improvement in cerebral blood perfusion (ICBP) and the recovery of cognitive function (RCF).