Defective β-catenin signaling is accompanied with compensatory neurogenesis process that may pave to anxiety. β-Catenin has a distinct role in alleviating anxiety in adolescence; however, it undergoes degradation by the degradation complex Axin and APC. Vilazodone (VZ) is a fast, effective antidepressant with SSRI activity and 5-HT_1A partial agonism that amends somatic and/or psychic symptoms of anxiety. Yet, there is no data about anxiolytic effect of VZ on anxiety-related neurogenesis provoked by stress-reduced β-catenin signaling. Furthermore, females have specific susceptibility toward psychopathology. The aim of the present study is to uncover the molecular mechanism of VZ relative to Wnt/β-catenin signaling in female rats. Stress-induced anxiety was conducted by subjecting the rats to different stressful stimuli for 21 days. On the 15th day, stressed rats were treated with VZ(10 mg/kg, p.o.) alone or concomitant with the Wnt inhibitor: XAV939 (0.1 mg/kg, i.p.). Anxious rats showed low β-catenin level turned over by Axin-1 with unanticipated reduction of APC pursued with elevated protein levels of neurogenesis-stimulating proteins: c-Myc and p^Thr183-Erk likewise gene expressions of miR-17-5p and miR-18. Two weeks of VZ treatment showed anxiolytic effect figured by alleviation of hippocampal histological examination. VZ protected β-catenin signal via reduction in Axin-1 and elevation of APC conjugated with modulation of β-catenin downstream targets. The cytoplasmic β-catenin turnover by Axin-1 was restored by XAV939. Herein, VZ showed anti-anxiety effect, which may be in part through regaining the balance of the reduced β-catenin and its subsequent exaggerated response of p-Erk, c-Myc, Dicer-1, miR-17-5p, and miR-18.

Graphical Abstract

中文翻译：

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维拉佐酮减轻慢性不可预测的轻度应激雌性大鼠模型中神经发生引起的焦虑：Wnt/β-连环蛋白信号传导的作用

有缺陷的β-连环蛋白信号传导伴随着代偿性神经发生过程，可能会导致焦虑。 β-Catenin 在缓解青春期焦虑方面具有独特作用；然而，它会被降解复合物 Axin 和 APC 降解。维拉佐酮 (VZ) 是一种快速、有效的抗抑郁药，具有 SSRI 活性和 5-HT _1A部分激动作用，可改善焦虑的躯体和/或精神症状。然而，尚无关于 VZ 对由应激减少的 β-连环蛋白信号传导引起的焦虑相关神经发生的抗焦虑作用的数据。此外，女性对精神病理学具有特殊的敏感性。本研究的目的是揭示雌性大鼠中 VZ 与 Wnt/β-catenin 信号传导相关的分子机制。通过让大鼠接受不同的应激刺激 21 天来进行应激诱导的焦虑。第15天，应激大鼠单独接受VZ（10 mg/kg，口服）或与Wnt抑制剂XAV939（0.1 mg/kg，腹膜内注射）同时治疗。焦虑大鼠表现出 Axin-1 引起的低 β-连环蛋白水平，并伴随着神经发生刺激蛋白 c-Myc 和 p ^Thr183 -Erk的蛋白水平升高而导致 APC 意外减少，同样，miR-17-5p 和 miR-17-5p 的基因表达也随之升高。 18.通过海马组织学检查的缓解表明，两周的 VZ 治疗显示出抗焦虑作用。 VZ 通过减少 Axin-1 和升高 APC 与调节 β-连环蛋白下游靶标来保护 β-连环蛋白信号。 XAV939 恢复了 Axin-1 引起的细胞质 β-连环蛋白周转。在此，VZ 显示出抗焦虑作用，部分原因可能是通过恢复还原的 β-catenin 的平衡及其随后的 p-Erk、c-Myc、Dicer-1、miR-17-5p 和 miR 的夸大反应-18。

图形概要