The Wnt signaling regulator Dkk3 improves neural-activity homeostasis to prevent stress-induced anxiety disorder.
OBJECTIVES The medial prefrontal cortex (mPFC) is a cortical brain region that involved in various emotional disorder. Neuroinflammation and oxidative stress are reported to associated with the pathogenesis of anxiety, but the underlying brain mechanisms remain unclear. METHODS AND RESULTS Here, using a mouse model of chronic restraint stress (CRS), we found that the stress-induced anxiety-like behavior is accompanied with enhanced neuroinflammation and oxidative stress in mPFC. Specifically, we found that the expression of Dkk3, a dickkopf Wnt signaling pathway regulator, was significantly decreased in the stressed human participants and CRS model mice. Dkk3 deficiency increased neuroinflammation and oxidative stress, impaired the neuronal synaptic plasticity, decreased the neural network synchronization, and thereby contributing to anxiety-like behaviors via RhoA/Rock2/NF-κB signaling pathway. However, overexpression of Dkk3 or pharmacological prevent the RhoA/Rock2/NF-κB signaling pathway in the stressed mice could significantly rescue neural injury and anxiety-like phenotypes. CONCLUSION Taken together, this study reveal that Dkk3 may plays a critical role within the stress-induced behavioral deficits via regulating neuroinflammation and oxidative stress to maintain neural-activity homeostasis, through which may serve as a potential therapeutic target for the treatment of anxiety disorders.