Involvment Of Wnt Signaling Mediated Eurogenesis In The Chronic Pain Induced Anxiety And Spatial Memory Impairment

It is now generally accepted that there are two regions in the adult brain where neurogenesis occur.They are subgranular zone(SGZ)of the hippoc ampus and the subve ntricular zone(SVZ).Among them,the hippoc ampus is closely related to the emotional system of the limbic system.In recent years,there are many studies on the relationship between neuronal regeneration and anxiety/depression in the hippocampal dentate gyrus.Some studies have pointed out that anxiety and depression affect adult hippoc ampal neuronalgenesis(AHN).In addi tion,AHN regulating also affects the appearance of anxiety and depression.However,the specific mechanism of neurogenesis in SGZ is not fully understood yet.Wnt signaling is a glycoprotein that is about 39,000 to 46,000 and L-cysteine rich.It specifically binds to its receptor on the cell membrane and regulates downstream signaling pathways through a series of intracellular signal transduction.Wnt signaling activates in neural precursor cells in the SGZ region of the hippocampus and affects the number of newborn neurons.Overexpression of Wnt/?-catenin signaling may increase AHN,while inhibition of Wnt/?-catenin signaling may decrease AHN.However,the specific mechanisms and causes of AHN reduction after chronic pain are still unclear.The effect of Wnt/?-catenin signaling pathway,which is closely related to AHN,on the neuronal function of SGZ has not been studied yet.Therefore,exploring the relationship between Wnt/?-catenin signaling pathway changes and hippocampal function plays an important role in understanding the specific mechanism of hippoc ampal brain function and exploring some new methods of disease treatment.ObjectiveIn this study,we investigated the relationship between Wnt/?-catenin signaling and the function of the hippocampus of mice under chronic pain model,trying to explore the following questions: Firstly,whether the activation of Wnt/?-catenin signal in the hippoc ampal neurons of mice changed,and whether consistent with the change of AHN after chronic pain? Secondly,is there any correlation between this change and anxiety-like emotion regulation and learning and memory in the hippoc ampus? Thirdly,can this effect change the ability of hippocampal neurons to affect emotions or memory? Last but not least,do anti-anxiety drugs affect the activation of Wnt / ?-catenin in the hippocampus? Materials and MethodsThe adult male wild-type C57BL/6 mice,Wnt/?-catenin signal report mice,?-catenin conditional knockout Nestin-Cre ER:?-cateninlo xp/ lo xp(Nes/?-cat,CKO)mice,?-catenin conditional expression of Nestin-Cre ER: beta-catenin EX3 lo xp/+(Nestin/?-cat EX3)mice were used.The techniques such as Western blot(WB),immunohistochemistry(IHC)and behavioral experiments were used.Results1.After 21 days of SNI surgery,the pain threshold of the feet of the mice decreased significantly.2.Behavioral tests performed within the first 21 days after surgery revealed significant appearance of mechanical and thermal hyperalgesia in mice.3.After 21 days of chronic pain,the number of newborn neurons in the dorsal and ventral hippocampus and the activation of Wnt/?-catenin in neonatal neurons decreased.21 d after chronic pain,adult mice showed obvious anxiety-like behavior and decline in spa tial memory.4.Over activating of Wnt/ ?-catenin signaling pa thway can increase the number of newborn neurons in the dorsal and ventral SGZ of the hippocampus and alleviate the anxiety-like emotion and the impairment of spatial memory.5.Inhibition of Wnt/?-catenin signaling pathway accelerated the development of anxiety-like emotion in mice after SNI.6.Anti-anxiety and anti-depressants will increase the occurrence of newborn neurons and activation of Wnt/?-catenin signaling in SGZ hippoc ampus in nomal mice and chronic pain models.7.The changes of Wnt/?-catenin signaling pathway and the use of Fluoxetine had no obvi ous effect on the pain threshold of mice after SNI.ConclusionUnder the chronic neuropathic pain model,with the decrease of the AHN,anxiety-like emotions appear,learning and memory abilities decrease,and the level of Wnt/?-catenin signaling pathway decreases.However,by regulating the expression of Wnt/?-catenin signaling pathway,it can relieve the anxiety-like behavior of chronic pain and reduce the impairment of spatial memory.With the inhibition of Wnt/?-catenin signaling pathway,it will aggravate the occurrence of anxiety-like emotions.This study suggests that the Wnt/?-catenin signaling pathway in adult mice may play a crucial role in the generation of anxiety and learning and memor y ability after chronic pain.