The Role And Mechanism Of Lateral Habenula In Improving The Sleep Activity By Agomelatine In Depressed Mice

EEG studies have shown that there are some characteristic changes in patients with depression.Among all these changes,the abnormality of REM sleep is an important of changes in the EEG of patients with depression.It can indicate the severity of the disease and indicate the effect of individualized antidepressant treatment.Studies have pointed out that if the sleep quality of patients with depression can be improved,the recurrence rate and severity of depression can be better reduced.Therefore,it is of great significance to study the changes in sleep and wakefulness in depression and its regulatory mechanism.More and more increasing evidence shows that the abnormal activity of LHb is related to the onset of depression,LHb is an important brain region for depression-related research,which is also closely related to sleep.Ago is a new type of antidepressant drug,which has obvious therapeutic effects on depressed mood in depressed person,can effectively improve the quality of sleep and regulate biological rhythms.However,the related brain regions and molecular mechanisms of its antidepressant effects are still not completely clear.CRS can better simulate the onset of depression in humans,but the exact relationship between CRS and various sleep phases is still unclear.Using animal models,there are fewer studies about the relationship between Ago and sleep disorder caused by depression.The effect of AGO on CRS-induced sleep disorders is unknown.This experiment used a depression-like mouse model established by the chronic restraint stress(chronic restraint stress,CRS)method.First,the open field test(OFT),the forced swimming test(FST),the tail suspension test(TST)and the EEG-EMG recording technology detected whether the depression-like mouse model is successfully established.Using chemogenetic methods,specifically inhibited the activity of LHb neurons in vivo to observe the effect on sleep-wake state.After intraperitoneal injection of Ago into CRS mice,we used open field test,forced swimming test and tail suspension test to detect depression-like behaviors,and used EEG-EMG recording technology to detect the effect on its sleep-wake state.In addition,after intraperitoneal injection of Ago to CRS mice,western blotting was used to detect the expression of BDNF and c-Fos protein in LHb.We found that chemogenetic inhibition of LHb neuron activity significantly reduced the time of REM sleep and improved the sleep disorder induced by CRS.Intraperitoneal injection of Ago significantly increased the time spent in the central area in the open field test,reduced the immobile time in the forced swimming test and the tail suspension test,and also significantly reduced the time of REM sleep.Intraperitoneal injection of Ago down-regulated the expression of BDNF and c-Fos in LHb.These results collectively indicate that chemogenetic inhibition of LHb neuron activity by chemical genetic methods can improve sleep disorders in CRS depression model mice;intraperitoneal injection of Ago can improve depression-like behaviors and sleep disorders in CRS depression model mice;Ago improves depression-like behaviors and sleep disorders in CRS depression model mice may be achieved by down-regulating the expression of BDNF in LHb,thereby inhibiting the activity of LHb neurons.