The Role Of GDNF In Neuronal Injury Induced By Chronic Stress

Using the multi-factor chronic unpredictable stressors animal model (foot shock, iceswimming, high-profile, oblique cage, food deprivation, water deprivation, night lighting,21days), the present study investigated the changes of chronic stressors mice behavior and glialcell line-derived neurotrophic factor (GDNF) damage in hippocampus (HP) and prefrontalcortex (PFC). The animals were given different doses of Zhijujieyu-tang and single herb radixcurcumae (RC) and acori graminei rhizome (AGR). Through open-field test and tail-suspensiontest, we observed the changes of emotion, spontaneous activity and the exploratory behavior.Through Morris water maze test, we observed the changes of learning and memory ability.Using HE dye, we observed the changes of morphological structure in HP and PFC. Usingimmunohistochemical method, we detected the expression of GDNF in HP and PFC. The studyaims to explore the relationship between chronic stress and depression, and anti-depressiveeffect and mechanism of Zhijujieyu-tang.Results:1. After stress immediately, the number of horizontal movement, vertical movement andmodification times of the stress group mice were significantly reduced, the central cellresidence time and defecation were remarkably increased, compared with the control groupmice. The12h and24h after stress, the number of horizontal movement, vertical movement andmodification times of stress group mice were reduced, and defecation was increased, but thedifference was not statistically significant, and the central cell residence time was obviouslyadded. A week after stress, the number of horizontal activities and vertical activities of stressgroup mice were significantly reduced, the central cell residence time and defecation wereobviously added.2. After stress immediately, the escape latency of the stress group mice and the control groupmice in the navigation test were significantly decreased. The12h,24h and a week after stress,the escape latency of the control group mice was obviously reduced, and the escape latency ofthe stress group mice had downward trend, but the difference was not statistically significant. Inthe spatial search test, immediately and a week after stress, compared with the control groupmice, the original platform quadrant swimming time of the stress group mice was significantlyshorter. The12h and24h after stress, the original platform quadrant swimming time of thestress group mice was reduced, but not statistically significant. A week after stress, the originalplatform quadrant dwell time of stress group was shortened. 3. The stress group mice in hippocampus and frontal cortex neurons, compared with thecontrol group mice, were decreased, sparsely arranged and cell dyed uneven. The number ofGDNF positive neurons of HP and PFC in the stress group was significantly reduced comparedwith the control group, and the average target gray value was significantly increased. The12hand24h after stress, the number of GDNF positive neurons of the stress group weresignificantly reduced, and the gray value were increased significantly, but not significantdifference. A week after stress the number of GDNF positive neurons of the stress group wereobviously reduced, and the gray value were increased.4.①In the behavioral tests, compared with the control group mice, the opening behaviorindexes of the model group mice were significant differences. Compared with the model group,the opening behavior indexes in the fluoxetine group and medium-dose of Zhijujieyu-tanggroup mice were significant differences, the number of horizontal movement, verticalmovement and the central cell residence time in high-dose group were significantly differences,but the low-dose group, RC group, AGR group hadn’t significant difference.②In the tailsuspension test, compared with the control group mice, the first immobile time and latter4minutes immobile time of the model group mice were significantly increased. Compared withthe model group, the first immobile time and latter4minutes immobile time of fluoxetine groupand medium-dose group were significantly reduced. The first second stationary time in thelow-dose and high-dose group is only significantly reduced. The RC and AGR group had nosignificant difference.③In the Morris water maze test, compared with the control group, theescape latency and the total distance of the model group mice were significantly prolonged, theresident time in the target quadrant of model group mice in the search space test wassignificantly shortened. Compared with model group, the escape latency and the total distanceof the fluoxetine group and Zhijujieyu-tang medicine-dose group mice had a significantdifference. The escape latency in the high-dose group was significantly shorter on the fourthday. The escape latency and total distance in the low-dose group, RC group and AGR groupmice were no significant difference. Compared with model group, the resident time in targetquadrant remarkable increased in the fluoxetine group, low, medium and high dose group micewere prolonged, the resident time in target quadrant in RC group and AGR group mice wereprolonged but no significant difference. The number of through platforms of the control groupmice was significantly more than the model group. Compared with the model group, thenumber of through platforms of the fluoxetine group and drug group were increased, and thenumber of through platforms in the fluoxetine group and the medium-dose group and thehigh-dose group had significant difference.5. In the control group, fluoxetine group, medium and high dose group mice, there are many neurons in CA1, CA3areas and DG area of HP, and the cell structure are intact and sharp edge.Cell nucleus was deeply stained and cell bodies located in the center. The neuronal morphologyin the prefrontal cortex is regular and uniform dyeing. The cells in the low-dose group, the RCgroup and AGR group mice of HP and PFC arranged relatively sparse, loose, and lighterstaining, and its number has decreased. In the model group mice, the HP and PFC nerve celldeformation, with some atrophy, irregular shape, lightly stained cells, uneven coloring and thenumber of cells decreased.6. The number of GDNF positive cells in HP and PFC of the model group was significantlyreduced, and the average target gray value was increased significantly, compared with thecontrol group. Compared with the model group, the number of GDNF positive cells in HP andPFC in the fluoxetine group and medicine-dose group mice were increased, and the averagetarget gray value were declined, and the medium, high doses group have significantly different,but low dose group, RC group and AGR group mice had no significant difference.Conclusions:1. Chronic stress can significantly weaken spontaneous behavior and ability to explore in thenew environment, and damage spatial learning and memory ability.2. Chronic stress can cause significant morphological changes in the HP and PFC neurons,and GDNF expression to significantly reduce.3. Zhijujieyu-tang can significantly improve the behavioral changes and spatial learning-memory ability in depression model mice induced by chronic stress, and it shows someantidepressant effect.4. Zhijujieyu-tang can increase the expression of GDNF of HP and PFC in depression modelgroup mice, and lower the brain neuronal damage. This may be one of the mechanism ofantidepressant-like effects of Zhijujieyu-tang.