| ObjectiveDepression has gradually developed into a common and high-incidence disease in modern society,exerting great pressure on both the patients and the society.However,the pathogenesis of depression is complex,and to clarify the pathogenesis of depression is of great significance to the diagnosis and treatment of depression.Taking the similiarity between "liver depression" and depression as the breakthrough point,this study aims to explain the vital mechanism for “liver depression” in TCM and provide theoretical and experimental basis on anti-depression mechanism of Shugan Hewei Decoction according to the pathological and physiological changes in PFC-NAc-VTA neural loop.Methods1.Theoretical study:Analyze the literatures and summarize the historical and clinical manifestations or symptoms similar to depression disease,and untangle the differentiation and manifestation rules in "Treatise on Febrile and Miscellaneous Diseases" to explore the correlation between TCM “liver depression” and modern depression disease;explore the function of PFC-NAc-VTA neural loop in depression disease to verify the correlation between TCM “liver depression” and PFC-NAc-VTA neural loop.2.Experimental study:(1)Modeling:The rats were modelled by using chronic unpredictable mild stress method for 4 weeks,then the Shugan Hewei Decoctions and fluoxetine were administered for 7 day and then the behavior valuation was conducted by open field experiment and forced swimming tests.(2)Detecting:Observe the pathological change in PFC brain region of model group by Nissl staining and collect statistics on the number of normal neuron.The content of DA,GABA and Glu in PFC,NAc and VTA neurons within PFC-NAc-VTA nerve loops of model group were detected by high performance liquid chromatography(HPLC).The relative expression of PSD95 m RNA and NR2 B m RNA in NAc region of rats was detected by RT-PCR.The relative expression of PSD95 and NR2 B in the NAc region of the depressive model rats was observed by the method of Western blot.Results1.Theoretical study:Ancient physicians believed that depressant disease had a close relationship with depressed emotion than other factors,which can be mingled with emotion congestion and dysfunction of organs or blood and body fluid.Clinical syndrome differentiation principle study shows that emotional disorder is the main cause of depression.Liver dysfunction is the core of its pathogenesis.Transmission characteristics of Depression is its affection on the heart,spleen,stomach and other organs.Imbalance of Qi,blood,body fluid,Yin and Yang is the characteristics of pathological changes.Soothing the liver and regulating Qi is the treatment to liver Qi stagnation.Modern medicine suggests that the pathogenesis of depression is associated with dysfunction of the PFC-NAc-VTA neural loop,so the vital mechanism of "liver depression" can be explored from the perspective of PFC-NAc-VTA neural loop.2.Experimental study:Experiment 1:Effect of Shugan Hewei Decoction on Behavior of Depression Model Rats(1)The static time of the open field experiment in the model group was longer than that in the normal saline group,and the difference was statistically significant(P<0.01);and the static time of the Shugan Hewei Decoction group and the fluoxetine group was shortened,which was statistically different compared with the model group(P<0.01);There was no significant difference between the high dose group and the fluoxetine group(P>0.05).(2)The total movement distance of the experiment in the model group was shorter than that of the normal saline group(P<0.01),and the difference was statistically significant(P<0.01).The total movement distance of Shugan Hewei Decoction group and fluoxetine group increased,compared with the model group,and the difference was statistically significant(P<0.01).There was no significant difference between high dose group and fluoxetine group(P>0.05).(3)The central area crossing lattice of open field experiment in the model group is less than that of the normal saline group and the difference between the two groups was statistically significant(P<0.01);In the middle and high dose group and the fluoxetine group,the central area crossing lattice is more than that of the model group and the difference was statistically significant(P<0.01).There was no significant difference between the middle and high dose group and the fluoxetine group(P>0.05).(4)The time of immobilization in forced swimming test in the model group is longer than that of the normal saline group and the difference between the two groups was statistically significant(P<0.01);The time of immobilization of Shugan Hewei Decoction group and fluoxetine group was shorter than that of model group and the difference was statistically significant(P<0.01);There was no significant difference between the middle and high dose group and the fluoxetine group(P>0.05).Experiment 2:Effect of Shugan Hewei Decoction on Pathological Changes of PFC in Depression Model Rats(1)Under light microscopic,Nissl body was dark blue or purple blue,mostly massive or fine particles,distributing around the nucleus or dendrites,and was more obvious near the cell body.The number of neurons in the PFC region of the normal saline group was more,and the Nissl body was darker and distributing around the nucleus.The number of neurons in the PFC region of the model group is relatively less,and the Nissl body is with lighter color,loose distribution,irregular cell morphology,incomplete structure.The number of Nissl bodies reduced or disappeared,part of the nucleus to the side,with the enlargement of cell and the emergence of vacuole area.After treatment of drug intervention,the number of Nissl body in the treatment group increased and was more than that of the model group but less than the normal saline group.The color of Nissl body in the treatment group was darker and the structure was more complete and clear than those of the model group.(2)The number of normal neurons in the PFC region in the model group was less than that of the normal saline group and the difference between the two groups was statistically significant(P<0.01);The number of normal neurons in the PFC region of Shugan Hewei Decoction group and fluoxetine group increased and was more than that of the model group,and the difference was statistically significant(P<0.01).There was no statistically significant difference between the middle and high dose group and the fluoxetine group(P>0.05).Experiment 3:Effect of Shugan Hewei Decoction on DA,GABA and Glu in PFC-NAc-VTA Neuronal Loop of Depression Model Rats(1)In the PFC region,the DA content in the model group decreased,which was significantly different from that in the normal saline group(P<0.01).The DA content in the middle and high dose group and fluoxetine group was higher than that in the model group,and the difference was statistically significant(P<0.05 or P<0.01).There was no significant difference between the high dose group and the fluoxetine group(P>0.05).In the NAc region,the DA content in the model group decreased,which was statistically significantly different from that in the normal saline group(P<0.01);The DA content in each dose group of Shugan Hewei Decoction group and fluoxetine group increased,compared with the model group,and the difference was statistically significant(P<0.05 or P <0.01).Among them,there was no significant difference between the middle dose group and the fluoxetine group(P>0.05).In the VTA region,the DA content in the model group decreased,which was significantly different from that in the normal saline group(P<0.01).The DA content in the low and middle dose group and fluoxetine group was higher than that in the model group(P<0.05 or P<0.01).Among them,the content of DA in the low and middle dose of Shugan Hewei Decoction was lower than that of fluoxetine group and the difference was statistically significant(P<0.01).(2)In the PFC region,the Glu content in the model group increased,compared with the normal saline group,and the difference was statistically significant(P<0.01).The difference of Glu content between Shugan Hewei Decoction group and fluoxetine group was lower than that of the model group(P<0.01).Among them,the content of Glu in low dose of Shugan Hewei Decoction group was lower than that in the fluoxetine group(P<0.05).There was no significant difference between low and high dose groups and fluoxetine group(P>0.05).In the NAc region,the Glu content in the model group decreased,which was significantly different from that in the normal saline group(P<0.01).The levels of Glu in Shugan Hewei Decoction group and fluoxetine group were significantly higher than those in model group(P<0.01).Among them,the difference between the middle dose of Shugan Hewei Decoction group and fluoxetine group was not statistically significant(P>0.05).In the VTA region,the Glu content in the model group increased,which was significantly different from that in the normal saline group(P<0.01).The levels of Glu in Shugan Hewei Decoction group and fluoxetine group were significantly lower than those in model group(P<0.05 or P<0.01).Among them,there was no significant difference between the Shugan Hewei Decoction group and fluoxetine group(P>0.05).(3)In the PFC region,the GABA content in the model group decreased,which was significantly different from that in the normal saline group(P<0.01).The GABA content in the middle dose of Shugan Hewei Decoction group and the fluoxetine group was higher than that in the model group,and the difference was statistically significant(P<0.01).There was no significant difference between the middle dose group and the fluoxetine group(P>0.05).In the NAc region,the GABA content in the model group increased,which was significantly different from that in the normal saline group(P<0.01).The GABA content in the middle and high dose groups of Shugan Hewei Decoction decreased,which was significantly different from that of the model group(P<0.01).There was significant difference between the middle and high dose group and the fluoxetine group(P<0.01).In the VTA region,the GABA content in the model group increased,which was significantly different from that of the normal saline group (P<0.01).The GABA content in the middle dose group and the fluoxetine group was lower than that in the model group and the difference was statistically significant(P<0.01).There was no significant difference between the middle dose group and the fluoxetine group(P>0.05).Experiment 4:Effect of Shugan Hewei Decoction on Expression of PSD95 m RNA and NR2 B m RNA in NAc Region of Depression Model Rats(1)The relative expression of PSD95 m RNA in NAc region of model group decreased,which was significantly different from that of normal saline group(P<0.01).The relative expression of PSD95 m RNA in the NAc region of the Shugan Hewei Decoction group and the fluoxetine group was significantly higher than that in the model group(P<0.01)The relative expression of PSD95 m RNA in middle and high dose group was significantly higher than that in fluoxetine group(P<0.01).There was no statistically significant difference between low dose group and fluoxetine group(P>0.05).(2)The relative expression of NR2 B m RNA in NAc region of model group NAc decreased,which was significantly different from that in normal saline group(P<0.05).The relative expression of NR2 B m RNA in the NAc region of Shugan Hewei Decoction group and fluoxetine group was significantly higher than that in the model group(P<0.01).The expression of NR2 B m RNA in the NAc region of Shugan Hewei Decoction group was higher than that in the fluoxetine group,and the difference was statistically significant(P<0.01).Experiment 5:Effect of Shugan Hewei Decoction on Expression of PSD95 and NR2 B in NAc Region of Depression Model Rats(1)In the NAc region,the relative expression of PSD95 in model group decreased,compared with the normal saline group,and the difference was statistically significant(P<0.01).The relative expression of PSD95 in Shugan Hewei Decoction group and fluoxetine group was statistically significantly higher than that in model group(P<0.01).The relative expression of PSD95 in the middle and high dose group was higher than that in the fluoxetine group(P<0.01).The difference between the low dose group and the fluoxetine group was not statistically significant(P>0.05).(2)The relative expression of NR2 B in NAc region of model group decreased,which was significantly different from that of normal saline group(P<0.01).The relative expression of NR2 B in Shugan Hewei Decoction group and fluoxetine group was significantly higher than that in model group(P<0.01).The expression of NR2 B in the low and middle dose group was higher than that in the fluoxetine group,and the difference was statistically significant(P<0.01).Conclusion1.Theories about "depression" of ancient TCM physicians involve a wide range,including Wu Yun Liu Qi stagnation,viscera stagnation,emotional depression,etc.It was not until the Ming and Qing Dynasties that the concept of depression was closely linked to modern "depression".2.Study on etiology and syndrome distribution principle of TCM depression in recent decade has shown that,emotional disorders is the main cause of depression.Liver dysfunction is the core of its pathogenesis.Transmission characteristics of Depression is its affection on the heart,spleen,stomach and other organs.Imbalance of Qi,blood,body fluid,Yin and Yang is the characteristics of pathological changes.Soothing the liver and regulating Qi is the treatment to liver Qi stagnation.3.The pathological changes of neurons in PFC region,the decrease of DA content,the increase of Glu content,the corresponding changes of GABA content in PFC-NAc-VTA nerve loop,and the descending expression of the synaptic-related proteins PSD95,NR2 B and its m RNA caused by chronic stress may be the pathogenesis of depression.4.Shugan Hewei Decoction can improve the depression status of depressive model rats and reduce the damage degree of neurons in PFC region of depressive model rats and regulate the abnormal ascending or descending of contents of DA,Glu and GABA in PFC-NAc-VTA nerve loop.Shugan Hewei Decoction can also reverse the down-regulation of synaptic-associated protein PSD95,NR2 B and its m RNA in NAc region of model rats,which suggests that,the mechanism of Shugan Hewei Decoction's antidepressant effect,may be regulating the above indexes in the PFC-NAc-VTA neural loop.5.The central nervous system mechanism of "liver depression" in TCM may be related to the pathological changes of neurons in PFC region,the abnormal expression of DA,Glu and GABA in PFC-NAc-VTA neural network and the down-regulation of synaptic-related proteins PSD95,NR2 B and its m RNA in NAc region.6.The results suggest that one of the underlying mechanisms of antidepressant effect of Shugan Hewei Decoction may be achieved by regulating multiple targets in the PFC-NAc-VTA neural loop. |
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