| Background:A large number of studies have shown that major depressive disorder（MDD）is closely related to dendritic atrophy and loss of dendritic spines,especially in brain regions related to emotions,including the hippocampus.Stressors,all internal and external environmental stimuli that can cause the body to produce a stress response,are divided into endogenous stressors（produced inside the individual）and exogenous stressors（produced outside the individual）according to their sources;according to the duration of stressors,stressors can be divided into acute stressors and chronic stressors.The core symptom of depression is persistent upset,accompanied by loss of will,sleep dysfunction,cognitive impairment and gastrointestinal dysfunction,which brings a huge burden to the society.At present,the pathophysiological mechanism of depression is not very clear.Among them,the change of neuroplasticity is closely related to the occurrence and development of depression.The core content of neuroplasticity is synaptic connection,which is also the main way of information transmission between neurons.Synaptic plasticity is the ability to change the shape,number and function of synapses under certain conditions,including changes in morphological structure and transmission efficiency,so the changes of synaptic plasticity are directly related to the occurrence and development of depression.Moreover,there is a two-way relationship between cardiovascular disease and depression,depression will cause damage to the cardiovascular system,at the same time,cardiovascular system damage will also cause pathological changes of depression.The previous research of our research group found that the traditional Chinese medicine prescription Chaihu-shugansan（CSS）and its absorbing ingredient Meranzin hydrate（MH）not only improve depression,but also promote motivation（improve intestinal propulsion and gastric emptying）and dilate blood vessels（increase coronary blood flow）.Objective:The purpose of this study was to evaluate the psychopathological changes of dentate gyrus of hippocampus in acute and chronic depression models of Chaihu-shugansan（CSS）and its absorbing component meranzin hydrate（MH）on the basis of antidepressant,promoting force and vasodilation,and to research possible mechanism.And to study whether cardiovascular injury（myocardial infarction and atherosclerosis）has an effect on neurons in the dentate gyrus,so as to make up for the shortcomings of the lack of physiological and pathological mechanisms of depression..Methods:The acute stress model of SD rats was established by 15min acute forced swimming（AFS）.Golgi staining was performed at different time points（1h,12h,24h）.AFS12h.which had the most obvious effect,was selected for administration.The experiment was divided into control group,AFS12h group,CSS（30g/kg）group,MH（9.18mg/kg）group and fluoxetine（20mg/kg）group.SD rats were subjected to chronic unpredictable mild stress（CUMS）for three weeks,which were divided into control group,CUMS group,CSS（3g/kg）group,MH（6.18mg/kg）group and fluoxetine（10mg/kg）group.Firstly,Golgi staining was used to study the morphology of neurons in hippocampal dentate gyrus,westernblot was used to detect the expression of synaptic related proteins BDNF,GluAl and PSD95 in hippocampal dentate gyrus,electron microscope was used to observe the synaptic ultrastructural changes in hippocampal dentate gyrus,ELISA was used to detect the levels of CORT,5-HT1A and ghrelin in serum,and HE staining was used to detect the damage of myocardial cells caused by stress.In addition,the CUMS model also verified the antidepressant effects of CSS and MH through depression-related behavioral tests（opening test and forced swimming test）.The levels of serum inflammatory factors（IL-β,IL-6,TNF-α）were measured by ELISA,and the myocardial injury index（CK-MB）and myocardial apoptosis index（Caspase3）were measured by western blot.In addition,we also studied the model of acute myocardial infarction,24 hours after myocardial infarction,the changes of neurons were observed by Golgi staining.And the model of chronic atherosclerosis in APOE-/-rats,after three months,Golgi staining was used to observe the changes of neurons,while in the model of chronic atherosclerosis in APOE-/-mice,CSS（9g/kg）and its absorbent component MH（10mg/kg）were given daily,and two months later,Golgi staining was used to observe the changes of neurons.Results:Acute experiment:Rats were subjected to different time-dependent AFS stress,12h after forced swimming stress had the most significant effect on neurons,showing that the density of dendritic spines was significantly reduced and the length of neurons became shorter,but the number of dendritic branches,namely the complexity of dendrites,did not change.It was found that CSS and MH could increase synaptic density,significantly decrease the levels of serum CORT and 5-HT1a,and increase the level of ghrelin related to gastrointestinal depression.We also studied the indicators related to synaptic plasticity and found that CSS could fine-tune neurotrophin BDNF,postsynaptic density protein PSD95 and GluAl,but had little effect.MH can significantly up-regulate the level of BDNF and increase GluAl to play the role of antidepressant and increase the length of neurons;after administration of CSS and MH,it can significantly reverse the abnormalities caused by the above stress.Cardiac HE staining showed that the myocardial fiber tissue of the model group was light stained and the infarcted area was grayish white.Administration of CSS and MH could improve the abnormality caused by acute stress.Chronic experiment:CSS and MH could alleviate the depressive behavior induced by CUMS,accompanied by morphological changes of hippocampal neurons.After one week of treatment with CSS and MH,the length and complexity of（DG）dendrites and the density of dendritic spines in hippocampal dentate gyrus remarkably increased.The induction of CUMS down-regulated the level of BDNF,while MH reversed this trend.CSS and MH decreased the expression of serum pro-inflammatory cytokines（IL-1β,IL-6 and TNF-α）and serum CORT and 5-HT1A in rats exposed to CUMS.In addition,MH also improved the loss of hippocampal synaptic-related protein GluA1 induced by CUMS.In addition,the myocardial injury of CUMS rats treated with CSS and MH was improved compared with CUMS group,the Caspase3 of cardiomyocytes decreased,and MH also reduced the level of CK-MB.After three weeks of chronic modeling,the morphology of rat cardiomyocytes was observed by HE staining.In the control group,the myocardial tissue structure was clear and no obvious abnormality;in the CUMS group,the epicardial myocardial fiber cells were broken and stained grayish white,and the infarction was obvious;After the administration of CSS and MH,the myocardial fiber epicardium was slightly infarcted and the injury was improved.24h after acute myocardial infarction,Golgi staining showed that the length of hippocampal dentate gyrus became shorter and the density of dendritic spines decreased,but it had no effect on the number of dendritic branches and did not affect the complexity of neurons.After three months of high-fat feeding,it was found that the dendritic length,the number of branches and the density of dendritic spines decreased in APOE-/-rats.After feeding APOE-/-mice with high fat for two months,the dendritic length,number of branches and density of dendritic spines decreased compared with the control group.CSS could increase the length of dendrites,but had no effect on the number of dendritic branches and the density of dendritic spines.MH could reverse the abnormality.Conclusion:Both acute and chronic depression models can change the morphology of hippocampal dentate gyrus neurons,shorten the length of dendrites,decrease the density of dendritic spines,and change the plasticity of hippocampal neurons after stress.CSS and MH may have antidepressant effects through anti-inflammation,synaptic plasticity,reducing serum CORT and 5-HT1 A,and increasing ghrelin levels,and have protective effects on the heart. |
PDF Full Text Request