| Depression disorder is the main type of the mood disorder,is a kind of clinical syndrome or state,which cardinal symptom is persistent depressing mood.The morbidity rate of depressive disorder increases sharply,because of the social and environmental factors.World health organization predicted,until 2020,the depressive disorder would have become the second largest disease,which had a strong impact on human physical and mental health.The harm of depressive disorder to the patients mainly includes depressing mood,retardation of thinking,decline of volitional activity,lesion of cognitive function and somatization.However,the most dangerous point is the suicide risk caused by the passive and pessimistic emotion.The pathogen of depressive disorder has not been clear so far.There are some leading hypotheses in the current state of knowledge of the neural and molecular mechanisms of depression,such as neural circuitry,monoamines system,neurotrophins and neurogenesis,neuroendocrine and neuroimmune interactions etc.A large body of post-mortem and neuro-imaging studies of depressed patients have reported the changes in the prefrontal cortex and the hippocampus,regions thought to mediate the cognitive aspects of depression,such as feelings of worthlessness and guilt.The monoamine hypothesis of depression,which posits that the depression is caused by decreased monoamine function in the brain,originated from early clinical observations.Volumetric decreases observed in the hippocampus and other forebrain regions in subsets of depressed patients have supported a popular hypothesis for depression involving decrements in neurotrophic factors that also regulate plasticity within adult brain.The neuroendocrine and neuroimmune interactions hypothesis delineate the intercellular interactions involved between brain macrophages(microglia),glia and neurons within neural circuitry.At present,the first choice of curing depressive disorder,especially the medium and major depressive disorder,was still the pharmacotherapy.All kinds of antidepressant existed problems more or less,such as slow efficacy,side effect and bad obedience.Moreover,psychotherapy and physiotherapy are also used in depressive disorder separately or combined.Depressive disorder had become a challenge of research in neurology for its complicated pathogen,nonstandard diagnosis and poor effect.There were three levels in exploring the internal mechanism of depressive disorder.Genetic,molecular,and neuro-imaging studies continue to contribute to advances in our understanding of the neurobiological basis of major depressive disorder.The research based on gene was known as the most fundamental one,as secretion of hormone and establishment of cerebrum circuit directly related to regulation of gene expression.The procedure of regulating gene expression was extremely exact.In such procedure,the transcription factor(TF)played an important role.With chromatin regulatory factor and epigenetic regulatory factor,transcription factor regulated many life procedures,such as proliferation,differentiation,aging and death of cell.It was also closely related to cytothesis and neoplasia.Peroxisome proliferator-activated receptor(PPARs),a kind of ligand-dependent nuclear transcription factors,was one of the nuclear receptor super family type 2 members.PPARs act in a similar manner to other nuclear hormone receptors.First,they bind a specific element in the promoter region of target genes.PPAR and some other nuclear hormone receptors bind the promoter only as a heterodimer with the receptor for 9-cis retinoic acid,RXR(retinoid X receptor).Second,they activate transcription in response to binding of the hormone(ligand).For the PPAR-RXR heterodimer,binding of the ligand of either receptor can activate the complex,but binding of both ligands simultaneously is more potent.Three PPAR isotypes have been identified:a,(3 and ? In the three isotypes of PPARs,PPARy was popular in neurology research.PPARy,which was found in adipocyte firstly,helped regulating the glycolipid energy metabolism,increasing the insulin sensitivity,keeping the steady state.In the following studies,it was demonstrated that PPARy participated in the regulation of renal edema,cancer and atherosclerosis.In the research of neurology,PPARy presented a variety of specific expression.In the normal adult brain,the expression level of PPARy was very low.Meanwhile,it was notably increased in the embryonic nervous system and brain with lesion.This characteristic expression presented PPARy might play an important role in the neurodevelopment and the repair procedure after never injury.Plenty of research articles reported that PPAR? acted out the neuroprotection in ischemic stroke,spinal cord injury and nervous system degenerative diseases,such as Alzheimer's disease,Parkinson's disease.The neuroprotection of PPAR? included multiple mechanisms.In the metabolic regulation,PPARy corrected the metabolic disorder by improving the insulin sensitivity and increasing the glucose use.In the anti-inflammatory,PPARy relieved the inflammatory response by inhibiting the proinflammatory factor activity and the neuroglia activation.In the oxidative stress,PPARy inhibited the oxidase activity and promoted the antioxidase activity,reducing the free radical.In the anti-apoptosis,PPAR? activated the survival signal path,keeping the cytomembrane and the mitochondrial membrane stable.In addition,PPARy also took part in the neuroregulation,such as the HPA axis function and the feeding behavior.There are some investigations confirmed that the neuronal PPAR? acted the neuroprotection without the neuroglia activation by the transgene animal model.Neuroinflammatory,neuron death and HPA axis dysfunction all took part in the depressive disorder.The research of depressive disorder based on PPAR? was imperative.There were several research articles reported PPARy agonist decreased the depression-like behavior in recent years.We expected to prove if the neuronal PPAR? participate regulating the depression-like behavior,and to find out its mechanism.Our results will provide the theoretical basis for the clinical diagnosis,the treatment and the development of new anti-depression drug.In order to observe the PPAR? content change from depressive disorder,we designed the following experiments.According to the experiment environment and equipment and the results of preliminary experiment,through comparing we chose the chronic social defeat stress(CSDS)model as the depression animal model of our experiment.Male C57BL/6J mice,10week,23g-25g,were grouped randomly.According to the standard method of CSDS,the animal model was prepared.After molding,the interaction time and the ratio of two groups were tested with the social interaction test.The mice whose ratio was less than 0.9 were defined as the susceptible group,and the ones whose ratio was more than 1.1 were defined as the resilient group.The cerebrum was isolated acutely,without the cerebellum,midbrain,brainstem and olfactory bulb.The protein and mRNA level of PPARy was tested by western blot and Q-PCR separately.We found that there was no significant difference between the control and the susceptible group in the expression of PPARy.While the expression of PPARy in the resilient group increased remarkably comparing with another two groups.In the following study,we tested the PPAR? expression in several encephalic regions germane with the depression in the same methods.The difference among the three groups was not significant in the hippocampus.Iin the prefrontal cortex,the PPAR? expression in the susceptible group decreased remarkably comparing with its expression in control group;the difference between the PPARy expression in the resilient group and it in control group was not significant.These results indicated that the high level of PPARy expression was associated with the anti-depression-like behavior.However,the depression-like behavior may not be involved in the change of PPARy expression.In order to explore if the PPARy agonist is effective for CSDS model,we designed the following experiments.After 10-day molding,the mice of the treatment group were grouped into 3 groups,which were received placebo,rosiglitazone and imipramine respectively.After 10 successive days of intraperitoneal injection,these mice were arranged to do the social interaction test.The mean time in interaction zone in each group acted the standard valuating the anti-depressive effect of the drug or placebo.The mice of rosiglitazone group showed less avoidance behavior caused by repeated social defeat stress than the mice of placebo group,while the effect of imipramine had not come out.These results indicated that the PPARy agonist reduced the depression-like behavior in the CSDS depression model.In order to probe if the lack of PPARy modulating the occurrence of depression-like behavior,we established the pyramidal neuron conditional PPARy knockout mice in two kinds of transgenic mouse(PPARy loxp/loxp and CamKII-cre).Through the genotype and phenotype identification,the knockout mice strain we established was successful.We tested the knockout mice in the behavior tests,observing presence and absence of depression-like behavior.In the open field test,the KO mice presented normal motor ability and anxiety level.In the social interaction test,the interaction time of the KO mice decreased significantly.This result indicated that the KO mice performed the communication disorder phenotype.Because of the impaired ability of the social interaction,it was unsuitable for molding in the CSDS.Then,we did some other depression-related tests.In the forced swimming test(FST),the immobility time of the KO mice increased significantly.And the trend of high level of immobility time could be rescued by the classical anti-depression drug imipramine.These results indicated that the absence of PPAR? in the pyramidal neurons lead to the occurrence of depression-like behavior.In the tail suspension test(TST)and sucrose preference test(SPT),the immobility time and the sucrose preference(SP)of the KO and the control mice had no significantly difference.This might be caused by the different mechanism of FST and TST.These differences might be caused by the.different mechanisms of FST,TST and SPT.It also showed us that the modulation of PPAR? toward the depression-like behavior was specific.The following conclusions might be gained from our experiment results.In the CSDS depression model,the PPARy expression in the whole brain cortex had changed.The change was relatively obvious in PFC,while in hippocampus thechange was few.The PPAR? agonist decreased the occurrence rate of the depression-like behavior in the CSDS depression model.The lack of PPAR? in pyramidal neuron participated in modulating the occurrence of depression-like behavior. |
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