The tree shrew(Tupaia belangeri)has long been proposed as a suitable alternative to non-human primates(NHPs)in biomedical and laboratory research due to its close evolutionary relationship with primates.In recent year...The tree shrew(Tupaia belangeri)has long been proposed as a suitable alternative to non-human primates(NHPs)in biomedical and laboratory research due to its close evolutionary relationship with primates.In recent years,significant advances have facilitated tree shrew studies,including the determination of the tree shrew genome,genetic manipulation using spermatogonial stem cells,viral vector-mediated gene delivery,and mapping of the tree shrew brain atlas.However,the limited availability of tree shrews globally remains a substantial challenge in the field.Additionally,determining the key questions best answered using tree shrews constitutes another difficulty.Tree shrew models have historically been used to study hepatitis B virus(HBV)and hepatitis C virus(HCV)infection,myopia,and psychosocial stress-induced depression,with more recent studies focusing on developing animal models for infectious and neurodegenerative diseases.Despite these efforts,the impact of tree shrew models has not yet matched that of rodent or NHP models in biomedical research.This review summarizes the prominent advancements in tree shrew research and reflects on the key biological questions addressed using this model.We emphasize that intensive dedication and robust international collaboration are essential for achieving breakthroughs in tree shrew studies.The use of tree shrews as a unique resource is expected to gain considerable attention with the application of advanced techniques and the development of viable animal models,meeting the increasing demands of life science and biomedical research.展开更多
BACKGROUND Cyclic vomiting syndrome(CVS)is a chronic functional gastrointestinal disorder involving the gut–brain interaction that is characterized by recurring episodes of nausea,vomiting,abdominal pain,and interspe...BACKGROUND Cyclic vomiting syndrome(CVS)is a chronic functional gastrointestinal disorder involving the gut–brain interaction that is characterized by recurring episodes of nausea,vomiting,abdominal pain,and interspersed complete normal periods.Superior mesenteric artery(SMA)syndrome(SMAS)is a vascular condition in which the horizontal portion of the duodenum is compressed due to a reduced angle between the aorta and the SMA.This condition presents with symptoms similar to CVS,posing challenges in distinguishing between the two and often resulting in misdiagnosis or inappropriate treatment.CASE SUMMARY A 20-year-old female patient presented with recurrent episodes of vomiting and experienced a persistent fear of vomiting for the past 2 years.She adopted conscious dietary restrictions,which led to severe malnutrition.Initially,she was diagnosed with SMAS,as revealed by computed tomography angiography.Despite efforts to increase the angle between the aorta and the SMA through weight gain,her vomiting did not improve.Finally,she was diagnosed with comorbidities including CVS,SMAS and anxiety disorder.She underwent comprehensive interventions,including enteral and parenteral nutritional supplementation,administration of antiemetic and anti-anxiety agents,and participation in mindfulness-based cognitive therapy.The patient eventually experienced a notable improvement in both body weight and clinical symptoms.CONCLUSION We present a rare case of CVS in an adult complicated with SMAS and propose additional treatment with nutritional support,pharmacological intervention,and psychotherapy.展开更多
Background Elevated platelet count(PLTc)is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis.However,the impact of antipsychotic medications on PLTc and its asso...Background Elevated platelet count(PLTc)is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis.However,the impact of antipsychotic medications on PLTc and its association with symptom improvement remain unclear.Aims We aimed to investigate changes in PLTc levels following antipsychotic treatment and assess whether PLTc can predict antipsychotic responses and metabolic changes after accounting for other related variables.Methods A total of 2985 patients with schizophrenia were randomised into seven groups.Each group received one of seven antipsychotic treatments and was assessed at 2,4 and 6 weeks.Clinical symptoms were evaluated using the positive and negative syndrome scale(PANSS).Additionally,we measured blood cell counts and metabolic parameters,such as blood lipids.Repeated measures analysis of variance was used to examine the effect of antipsychotics on PLTc changes,while structural equation modelling was used to assess the predictive value of PLTc on PANSS changes.Results PLTc significantly increased in patients treated with aripiprazole(F=6.00,p=0.003),ziprasidone(F=7.10,p<0.001)and haloperidol(F=3.59,p=0.029).It exhibited a positive association with white blood cell count and metabolic indicators.Higher baseline PLTc was observed in non-responders,particularly in those defined by the PANSS-negative subscale.In the structural equation model,PLTc,white blood cell count and a latent metabolic variable predicted the rate of change in the PANSS-negative subscale scores.Moreover,higher baseline PLTc was observed in individuals with less metabolic change,although this association was no longer significant after accounting for baseline metabolic values.Conclusions Platelet parameters,specifically PLTc,are influenced by antipsychotic treatment and could potentially elevate the risk of venous thromboembolism in patients with schizophrenia.Elevated PLTc levels and associated factors may impede symptom improvement by promoting inflammation.Given PLTc’s easy measurement and clinical relevance,it warrants increased attention from psychiatrists.Trial registration number ChiCTR-TRC-10000934.展开更多
Acute administration of MK-801(dizocilpine),an N-methyl-D-aspartate receptor(NMDAR)antagonist,can establish animal models of psychiatric disorders.However,the roles of microglia and inflammation-related genes in these...Acute administration of MK-801(dizocilpine),an N-methyl-D-aspartate receptor(NMDAR)antagonist,can establish animal models of psychiatric disorders.However,the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown.Here,we found rapid elimination of microglia in the prefrontal cortex(PFC)and hippocampus(HPC)of mice following administration of the dual colony-stimulating factor 1 receptor(CSF1R)/c-Kit kinase inhibitor PLX3397(pexidartinib)in drinking water.Single administration of MK-801 induced hyperactivity in the open-field test(OFT).Importantly,PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801.However,neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity.Importantly,microglial density in the PFC and HPC was significantly correlated with behavioral changes.In addition,common and distinct glutamate-,GABA-,and inflammation-related gene(116 genes)expression patterns were observed in the brains of PLX3397-and/or MK-801-treated mice.Moreover,10 common inflammation-related genes(CD68,CD163,CD206,TMEM119,CSF3R,CX3CR1,TREM2,CD11b,CSF1R,and F4/80)with very strong correlations were identified in the brain using hierarchical clustering analysis.Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes(NLRP3,CD163,CD206,F4/80,TMEM119,and TMEM176a),but not glutamate-or GABA-related genes in PLX3397-and MK-801-treated mice.Thus,our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist,which is associated with modulation of immune-related genes in the brain.展开更多
Over the last decade the combination of brain neuroimaging techniques and graph theoretical analysis of the complex anatomical and functional networks in the brain have provided an exciting new platform for exploring ...Over the last decade the combination of brain neuroimaging techniques and graph theoretical analysis of the complex anatomical and functional networks in the brain have provided an exciting new platform for exploring the etiology of mental disorders such as schizophrenia. This review introduces the current status of this work, focusing on the topological properties of human brain networks - called 'small-world brain networks'- and on the disruptions in these networks in schizophrenia. The evidence supporting the findings of reduced efficiency of information exchange in schizophrenia both within local brain regions and globally throughout the brain is reviewed and the potential relationship of these changes to cognitive and clinical symptoms is discussed. Finally we propose some suggestions for future research.展开更多
Major depressive disorder(MDD)is a chronic,generally episodic and debilitating disease that affects an estimated 300 million people worldwide,but its pathogenesis is poorly understood.The heritability estimate of MDD ...Major depressive disorder(MDD)is a chronic,generally episodic and debilitating disease that affects an estimated 300 million people worldwide,but its pathogenesis is poorly understood.The heritability estimate of MDD is 30–40%,suggesting that genetics alone do not account for most of the risk of major depression.Another factor known to associate with MDD involves environmental stressors such as childhood adversity and recent life stress.Recent studies have emerged to show that the biological impact of environmental factors in MDD and other stress-related disorders is mediated by a variety of epigenetic modifications.These epigenetic modification alterations contribute to abnormal neuroendocrine responses,neuroplasticity impairment,neurotransmission and neuroglia dysfunction,which are involved in the pathophysiology of MDD.Furthermore,epigenetic marks have been associated with the diagnosis and treatment of MDD.The evaluation of epigenetic modifications holds promise for further understanding of the heterogeneous etiology and complex phenotypes of MDD,and may identify new therapeutic targets.Here,we review preclinical and clinical epigenetic findings,including DNA methylation,histone modification,noncoding RNA,RNA modification,and chromatin remodeling factor in MDD.In addition,we elaborate on the contribution of these epigenetic mechanisms to the pathological trait variability in depression and discuss how such mechanisms can be exploited for therapeutic purposes.展开更多
To the Editor:Major depressive disorder(MDD)is a common mood disorder that contributes considerably to disability worldwide.Abnormalities in either structural connectivity or functional connectivity in the brains of p...To the Editor:Major depressive disorder(MDD)is a common mood disorder that contributes considerably to disability worldwide.Abnormalities in either structural connectivity or functional connectivity in the brains of patients with MDD have been widely reported,which greatly extends our knowledge of the pathophysiology of MDD.展开更多
The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients wi...The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia.We used prepulse inhibition(PPI)and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls.Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions.Concurrently,we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in firstepisode treatment-naı¨ve schizophrenic patients(n=117)and in age-and sex-matched healthy controls(n=86).We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia.Significant correlations between gray matter volumes(GMVs)in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice.Furthermore,these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients.The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients.Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation,providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.展开更多
Despite a growing neuroimaging literature on the pathophysiology of major depressive disorder(MDD),repro-ducible findings are lacking,probably reflecting mostly small sample sizes and heterogeneity in analytic approac...Despite a growing neuroimaging literature on the pathophysiology of major depressive disorder(MDD),repro-ducible findings are lacking,probably reflecting mostly small sample sizes and heterogeneity in analytic approaches.To address these issues,the Depression Imaging REsearch ConsorTium(DIRECT)was launched.The REST-meta-MDD project,pooling 2428 functional brain images processed with a standardized pipeline across all participating sites,has been the first effort from DIRECT.In this review,we present an overview of the moti-vations,rationale,and principal findings of the studies so far from the REST-meta-MDD project.Findings from the first round of analyses of the pooled repository have included alterations in functional connectivity within the default mode network,in whole-brain topological properties,in dynamic features,and in functional lat-eralization.These well-powered exploratory observations have also provided the basis for future longitudinal hypothesis-driven research.Following these fruitful explorations,DIRECT has proceeded to its second stage of data sharing that seeks to examine ethnicity in brain alterations in MDD by extending the exclusive Chinese original sample to other ethnic groups through international collaborations.A state-of-the-art,surface-based preprocessing pipeline has also been introduced to improve sensitivity.Functional images from patients with bipolar disorder and schizophrenia will be included to identify shared and unique abnormalities across diag-nosis boundaries.In addition,large-scale longitudinal studies targeting brain network alterations following antidepressant treatment,aggregation of diffusion tensor images,and the development of functional magnetic resonance imaging-guided neuromodulation approaches are underway.Through these endeavours,we hope to accelerate the translation of functional neuroimaging findings to clinical use,such as evaluating longitudinal effects of antidepressant medications and developing individualized neuromodulation targets,while building an open repository for the scientific community.展开更多
Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) ...Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in Chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.展开更多
Schizophrenia is a severe and complex mental disorder 111.Neuroimaging offers a powerful window for identifying the brain biomarkers and investigating the neuropathological mechanisms of psychiatric disorders.A study ...Schizophrenia is a severe and complex mental disorder 111.Neuroimaging offers a powerful window for identifying the brain biomarkers and investigating the neuropathological mechanisms of psychiatric disorders.A study led by Professors Jiang and Liu,published recently in Nature Medicine,developed a new neuroimaging biomarker to characterize striatal dysfunction based on a multi-site functional MRI dataset with>1000 individuals.They show that this biomarker can distinguish individuals with schizophrenia and predict the short-term effects of antipsychotic treatmem[2].展开更多
基金supported by the STI2030-Major Projects(2021ZD0200900 to Y.G.Y.)"Light of West China" Program of the Chinese Academy of Sciences(xbzg-zdsys-202302 to Y.G.Y.)
文摘The tree shrew(Tupaia belangeri)has long been proposed as a suitable alternative to non-human primates(NHPs)in biomedical and laboratory research due to its close evolutionary relationship with primates.In recent years,significant advances have facilitated tree shrew studies,including the determination of the tree shrew genome,genetic manipulation using spermatogonial stem cells,viral vector-mediated gene delivery,and mapping of the tree shrew brain atlas.However,the limited availability of tree shrews globally remains a substantial challenge in the field.Additionally,determining the key questions best answered using tree shrews constitutes another difficulty.Tree shrew models have historically been used to study hepatitis B virus(HBV)and hepatitis C virus(HCV)infection,myopia,and psychosocial stress-induced depression,with more recent studies focusing on developing animal models for infectious and neurodegenerative diseases.Despite these efforts,the impact of tree shrew models has not yet matched that of rodent or NHP models in biomedical research.This review summarizes the prominent advancements in tree shrew research and reflects on the key biological questions addressed using this model.We emphasize that intensive dedication and robust international collaboration are essential for achieving breakthroughs in tree shrew studies.The use of tree shrews as a unique resource is expected to gain considerable attention with the application of advanced techniques and the development of viable animal models,meeting the increasing demands of life science and biomedical research.
基金Supported by 1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,No.ZYJC21004.
文摘BACKGROUND Cyclic vomiting syndrome(CVS)is a chronic functional gastrointestinal disorder involving the gut–brain interaction that is characterized by recurring episodes of nausea,vomiting,abdominal pain,and interspersed complete normal periods.Superior mesenteric artery(SMA)syndrome(SMAS)is a vascular condition in which the horizontal portion of the duodenum is compressed due to a reduced angle between the aorta and the SMA.This condition presents with symptoms similar to CVS,posing challenges in distinguishing between the two and often resulting in misdiagnosis or inappropriate treatment.CASE SUMMARY A 20-year-old female patient presented with recurrent episodes of vomiting and experienced a persistent fear of vomiting for the past 2 years.She adopted conscious dietary restrictions,which led to severe malnutrition.Initially,she was diagnosed with SMAS,as revealed by computed tomography angiography.Despite efforts to increase the angle between the aorta and the SMA through weight gain,her vomiting did not improve.Finally,she was diagnosed with comorbidities including CVS,SMAS and anxiety disorder.She underwent comprehensive interventions,including enteral and parenteral nutritional supplementation,administration of antiemetic and anti-anxiety agents,and participation in mindfulness-based cognitive therapy.The patient eventually experienced a notable improvement in both body weight and clinical symptoms.CONCLUSION We present a rare case of CVS in an adult complicated with SMAS and propose additional treatment with nutritional support,pharmacological intervention,and psychotherapy.
基金This work was partly supported by the National Natural Science Foundation of China(grant number 81920108018 to TL,82001409 to YZhang)the Key R&D Programme of Zhejiang(2022C03096 to TL)Project for Hangzhou Medical Disciplines of Excellence&Key Project for Hangzhou Medical Disciplines(grant number 202004A11 to TL).
文摘Background Elevated platelet count(PLTc)is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis.However,the impact of antipsychotic medications on PLTc and its association with symptom improvement remain unclear.Aims We aimed to investigate changes in PLTc levels following antipsychotic treatment and assess whether PLTc can predict antipsychotic responses and metabolic changes after accounting for other related variables.Methods A total of 2985 patients with schizophrenia were randomised into seven groups.Each group received one of seven antipsychotic treatments and was assessed at 2,4 and 6 weeks.Clinical symptoms were evaluated using the positive and negative syndrome scale(PANSS).Additionally,we measured blood cell counts and metabolic parameters,such as blood lipids.Repeated measures analysis of variance was used to examine the effect of antipsychotics on PLTc changes,while structural equation modelling was used to assess the predictive value of PLTc on PANSS changes.Results PLTc significantly increased in patients treated with aripiprazole(F=6.00,p=0.003),ziprasidone(F=7.10,p<0.001)and haloperidol(F=3.59,p=0.029).It exhibited a positive association with white blood cell count and metabolic indicators.Higher baseline PLTc was observed in non-responders,particularly in those defined by the PANSS-negative subscale.In the structural equation model,PLTc,white blood cell count and a latent metabolic variable predicted the rate of change in the PANSS-negative subscale scores.Moreover,higher baseline PLTc was observed in individuals with less metabolic change,although this association was no longer significant after accounting for baseline metabolic values.Conclusions Platelet parameters,specifically PLTc,are influenced by antipsychotic treatment and could potentially elevate the risk of venous thromboembolism in patients with schizophrenia.Elevated PLTc levels and associated factors may impede symptom improvement by promoting inflammation.Given PLTc’s easy measurement and clinical relevance,it warrants increased attention from psychiatrists.Trial registration number ChiCTR-TRC-10000934.
基金supported by the National Natural Science Foundation of China(81920108018,82230046,82001432)Ministry of Science and Technology of the People’s Republic of China(2022ZD0211700,2022ZD0205200)+5 种基金Natural Science Foundation of Sichuan Province(2022NSFSC1607)Key Research and Development Program of Science and Technology Department of Sichuan Province(22ZDYF1531,22ZDYF1696)Key R&D Program of Zhejiang(2022C03096)Special Foundation for Brain Research from Science and Technology Program of Guangdong(2018B030334001)China Postdoctoral Science Foundation(2020TQ0213,2020M683319)Sichuan University(2022SCUH0023)。
文摘Acute administration of MK-801(dizocilpine),an N-methyl-D-aspartate receptor(NMDAR)antagonist,can establish animal models of psychiatric disorders.However,the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown.Here,we found rapid elimination of microglia in the prefrontal cortex(PFC)and hippocampus(HPC)of mice following administration of the dual colony-stimulating factor 1 receptor(CSF1R)/c-Kit kinase inhibitor PLX3397(pexidartinib)in drinking water.Single administration of MK-801 induced hyperactivity in the open-field test(OFT).Importantly,PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801.However,neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity.Importantly,microglial density in the PFC and HPC was significantly correlated with behavioral changes.In addition,common and distinct glutamate-,GABA-,and inflammation-related gene(116 genes)expression patterns were observed in the brains of PLX3397-and/or MK-801-treated mice.Moreover,10 common inflammation-related genes(CD68,CD163,CD206,TMEM119,CSF3R,CX3CR1,TREM2,CD11b,CSF1R,and F4/80)with very strong correlations were identified in the brain using hierarchical clustering analysis.Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes(NLRP3,CD163,CD206,F4/80,TMEM119,and TMEM176a),but not glutamate-or GABA-related genes in PLX3397-and MK-801-treated mice.Thus,our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist,which is associated with modulation of immune-related genes in the brain.
基金partly supported by National Natural Science Foundation of China (81130024, 30530300 and 30125014, TL)the National Basic Research Program of China (973 Program 2007CB512301, TL)+1 种基金the PhD Programs Foundation of the Ministry of Education of China (20110181110014, TL)National Key Technology R & D Program of the Ministry of Science and Technology of China during the 12th Five-Year Plan (2011BAZ02530, TL)
文摘Over the last decade the combination of brain neuroimaging techniques and graph theoretical analysis of the complex anatomical and functional networks in the brain have provided an exciting new platform for exploring the etiology of mental disorders such as schizophrenia. This review introduces the current status of this work, focusing on the topological properties of human brain networks - called 'small-world brain networks'- and on the disruptions in these networks in schizophrenia. The evidence supporting the findings of reduced efficiency of information exchange in schizophrenia both within local brain regions and globally throughout the brain is reviewed and the potential relationship of these changes to cognitive and clinical symptoms is discussed. Finally we propose some suggestions for future research.
基金This work was supported by grants from the Ministry of Science and Technology of the People’s Republic of China(2021ZD0201900)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC21004,ZYGD22007)+2 种基金the National Natural Science Foundation of China(82120108002,81821002,82171527,82200695)Distinguished Young Scholar of Zhejiang(LR20H090001 to C.W.)Municipal Key R&D Program of Ningbo(2022Z127).
文摘Major depressive disorder(MDD)is a chronic,generally episodic and debilitating disease that affects an estimated 300 million people worldwide,but its pathogenesis is poorly understood.The heritability estimate of MDD is 30–40%,suggesting that genetics alone do not account for most of the risk of major depression.Another factor known to associate with MDD involves environmental stressors such as childhood adversity and recent life stress.Recent studies have emerged to show that the biological impact of environmental factors in MDD and other stress-related disorders is mediated by a variety of epigenetic modifications.These epigenetic modification alterations contribute to abnormal neuroendocrine responses,neuroplasticity impairment,neurotransmission and neuroglia dysfunction,which are involved in the pathophysiology of MDD.Furthermore,epigenetic marks have been associated with the diagnosis and treatment of MDD.The evaluation of epigenetic modifications holds promise for further understanding of the heterogeneous etiology and complex phenotypes of MDD,and may identify new therapeutic targets.Here,we review preclinical and clinical epigenetic findings,including DNA methylation,histone modification,noncoding RNA,RNA modification,and chromatin remodeling factor in MDD.In addition,we elaborate on the contribution of these epigenetic mechanisms to the pathological trait variability in depression and discuss how such mechanisms can be exploited for therapeutic purposes.
基金Key Research and Development Program of Science and Technology Department of Sichuan Province(Nos.22ZDYF1531 and 22ZDYF1696)Program of Chengdu Science and Technology(No.2021-YF05-00272-SN)+3 种基金National Natural Science Foundation of China(No.82001432)China Postdoctoral Science Foundation(Nos.2020TQ0213 and 2020M683319)Open Project Program of the National Laboratory of Pattern Recognition(No.202000034)West China Hospital Postdoctoral Science Foundation(No.2020HXBH104)
文摘To the Editor:Major depressive disorder(MDD)is a common mood disorder that contributes considerably to disability worldwide.Abnormalities in either structural connectivity or functional connectivity in the brains of patients with MDD have been widely reported,which greatly extends our knowledge of the pathophysiology of MDD.
基金supported by the National Natural Science Foundation of China(81630030,81130024,and 81528008)the National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme(81461168029)+2 种基金the National Basic Research Development Program of China(2016YFC0904300)the Science and Technology Project of the Health Planning Committee of Sichuan(19PJ090)the National Natural Science Foundation of China for Distinguished Young Scholars(81501159).
文摘The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia.We used prepulse inhibition(PPI)and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls.Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions.Concurrently,we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in firstepisode treatment-naı¨ve schizophrenic patients(n=117)and in age-and sex-matched healthy controls(n=86).We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia.Significant correlations between gray matter volumes(GMVs)in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice.Furthermore,these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients.The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients.Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation,providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.
基金funded by the National Key R&D Program of China no.2017YFC1309902the National Natural Science Foundation of China grant numbers 82122035,81671774,and 81630031+3 种基金the 13th Five-year Informatization Plan of Chinese Academy of Sciences grant no.XXH13505the Key Research Program of the Chinese Academy of Sciences no.ZDBS-SSW-JSC006Beijing Nova Program of Science and Technology no.Z191100001119104the China National Postdoctoral Program for Innovative Talents no.BX20200360.
文摘Despite a growing neuroimaging literature on the pathophysiology of major depressive disorder(MDD),repro-ducible findings are lacking,probably reflecting mostly small sample sizes and heterogeneity in analytic approaches.To address these issues,the Depression Imaging REsearch ConsorTium(DIRECT)was launched.The REST-meta-MDD project,pooling 2428 functional brain images processed with a standardized pipeline across all participating sites,has been the first effort from DIRECT.In this review,we present an overview of the moti-vations,rationale,and principal findings of the studies so far from the REST-meta-MDD project.Findings from the first round of analyses of the pooled repository have included alterations in functional connectivity within the default mode network,in whole-brain topological properties,in dynamic features,and in functional lat-eralization.These well-powered exploratory observations have also provided the basis for future longitudinal hypothesis-driven research.Following these fruitful explorations,DIRECT has proceeded to its second stage of data sharing that seeks to examine ethnicity in brain alterations in MDD by extending the exclusive Chinese original sample to other ethnic groups through international collaborations.A state-of-the-art,surface-based preprocessing pipeline has also been introduced to improve sensitivity.Functional images from patients with bipolar disorder and schizophrenia will be included to identify shared and unique abnormalities across diag-nosis boundaries.In addition,large-scale longitudinal studies targeting brain network alterations following antidepressant treatment,aggregation of diffusion tensor images,and the development of functional magnetic resonance imaging-guided neuromodulation approaches are underway.Through these endeavours,we hope to accelerate the translation of functional neuroimaging findings to clinical use,such as evaluating longitudinal effects of antidepressant medications and developing individualized neuromodulation targets,while building an open repository for the scientific community.
基金supported by the National Natural Science Foundation of China Key Project(91332205,81130024,81630030to T.L.)National Natural Science Foundation of China(8157051859 to W.D.et al.)+3 种基金National Key Technology R&D Program of the Ministry of Science and Technology of China(2016YFC0904300 to T.L.)National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme(8141101084 to T.L.)Sichuan Science&Technology Department(2015JY0173 to Q.W.)1.3.5 Project for disciplines of excellence,West China Hospital of Sichuan University(ZY2016103,ZY2016203 to T.L.)
文摘Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in Chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.
基金This highlight article was supported by the National Natural Science Foundation of China(81630030,81920108018,and 81801326)the 1.3.5 Project for Disciplines of Excellence,West China Hospital of Sichuan University(ZY2016103,ZY2016203,and ZYGD20004).
文摘Schizophrenia is a severe and complex mental disorder 111.Neuroimaging offers a powerful window for identifying the brain biomarkers and investigating the neuropathological mechanisms of psychiatric disorders.A study led by Professors Jiang and Liu,published recently in Nature Medicine,developed a new neuroimaging biomarker to characterize striatal dysfunction based on a multi-site functional MRI dataset with>1000 individuals.They show that this biomarker can distinguish individuals with schizophrenia and predict the short-term effects of antipsychotic treatmem[2].
