Social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics in the laboratory

Adult male tree shrews vigorously defend against intruding male conspecifics. However, the characteristics of social behavior have not been entirely explored in these males. In this study, male wild-type tree shrews(Tupaia belangeri chinensis)and C57 BL/6 J mice were first allowed to familiarize themselves with an open-field apparatus. The tree shrews exhibited a short duration of movement(moving) in the novel environment, whereas the mice exhibited a long duration of movement. In the 30 min social preference-avoidance test, target animals significantly decreased the time spent by the experimental tree shrews in the social interaction(SI)zone, whereas experimental male mice exhibited the opposite. In addition, experimental tree shrews displayed a significantly longer latency to enter the SI zone in the second 15 min session(targetpresent) than in the first 15 min session(targetabsent), which was different from that found in mice.Distinct behavioral patterns in response to a conspecific male were also observed in male tree shrews and mice in the first, second, and third 5 min periods. Thus, social behaviors in tree shrews and mice appeared to be time dependent. In summary,our study provides results of a modified social preference-avoidance test designed for the assessment of social behavior in tree shrews. Our findings demonstrate the existence of social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics. The tree shrew may be a new animal model, which differs from mice, for the study of social avoidance and prosocial behaviors.

Comprehensive interventions for adult cyclic vomiting syndrome complicated by superior mesenteric artery syndrome:A case report

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.

New role of platelets in schizophrenia:predicting drug response

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.

Study of tree shrew biology and models: A booming and prosperous field for biomedical research

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.

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex(mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206(40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania.Furthermore, selective knockdown of AKT via AAVAKT-sh RNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly,pharmacological activation of AKT signaling by SC79(40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002(25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin(mTOR)signaling with rapamycin(10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

精神分裂症小世界神经网络研究进展(英文)

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.

Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain

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.

GABAergic Abnormalities Associated with Sensorimotor Corticostriatal Community Structural Deficits in ErbB4 Knockout Mice and First-Episode Treatment-Naive Patients with Schizophrenia

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.

Atlas of the Striatum and Globus Pallidus in the Tree Shrew: Comparison with Rat and Mouse

The striatum and globus pallidus are principal nuclei of the basal ganglia. Nissl-and acetylcholinesterasestained sections of the tree shrew brain showed the neuroanatomical features of the caudate nucleus（Cd）,internal capsule（ic）, putamen（Pu）, accumbens, internal globus pallidus, and external globus pallidus. The ic separated the dorsal striatum into the Cd and Pu in the tree shrew, but not in rats and mice. In addition, computerbased 3 D images allowed a better understanding of the position and orientation of these structures. These data provided a large-scale atlas of the striatum and globus pallidus in the coronal, sagittal, and horizontal planes, the first detailed distribution of parvalbumin-immunoreactive cells in the tree shrew, and the differences in morphological characteristics and density of parvalbumin-immunoreactive neurons between tree shrew and rat. Our findings support the tree shrew as a potential model for human striatal disorders.

Age-Related Reduction in Cortical Thickness in First-Episode Treatment-Na?ve Patients with Schizophrenia

Substantial evidence supports the neurodevelopmental hypothesis of schizophrenia.Meanwhile,progressive neurodegenerative processes have also been reported,leading to the hypothesis that neurodegeneration is a characteristic component in the neuropathology of schizophrenia.However,a major challenge for the neurodegenerative hypothesis is that antipsychotic drugs used by patients have profound impact on brain structures.To clarify this potential confounding factor,we measured the cortical thickness across the whole brain using highresolution T1-weighted magnetic resonance imaging in 145 first-episode and treatment-naive patients with schizophrenia and 147 healthy controls.The results showed that,in the patient group,the frontal,temporal,parietal,and cingulate gyri displayed a significant age-related reduction of cortical thickness.In the control group,age-related cortical thickness reduction was mostly located in the frontal,temporal,and cingulate gyri,albeit to a lesser extent.Importantly,relative to healthy controls,patients exhibited a significantly smaller age-related cortical thickness in the anterior cingulate,inferior temporal,and insular gyri in the right hemisphere.These results provide evidence supporting the existence of neurodegenerative processes in schizophrenia and suggest that these processes already occur in the early stage of the illness.

Functional Striatal Abnormalities:A Distinct Brain Signature of Schizophrenia

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].

Effect of tetrahedral DNA nanostructures on LPS-induced neuroinflammation in mice

Neuroinflammation plays a significant role in inducing depression-like behavior. Tetrahedral DNA nanostructures(TDNs) are molecules that exhibit anti-inflammatory properties and can effectively penetrate the blood-brain barrier. Thus, researchers have hypothesized that TDNs regulate the secretion of proinflammatory cytokines and consequently alleviate depression-like behavior. To test this hypothesis, we investigated the effect of TDNs on the depression-like behavior of C57 mice induced by lipopolysaccharide(LPS). We performed open-field, tail suspension, and sucrose preference tests on LPS-and LPS/TDNtreated mice. The results indicated that the injection of TDNs into LPS-treated mice resulted in increased velocity, center zone duration, frequency to the center zone, and sucrose preference, and decreased immobility time. Immunofluorescence results indicated that peripheral administration of LPS in the mice activated inflammation, which culminated in distinct depression-like behavior. However, TDNs effectively alleviated the inflammation and depression-like behavior through the reduction of the expression levels of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α in the brain. Additionally, TDNs normalized the expression level of microglia cell activation markers, such as ionized calcium binding adaptor molecule 1, in the hippocampus of mice. These results indicated that TDNs attenuated the LPS-induced secretion of inflammatory factors and consequently alleviated depression-like behavior.

Morphological changes in gray matter volume correlate with catechol-O-methyl transferase gene Val158Met polymorphism in first-episode treatment-nave patients with schizophrenia

The catechol-O-methyltransferase（COMT） gene is a schizophrenia susceptibility gene. A common functional polymorphism of this gene,Val158/158 Met,has been proposed to influence gray matter volume（GMV）. However,the effects of this polymorphism on cortical thickness/surface area in schizophrenic patients are less clear. In this study,we explored the relationship between the Val158 Met polymorphism of the COMT gene and the GMV/ cortical thickness/cortical surface area in 150 firstepisode treatment-nave patients with schizophrenia and 100 healthy controls. Main effects of diagnosis were found for GMV in the cerebellum and the visual,medial temporal,parietal,and middle frontal cortex. Patients with schizophrenia showed reduced GMVs in these regions. And main effects of genotype were detected for GMV in the left superior frontal gyrus. Moreover,a diagnosis × genotype interaction was found for the GMV of the left precuneus,and the effect of the COMT gene on GMV was due mainly to cortical thickness rather than cortical surface area. In addition,a pattern ofincreased GMV in the precuneus with increasing Met dose found in healthy controls was lost in patients with schizophrenia. These findings suggest that the COMTMet variant is associated with the disruption of dopaminergic influence on gray matter in schizophrenia,and the effect of the COMT gene on GMV in schizophrenia is mainly due to changes in cortical thickness rather than in cortical surface area.

Altered topological properties in the heritable schizophrenic brain

It is well established that complex networks are responsible for the high-level information processing in the human brain.The topology of complex networks allows efficient dynamic interactions between spatially distinct brain areas,which may be studied by analyzing the topological

Testing the role of genetic variation of the MC4R gene in Chinese population in antipsychotic-induced metabolic disturbance

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.

Epigenetic regulation in major depression and other stressrelated disorders: molecular mechanisms, clinical relevance and therapeutic potential

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.

Interaction Between Variations in Dopamine D2 and Serotonin 2A Receptor is Associated with Short-Term Response to Antipsychotics in Schizophrenia

Dear Editor,Schizophrenia is a chronic and debilitating brain disorder,which has a strong genetic component with heritability ranging from 66%to 85%[1,2].Currently,antipsychotic drugs remain the most effective treatment for the psychotic symptoms of schizophrenia[3].Because of the severe sideeffects of first-generation antipsychotics(FGAs),secondgeneration antipsychotics(SGAs)have become more widely used in the treatment of schizophrenia.

Brain Impairment in Chronic Schizophrenia Patients with Depressive Symptoms Differs from Brain Impairment in Chronic Depression Patients with Psychotic Symptoms

Numerous studies have identified many specific structural alterations in the brains of patients with schizophrenia and depression. Schizophrenia is associated with gray matter volume （GMV） impairment in certain key brain regions, which progresses in the first 2-3 years after the first episode of schizophrenic symptoms,m Schizophrenia has also been shown to be associated with concurrent white matter （WM） alterations. The fasciculus uncinatus and arcuate fasciculus have been proposed to be a part of the quality index for schizophrenia.12j Similar to schizophrenia, major depressive disorder （MDD） is associated with a GMV reduction and aberrant WM. GMV reductions in the bilateral middle temporal gyrus left ventral medial prefrontal gyrus, left lingual gyms, and dorsal medial prefrontal gyrus have been correlated with the severity of the depressive symptoms. Schizophrenic and depressive symptoms usually coexist in schizophrenia and MDD. In this pilot study, we compared the GMV and WM differences in the brains of chronic schizophrenia patients with depressive symptoms with those of chronic depression patients with psychotic symptoms.

Disrupted association between structural and functional coupling of the supplementary motor area and neurocognition in major depressive disorder

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.