In this study,we investigated the role of structural asymmetry of the dorsolateral prefrontal cortex（DLPFC） in the continuum of depression from healthy individuals to patients.Structural magnetic resonance imaging w...In this study,we investigated the role of structural asymmetry of the dorsolateral prefrontal cortex（DLPFC） in the continuum of depression from healthy individuals to patients.Structural magnetic resonance imaging was performed in 70 patients with major depressive disorder（MDD）,49 matched controls,and 349 healthy university students to calculate structural asymmetry indexes of the DLPFC.First-episode,treatment-naive MDD patients showed a relatively lower asymmetry index than healthy controls,and their asymmetry index was negatively correlated with the depressive symptoms.This abnormality was normalized by antidepressants in medicated MDD patients.Furthermore,the asymmetry index was negatively correlated with the depressive symptoms in university students;this was replicated at two time points in a subgroup of students,suggesting good test-retest reliability.Our findings are consistent with previous studiesthat support the imbalance hypothesis of MDD and suggest a potential structural basis underlying the functional asymmetry of the DLPFC in depression.In future,the structural index of the DLPFC may become a potential biomarker to evaluate individuals＇ risk for the onset of MDD.展开更多
Oligodendrocyte lineage cells(OL-lineage cells)are a cell population that are crucial for mammalian central nervous system(CNS)myelination.OL-lineage cells go through developmental stages,initially differentiating int...Oligodendrocyte lineage cells(OL-lineage cells)are a cell population that are crucial for mammalian central nervous system(CNS)myelination.OL-lineage cells go through developmental stages,initially differentiating into oligodendrocyte precursor cells(OPCs),before becoming immature oligodendrocytes,then mature oligodendrocytes(OLs).While the main function of cell lineage is in myelin formation,and increasing number of studies have turned to explore the immunological characteristics of these cells.Initially,these studies focused on discovering how OPCs and OLs are affected by the immune system,and then,how these immunological changes influence the myelination process.However,recent studies have uncovered another feature of OL-lineage cells in our immune systems.It would appear that OL-lineage cells also express immunological factors such as cytokines and chemokines in response to immune activation,and the expression of these factors changes under various pathologic conditions.Evidence suggests that OL-lineage cells actually modulate immune functions.Indeed,OL-lineage cells appear to play both"victim"and"agent"in the CNS which raises a number of questions.Here,we summarize immunologic changes in OL-lineage cells and their effects,as well as consider OL-lineage cell changes which influence immune cells under pathological conditions.We also describe some of the underlying mechanisms of these changes and their effects.Finally,we describe several studies which use OL-lineage cells as immunotherapeutic targets for demyelination diseases.展开更多
Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia.But it is unknown whether enhancing remyelination is a beneficial ...Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia.But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia.To investigate this hypothesis,we used clemastine,an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination,on a cuprizone-induced mouse model of demyelination.The mice exposed to cuprizone（0.2%in chow） for 6 weeks displayed schizophrenia-like behavioral changes,including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze,as well as evident demyelination in the cortex and corpus callosum.Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for3 weeks.As expected,myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes（APC-positive） and myelin basic protein.More importantly,the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle,suggesting a beneficial effect via promoting myelin repair.Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.展开更多
Anodal transcranial direct current stimulation(AtDCS)has been shown to alleviate cognitive impairment in an APP/PS1 model of Alzheimer’s disease in the preclinical stage.However,this enhancement was only observed imm...Anodal transcranial direct current stimulation(AtDCS)has been shown to alleviate cognitive impairment in an APP/PS1 model of Alzheimer’s disease in the preclinical stage.However,this enhancement was only observed immediately after AtDCS,and the long-term effect of AtDCS remains unknown.In this study,we treated 26-week-old mouse models of Alzheimer’s disease in the preclinical stage with 10 AtDCS sessions or sham stimulation.The Morris water maze,novel object recognition task,and novel object location test were implemented to evaluate spatial learning memory and recognition memory of mice.Western blotting was used to detect the relevant protein content.Morphological changes were observed using immunohistochemistry and immunofluorescence staining.Six weeks after treatment,the mice subjected to AtDCS sessions had a shorter escape latency,a shorter path length,more platform area crossings,and spent more time in the target quadrant than sham-stimulated mice.The mice subjected to AtDCS sessions also performed better in the novel object recognition and novel object location tests than sham-stimulated mice.Furthermore,AtDCS reduced the levels of amyloid-β42 and glial fibrillary acidic protein,a marker of astrocyte activation,and increased the level of neuronal marker NeuN in hippocampal tissue.These findings suggest that AtDCS can improve the spatial learning and memory abilities and pathological state of an APP/PS1 mouse model of Alzheimer’s disease in the preclinical stage,with improvements that last for at least 6 weeks.展开更多
Vascular dementia produced by permanent ligation of bilateral common carotid arteries involves progressive deterioration of intellectual and cognitive function in rats, which are closely associated with the hippocampu...Vascular dementia produced by permanent ligation of bilateral common carotid arteries involves progressive deterioration of intellectual and cognitive function in rats, which are closely associated with the hippocampus. This study used immunohistochemical analysis to detect the expression of glial fibrillary acidic protein and nestin in the hippocampus in a vascular dementia model. The results revealed that both glial fibrillary acidic protein and nestin expression were increased 1 day after permanent ligation of the bilateral common carotid arteries, compared with a sham-operated group. The expression of glial fibrillary acidic protein peaked at 7 days post-surgery. The expression of nestin was a little weaker than that of glial fibrillary acidic protein, and peaked at 14 days （P 〈 0.01）. The expression of both proteins slightly decreased at 21 and 28 days, accompanied by recovery of cerebral blood flow. In conclusion, this study demonstrated that glial fibrillary acidic protein and nestin exhibited dynamic expression in the rat hippocampus after permanent ligation of bilateral common carotid arteries. This finding suggests that dynamic alterations in protein expression play an important role in the pathogenesis of vascular dementia.展开更多
Oligodendrocyte precursor cells(OPCs)are a heterogeneous multipotent population in the central nervous system(CNS)that appear during embryogenesis and persist as resident cells in the adult brain parenchyma.OPCs could...Oligodendrocyte precursor cells(OPCs)are a heterogeneous multipotent population in the central nervous system(CNS)that appear during embryogenesis and persist as resident cells in the adult brain parenchyma.OPCs could generate oligodendrocytes to participate in myelination.Recent advances have renewed our knowledge of OPC biology by discovering novel markers of oligodendroglial cells,the myelin-independent roles of OPCs,and the regulatory mechanism of OPC development.In this review,we will explore the updated knowledge on OPC identity,their multifaceted roles in the CNS in health and diseases,as well as the regulatory mechanisms that are involved in their developmental stages,which hopefully would contribute to a further understanding of OPCs and attract attention in the field of OPC biology.展开更多
This research aimed to provide evidenee of a relationship between digit ratio and depression status in the cynomolgus monkey(Macaca fascicularis).In stable cyno molgus mon key social groups,we selected 15 depressed mo...This research aimed to provide evidenee of a relationship between digit ratio and depression status in the cynomolgus monkey(Macaca fascicularis).In stable cyno molgus mon key social groups,we selected 15 depressed monkeys based on depressive-like behavioral criteria and 16 normal control mon keys.All animals were video recorded for two weeks,with the duration and frequency of the core depressive behaviors and 58 other behaviors in 12 behavioral categories then evaluated via behavioral analysis.Fin ger len gths from the right and left forelimb hands of both groups were measured by X-ray imagi ng.Fin ger length and digit ratio comparisons between the two groups were con ducted using Stude nt's Mest.In terms of the durati on of each behavior,signifies nt differences emerged in“Huddling”and five other behavioral categories,including Ingestive,Amicable,Parental,Locomotive,and Resting.In addition to the above five behavioral categories,we found that depressed mon keys spent less time in parental and rubbing back and forth behaviors than the control group.Furthermore,the 4th fin gers were significantly Ion ger in the left and right hands in the control group relative to the depressed mon keys.The sec ond?to?fourth(2D:4D)digit ratio in the left and right forelimb hands was significantly lower in the control group tha n that in the depressed group.Our fin dings revealed significant differences in finger lengths and digit ratios between depressed mon keys and healthy controls,which concords with our view that relatively high fetal testosterone exposure may be a protective factor against developing depressive symptoms(or that low fetal testosterone exposure is a risk factor).展开更多
Eccrine Spiradenoma (ES) is an exceedingly rare sweat-gland tumor, it usually presents as a solitary lesion and painful nodule. ES is a kind of neoplasm with distinct histological characteristics and nonspecific clini...Eccrine Spiradenoma (ES) is an exceedingly rare sweat-gland tumor, it usually presents as a solitary lesion and painful nodule. ES is a kind of neoplasm with distinct histological characteristics and nonspecific clinical manifestations. Most ES cases have a benign course;however, malignant transformation would occur after a long period of latency. The diagnosis mostly depends on the clinic symptom, histological features and immunohistochemistry. Here, we report a case of ES and literature review. The aim of this study is to understand clinic and histological features for ES.展开更多
Medulloblastoma (MB) is common tumor of the central nervous system in children. It’s reported that PI3K/AKT and Wnt signal pathway have important roles in MB. This study aims to investigate the expression of PI3K, AK...Medulloblastoma (MB) is common tumor of the central nervous system in children. It’s reported that PI3K/AKT and Wnt signal pathway have important roles in MB. This study aims to investigate the expression of PI3K, AKT, Β-catenin and VEGFR-2 in MB to find a new pathway for MB. A total of 33 MB and 17 control brain cases were retrospectively evaluate d for PI3K, AKT, β-catenin and VEGFR-2 expression by immunohistochemical staining, and the relationship with clinical feature were analyzed. The positive rate of PI3K, AKT, β-catenin and VEGFR-2 in 33 MB were significantly greater than those in control group展开更多
Postmenopausal women with Alzheimer’s disease exhibit dramatically reduced sensitivity to estrogen replacement therapy,which is though to be related to an estrogen receptor(ER)α/ERβratio imbalance arising from a si...Postmenopausal women with Alzheimer’s disease exhibit dramatically reduced sensitivity to estrogen replacement therapy,which is though to be related to an estrogen receptor(ER)α/ERβratio imbalance arising from a significantly decreased level of ERs of the brain.The aim of our study was to investigate whether valproic acid(VPA)can enhance the beneficial effects of estrogen on cognitive function through restoration of ERαand ERβexpression in the brain.We removed the ovaries of female APP/PS1 mice to simulate the low estrogen levels present in postmenopausal women and then administered VPA(30 mg/kg,intraperitoneal injection,once daily),17β-estradiol(E2)(2.4μg,intraperitoneal injection,once daily),liquiritigenin(LG)(50μg/kg,intragastric infusion,once daily),VPA+E2,or VPA+LG for 4 successive weeks.Compared with treatment with a single drug,treatment with VPA+E2 or VPA+LG significantly increased the level of glycogen synthase kinase 3β,increased the expression of estrogen receptorα,reduced the expression of small ubiquitin-like modifiers,and increased the level of estrogen receptorβ.This resulted in enhanced sensitivity to estrogen therapy,reduced amyloidβaggregation,reduced abnormal phosphorylation of the tau protein,reduced neuronal loss,increased dendritic spine and postsynaptic density,and significantly alleviated memory loss and learning impairment in Alzheimer’s disease.This study was approved by the Chongqing Medical University Animal Protection and Ethics Committee,China on March 6,2013.展开更多
Vertebral artery orifice stenting may improve blood supply of the posterior circulation of the brain to regions such as the cerebellum and brainstem. However, previous studies have mainly focused on recovery of cerebr...Vertebral artery orifice stenting may improve blood supply of the posterior circulation of the brain to regions such as the cerebellum and brainstem. However, previous studies have mainly focused on recovery of cerebral blood flow and perfusion in the posterior circulation after interventional therapy. This study examined the effects of functional recovery of local brain tissue on cerebellar function remodeling using blood oxygen level-dependent functional magnetic reso- nance imaging before and after interventional therapy. A total of 40 Chinese patients with severe unilateral vertebral artery orifice stenosis were enrolled in this study. Patients were equally and randomly assigned to intervention and control groups. The control group received drug treat- ment only. The intervention group received vertebral artery orifice angioplasty and stenting ＋ identical drug treatment to the control group. At 13 days after treatment, the Dizziness Handicap Inventory score was compared between the intervention and control groups. Cerebellar function remodeling was observed between the two groups using blood oxygen level-dependent functional magnetic resonance imaging. The improvement in dizziness handicap and cerebellar function was more obvious in the intervention group than in the control group. Interventional therapy for severe vertebral artery orifice stenosis may effectively promote cerebellar function remodeling and exert neuroprotective effects.展开更多
Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and my...Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and myelin in serious mental illnesses. However, whether these deficits contribute to the brain dysfunction or pathogenesis of such diseases still lacks direct evidence. In this study, we conditionally deleted Olig2 in oligodendroglial lineage cells (Olig2 cKO) and screened the behavioral changes in adult mice. We found that Olig2 ablation impaired myelin development, which further resulted in severe hypomyelination in the anterior cingulate cortex. Strikingly, Olig2 cKO mice exhibited an anxious phenotype, aberrant responses to stress, and cognitive deficits. Moreover, Olig2 cKO mice showed increased vulnerability to social avoidance under the mild stress of social isolation. Together,these results indicate that developmental deficits in OL and myelin lead to cognitive impairment and increase the risk of phenotypes reminiscent of mental illnesses.展开更多
Schizophrenia is a mental disease that mainly affects young individuals （15 to 35 years old） but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunctio...Schizophrenia is a mental disease that mainly affects young individuals （15 to 35 years old） but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile （3 weeks）, young-adult （6 weeks） and middle-aged （8 months）, were subjected to a 6-week diet containing 0.2% cuprizone （CPZ） to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated： （1） CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; （2） the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1- positive mature oligodendrocytes, and higher levels of astrocyte activation; and （3） CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-relatedvulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.展开更多
Astrocytes(ASTs)and oligodendroglial lineage cells(OLGs)are major macroglial cells in the central nervous system.ASTs communicate with each other through connexin(Cx)and Cx-based network structures,both of which allow...Astrocytes(ASTs)and oligodendroglial lineage cells(OLGs)are major macroglial cells in the central nervous system.ASTs communicate with each other through connexin(Cx)and Cx-based network structures,both of which allow for quick transport of nutrients and signals.Moreover,ASTs interact with OLGs through connexin(Cx)-mediated networks to modulate various physiological processes in the brain.In this article,following a brief description of the infrastructural basis of the glial networks and exocrine factors by which ASTs and OLGs may crosstalk,we focus on recapitulating how the interactions between these two types of glial cells modulate myelination,and how the AST-OLG interactions are involved in protecting the integrity of the blood-brain barrier(BBB)and regulating synaptogenesis and neural activity.Recent studies further suggest that AST-OLG interactions are associated with myelin-related diseases,such as multiple sclerosis.A better understanding of the regulatory mechanisms underlying AST-OLG interactions may inspire the development of novel therapeutic strategies for related brain diseases.展开更多
Exposure to chronic hypoxia is considered to be a risk factor for deficits in brain function in adults,but the underlying mechanisms remain largely unknown.Since active myelinogenesis persists in the adult central ner...Exposure to chronic hypoxia is considered to be a risk factor for deficits in brain function in adults,but the underlying mechanisms remain largely unknown.Since active myelinogenesis persists in the adult central nervous system,here we aimed to investigate the impact of chronic hypoxia on myelination and the related functional consequences in adult mice.Using a transgenic approach to label newly-generated myelin sheaths(NG2-CreER^(TM);Tau-mGFP),we found that myelinogenesis was highly active in most brain regions,such as the motor cortex and corpus callosum.After exposure to hypoxia(10%oxygen)12 h per day for 4 weeks,myelinogenesis was largely inhibited in the 4-month old brain and the mice displayed motor coordination deficits revealed by the beam-walking test.To determine the relationship between the inhibited myelination and functional impairment,we induced oligoden-droglia-specific deletion of the transcription factor 01ig2 by tamoxifen(NG2-CreER^(TM);Tau-mGFP;Olig2 fl/fl)in adult mice to mimic the decreased myelinogenesis caused by hypoxia.The deletion of OHg2 inhibited myelinogenesis and consequently impaired motor coordination,suggesting that myelinogenesis is required for motor function in adult mice.To understand whether enhancing myelination could protect brain functions against hypoxia,we treated hypoxic mice with the myelination-enhancing drug-clemastine,which resulted in enhanced myelogenesis and improved motor coordination.Taken together,our data indicate that chronic hypoxia inhibits myelinogenesis and causes functional deficits in the brain and that enhancing myelinogenesis protects brain functions against hypoxia-related deficits.展开更多
Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulatio...Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood.Methods:Using the combined single-cell transcriptomics,metabolomics,and proteomics analysis from TBI patients and the TBI mouse model,we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests.We also characterized the underlying mechanisms both invitro and invivo through molecular simulations,signaling detections,gene expression regulation assessments[including dual-luciferase reporter and chromatin immunoprecipitation(ChIP)assays],primary cultures or co-cultures of neutrophils and oligodendrocytes,intracellular iron,and lipid hydroperoxide concentration measurements,as well as forkhead box protein O1(FOXO1)conditional knockout mice.Results:We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model.Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI,aggravating acute brain inflammatory damage and promoting late TBI-induced depression.In the acute stage,FOXO1 upregulated cytoplasmic Versican(VCAN)to interact with the apoptosis regulator B-cell lymphoma-2(BCL-2)-associated X protein(BAX),suppressing the mitochondrial translocation of BAX,which mediated the antiapoptotic effect companied with enhancing interleukin-6(IL-6)production of FOXO1high neutrophils.In the chronic stage,the“FOXO1-transferrin receptor(TFRC)”mechanism contributes to FOXO1high neutrophil ferroptosis,disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein,which contributes to the progression of late depression after TBI.Conclusions:FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI,which provides insight into the heterogeneity,reprogramming activity,and versatility of neutrophils in TBI.展开更多
Increasing evidence has shown that astrocytes are implicated in regulating oligodendrocyte myelination,but the underlying mechanisms remain largely unknown.To understand whether microRNAs in astrocytes function in reg...Increasing evidence has shown that astrocytes are implicated in regulating oligodendrocyte myelination,but the underlying mechanisms remain largely unknown.To understand whether microRNAs in astrocytes function in regulating oligodendroglial differentiation and myelination in the developing and adult CNS,we generated inducible astrocyte-specific Dicer conditional knockout mice(hGFAP-CreERT;Dicer fl/fl).By using a reporter mouse line(mT/mG),we confirmed that hGFAP-CreERT drives an efficient and astrocyte-specific recombination in the developing CNS,upon tamoxifen treatment from postnatal day 3(P3)to P7.The Dicer deletion in astrocytes resulted in inhibited oligodendroglial differentiation and myelination in the developing CNS of Dicer cKO mice at P10 and P14,and did not alter the densities of neurons or axons,indicating that Dicer in astrocytes is required for oligodendrocyte myelination.Consequently,the Dicer deletion in astrocytes at P3 resulted in impaired spatial memory and motor coordination at the age of 9 weeks.To understand whether Dicer in astrocytes is also required for remyelination,we induced Dicer deletion in 3-month-old mice and then injected lysolecithin into the corpus callosum to induce demyelination.The Dicer deletion in astrocytes blocked remyelination in the corpus callosum 14 days after induced demyelination.Together,our results indicate that Dicer in astrocytes is required for oligodendroglia myelination in both the developing and adult CNS.展开更多
The anterior auditory field(AAF)is a core region of the auditory cortex and plays a vital role in discrimination tasks.However,the role of the AAF corticostriatal neurons in frequency discrimination remains unclear.He...The anterior auditory field(AAF)is a core region of the auditory cortex and plays a vital role in discrimination tasks.However,the role of the AAF corticostriatal neurons in frequency discrimination remains unclear.Here,we used c-Fos staining,fiber photometry recording,and pharmacogenetic manipulation to investigate the function of the AAF corticostriatal neurons in a frequency discrimination task.c-Fos staining and fiber photometry recording revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task.Pharmacogenetic inhibition of AAF pyramidal neurons significantly impaired frequency discrimination.In addition,histological results revealed that AAF pyramidal neurons send strong projections to the striatum.Moreover,pharmacogenetic suppression of the striatal projections from pyramidal neurons in the AAF significantly disrupted the frequency discrimination.Collectively,our findings show that AAF pyramidal neurons,particularly the AAF–striatum projections,play a crucial role in frequency discrimination behavior.展开更多
The extremely low bioavailability of oral paclitaxel(PTX)mainly due to the complicated gastrointestinal environment,the obstruction of intestinal mucus layer and epithelium barrier.Thus,it is of great significance to ...The extremely low bioavailability of oral paclitaxel(PTX)mainly due to the complicated gastrointestinal environment,the obstruction of intestinal mucus layer and epithelium barrier.Thus,it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously.In this work,a high-density PEGylation-based glycocholic acid-decorated micelles(PTX@GNPs)was constructed by a novel polymer,9-Fluorenylmethoxy carbonyl-poly ethylene glycocholic acid(Fmoc-PEG-GCA).The Fmoc motif in this polymer could encapsulate PTX viaπ-πstacking to form the core of micelles,and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG.Based on this versatile and flexible carriers,PTX@GNPs possess mucus trapping escape ability due to the flexible PEG,and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter.The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX,and exhibited similar antitumor efficacy to Taxol injection via intravenous route.In addition,oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX,which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.展开更多
A multiplexed targeted proteomic assay using a mTRAQ-MRM/MS-based approach was developed and assessed to systematically quantify the relative expressions of five candidate plasma apolipoproteins that have been previou...A multiplexed targeted proteomic assay using a mTRAQ-MRM/MS-based approach was developed and assessed to systematically quantify the relative expressions of five candidate plasma apolipoproteins that have been previously shown to be dysregulated in neuropsychiatric disorders and cognitive dysfunction:apolipoprotein H(APOH),apolipoprotein J(APOJ),apolipoprotein A4(APOA4),apolipoprotein E(APOE),and apolipoprotein D(APOD).The peptides and transitions of each APO were carefully selected according to the tandem MS signals acquired on a TripleTOFTM 5600,followed by optimization of the declustering potential and collision energy voltages for transitions on a QTRAP 5500.Our results showed that the collision energies of mTRAQ-labeled peptides were approximately 15%–20%higher than corresponding non-labeled peptides.Through optimized transitions and parameters,we analyzed the relative abundances of the five APOs in human plasma with and without depletion of high abundant proteins.The results indicated that the MRM signals of four target APOs were significantly increased after depletion,while the MRM signal of one APO,APOD,was decreased.Furthermore,the relative abundances of the five target APOs in healthy human plasma were stable,and the ranking of these proteins according to their MS responses changed slightly.Therefore,we deduced that the rank order of the MS signals for these target proteins can be developed as a diagnostic signature for diseased plasma.展开更多
文摘In this study,we investigated the role of structural asymmetry of the dorsolateral prefrontal cortex（DLPFC） in the continuum of depression from healthy individuals to patients.Structural magnetic resonance imaging was performed in 70 patients with major depressive disorder（MDD）,49 matched controls,and 349 healthy university students to calculate structural asymmetry indexes of the DLPFC.First-episode,treatment-naive MDD patients showed a relatively lower asymmetry index than healthy controls,and their asymmetry index was negatively correlated with the depressive symptoms.This abnormality was normalized by antidepressants in medicated MDD patients.Furthermore,the asymmetry index was negatively correlated with the depressive symptoms in university students;this was replicated at two time points in a subgroup of students,suggesting good test-retest reliability.Our findings are consistent with previous studiesthat support the imbalance hypothesis of MDD and suggest a potential structural basis underlying the functional asymmetry of the DLPFC in depression.In future,the structural index of the DLPFC may become a potential biomarker to evaluate individuals＇ risk for the onset of MDD.
基金This work was supported by research grants from Shenzhen Fundamental Research Program(Grants No.RCYX20200714114644167,JCYJ20190809161405495,and JCYJ20210324123212035)National Natural Science Foundation of China(Grants No.81971309,32170980,and 32070964)Guangdong Basic and Applied Basic Research Foundation(Grants No.2019A1515011333 and 2022B1515020012).
文摘Oligodendrocyte lineage cells(OL-lineage cells)are a cell population that are crucial for mammalian central nervous system(CNS)myelination.OL-lineage cells go through developmental stages,initially differentiating into oligodendrocyte precursor cells(OPCs),before becoming immature oligodendrocytes,then mature oligodendrocytes(OLs).While the main function of cell lineage is in myelin formation,and increasing number of studies have turned to explore the immunological characteristics of these cells.Initially,these studies focused on discovering how OPCs and OLs are affected by the immune system,and then,how these immunological changes influence the myelination process.However,recent studies have uncovered another feature of OL-lineage cells in our immune systems.It would appear that OL-lineage cells also express immunological factors such as cytokines and chemokines in response to immune activation,and the expression of these factors changes under various pathologic conditions.Evidence suggests that OL-lineage cells actually modulate immune functions.Indeed,OL-lineage cells appear to play both"victim"and"agent"in the CNS which raises a number of questions.Here,we summarize immunologic changes in OL-lineage cells and their effects,as well as consider OL-lineage cell changes which influence immune cells under pathological conditions.We also describe some of the underlying mechanisms of these changes and their effects.Finally,we describe several studies which use OL-lineage cells as immunotherapeutic targets for demyelination diseases.
基金supported by the National Natural Science Foundation of China ( 81100897 and 81100926 )the Natural Science Foundation of Chongqing Municipality, China (cstc2011jj A0856)
文摘Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia.But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia.To investigate this hypothesis,we used clemastine,an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination,on a cuprizone-induced mouse model of demyelination.The mice exposed to cuprizone（0.2%in chow） for 6 weeks displayed schizophrenia-like behavioral changes,including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze,as well as evident demyelination in the cortex and corpus callosum.Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for3 weeks.As expected,myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes（APC-positive） and myelin basic protein.More importantly,the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle,suggesting a beneficial effect via promoting myelin repair.Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.
基金supported by the National Natural Science Foundation of China,No.31971287(to XYW)the Advanced Interdisciplinary Studies Foundation of School of Basic Medical Science,Army Medical University of China,No.2018JCQY07(to HZW).
文摘Anodal transcranial direct current stimulation(AtDCS)has been shown to alleviate cognitive impairment in an APP/PS1 model of Alzheimer’s disease in the preclinical stage.However,this enhancement was only observed immediately after AtDCS,and the long-term effect of AtDCS remains unknown.In this study,we treated 26-week-old mouse models of Alzheimer’s disease in the preclinical stage with 10 AtDCS sessions or sham stimulation.The Morris water maze,novel object recognition task,and novel object location test were implemented to evaluate spatial learning memory and recognition memory of mice.Western blotting was used to detect the relevant protein content.Morphological changes were observed using immunohistochemistry and immunofluorescence staining.Six weeks after treatment,the mice subjected to AtDCS sessions had a shorter escape latency,a shorter path length,more platform area crossings,and spent more time in the target quadrant than sham-stimulated mice.The mice subjected to AtDCS sessions also performed better in the novel object recognition and novel object location tests than sham-stimulated mice.Furthermore,AtDCS reduced the levels of amyloid-β42 and glial fibrillary acidic protein,a marker of astrocyte activation,and increased the level of neuronal marker NeuN in hippocampal tissue.These findings suggest that AtDCS can improve the spatial learning and memory abilities and pathological state of an APP/PS1 mouse model of Alzheimer’s disease in the preclinical stage,with improvements that last for at least 6 weeks.
基金the National Natural Science Foundation of China, No. 30973154Chongqing Science and Technology Commission Foundation, No. 2009BB5270Chongqing Municipal Education Commission Foundation, No. KJ090301
文摘Vascular dementia produced by permanent ligation of bilateral common carotid arteries involves progressive deterioration of intellectual and cognitive function in rats, which are closely associated with the hippocampus. This study used immunohistochemical analysis to detect the expression of glial fibrillary acidic protein and nestin in the hippocampus in a vascular dementia model. The results revealed that both glial fibrillary acidic protein and nestin expression were increased 1 day after permanent ligation of the bilateral common carotid arteries, compared with a sham-operated group. The expression of glial fibrillary acidic protein peaked at 7 days post-surgery. The expression of nestin was a little weaker than that of glial fibrillary acidic protein, and peaked at 14 days （P 〈 0.01）. The expression of both proteins slightly decreased at 21 and 28 days, accompanied by recovery of cerebral blood flow. In conclusion, this study demonstrated that glial fibrillary acidic protein and nestin exhibited dynamic expression in the rat hippocampus after permanent ligation of bilateral common carotid arteries. This finding suggests that dynamic alterations in protein expression play an important role in the pathogenesis of vascular dementia.
基金supported by grants from the National Natural Science Foundation of China (32271034,32070964,81971309,32170980,and 32300791)National Key Research and Development Program of China (2021ZD0201703)+4 种基金Chongqing Natural Science Fund for Distinguished Young Scholars (CSTB2023NSCQ-JQX0030)Guangdong Basic and Applied Basic Research Foundation (2022B1515020012,2021A1515110268,2023A1515010651)Shenzhen Medical Research Fund (A2303014)Shenzhen Fundamental Research Program (JCYJ20210324123212035,RCYX20200714114644167,ZDSYS20220606100801003,RCBS20210706092411028,and JCYJ20210324121214039)Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research (ZDSYS20220606100801003).
文摘Oligodendrocyte precursor cells(OPCs)are a heterogeneous multipotent population in the central nervous system(CNS)that appear during embryogenesis and persist as resident cells in the adult brain parenchyma.OPCs could generate oligodendrocytes to participate in myelination.Recent advances have renewed our knowledge of OPC biology by discovering novel markers of oligodendroglial cells,the myelin-independent roles of OPCs,and the regulatory mechanism of OPC development.In this review,we will explore the updated knowledge on OPC identity,their multifaceted roles in the CNS in health and diseases,as well as the regulatory mechanisms that are involved in their developmental stages,which hopefully would contribute to a further understanding of OPCs and attract attention in the field of OPC biology.
基金supported by the National Natural Science Foundation of China(816 01207)National Basic Research Program of China(973 Program)(2017YFA 0505700)
文摘This research aimed to provide evidenee of a relationship between digit ratio and depression status in the cynomolgus monkey(Macaca fascicularis).In stable cyno molgus mon key social groups,we selected 15 depressed monkeys based on depressive-like behavioral criteria and 16 normal control mon keys.All animals were video recorded for two weeks,with the duration and frequency of the core depressive behaviors and 58 other behaviors in 12 behavioral categories then evaluated via behavioral analysis.Fin ger len gths from the right and left forelimb hands of both groups were measured by X-ray imagi ng.Fin ger length and digit ratio comparisons between the two groups were con ducted using Stude nt's Mest.In terms of the durati on of each behavior,signifies nt differences emerged in“Huddling”and five other behavioral categories,including Ingestive,Amicable,Parental,Locomotive,and Resting.In addition to the above five behavioral categories,we found that depressed mon keys spent less time in parental and rubbing back and forth behaviors than the control group.Furthermore,the 4th fin gers were significantly Ion ger in the left and right hands in the control group relative to the depressed mon keys.The sec ond?to?fourth(2D:4D)digit ratio in the left and right forelimb hands was significantly lower in the control group tha n that in the depressed group.Our fin dings revealed significant differences in finger lengths and digit ratios between depressed mon keys and healthy controls,which concords with our view that relatively high fetal testosterone exposure may be a protective factor against developing depressive symptoms(or that low fetal testosterone exposure is a risk factor).
文摘Eccrine Spiradenoma (ES) is an exceedingly rare sweat-gland tumor, it usually presents as a solitary lesion and painful nodule. ES is a kind of neoplasm with distinct histological characteristics and nonspecific clinical manifestations. Most ES cases have a benign course;however, malignant transformation would occur after a long period of latency. The diagnosis mostly depends on the clinic symptom, histological features and immunohistochemistry. Here, we report a case of ES and literature review. The aim of this study is to understand clinic and histological features for ES.
文摘Medulloblastoma (MB) is common tumor of the central nervous system in children. It’s reported that PI3K/AKT and Wnt signal pathway have important roles in MB. This study aims to investigate the expression of PI3K, AKT, Β-catenin and VEGFR-2 in MB to find a new pathway for MB. A total of 33 MB and 17 control brain cases were retrospectively evaluate d for PI3K, AKT, β-catenin and VEGFR-2 expression by immunohistochemical staining, and the relationship with clinical feature were analyzed. The positive rate of PI3K, AKT, β-catenin and VEGFR-2 in 33 MB were significantly greater than those in control group
基金This study was supported by the National Natural Science Foundation of China,Nos.81671257,81371221,31600825(all to GQH).
文摘Postmenopausal women with Alzheimer’s disease exhibit dramatically reduced sensitivity to estrogen replacement therapy,which is though to be related to an estrogen receptor(ER)α/ERβratio imbalance arising from a significantly decreased level of ERs of the brain.The aim of our study was to investigate whether valproic acid(VPA)can enhance the beneficial effects of estrogen on cognitive function through restoration of ERαand ERβexpression in the brain.We removed the ovaries of female APP/PS1 mice to simulate the low estrogen levels present in postmenopausal women and then administered VPA(30 mg/kg,intraperitoneal injection,once daily),17β-estradiol(E2)(2.4μg,intraperitoneal injection,once daily),liquiritigenin(LG)(50μg/kg,intragastric infusion,once daily),VPA+E2,or VPA+LG for 4 successive weeks.Compared with treatment with a single drug,treatment with VPA+E2 or VPA+LG significantly increased the level of glycogen synthase kinase 3β,increased the expression of estrogen receptorα,reduced the expression of small ubiquitin-like modifiers,and increased the level of estrogen receptorβ.This resulted in enhanced sensitivity to estrogen therapy,reduced amyloidβaggregation,reduced abnormal phosphorylation of the tau protein,reduced neuronal loss,increased dendritic spine and postsynaptic density,and significantly alleviated memory loss and learning impairment in Alzheimer’s disease.This study was approved by the Chongqing Medical University Animal Protection and Ethics Committee,China on March 6,2013.
基金supported by the Natural Science Foundation of Yongchuan District of Chongqing in China,No.Ycstc,2013nc8031the Foundation of Chongqing Municipal Health Bureau in China,No.2010-2-250+1 种基金the Foundation of Chongqing Health and Family Planning Commission in China,No.20143001the Soft Science Foundation of Yongchuan District of Chongqing in China,No.Ycstc,2011BE5004
文摘Vertebral artery orifice stenting may improve blood supply of the posterior circulation of the brain to regions such as the cerebellum and brainstem. However, previous studies have mainly focused on recovery of cerebral blood flow and perfusion in the posterior circulation after interventional therapy. This study examined the effects of functional recovery of local brain tissue on cerebellar function remodeling using blood oxygen level-dependent functional magnetic reso- nance imaging before and after interventional therapy. A total of 40 Chinese patients with severe unilateral vertebral artery orifice stenosis were enrolled in this study. Patients were equally and randomly assigned to intervention and control groups. The control group received drug treat- ment only. The intervention group received vertebral artery orifice angioplasty and stenting ＋ identical drug treatment to the control group. At 13 days after treatment, the Dizziness Handicap Inventory score was compared between the intervention and control groups. Cerebellar function remodeling was observed between the two groups using blood oxygen level-dependent functional magnetic resonance imaging. The improvement in dizziness handicap and cerebellar function was more obvious in the intervention group than in the control group. Interventional therapy for severe vertebral artery orifice stenosis may effectively promote cerebellar function remodeling and exert neuroprotective effects.
基金supported by the National Natural Science Foundation of China (31671117).
文摘Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and myelin in serious mental illnesses. However, whether these deficits contribute to the brain dysfunction or pathogenesis of such diseases still lacks direct evidence. In this study, we conditionally deleted Olig2 in oligodendroglial lineage cells (Olig2 cKO) and screened the behavioral changes in adult mice. We found that Olig2 ablation impaired myelin development, which further resulted in severe hypomyelination in the anterior cingulate cortex. Strikingly, Olig2 cKO mice exhibited an anxious phenotype, aberrant responses to stress, and cognitive deficits. Moreover, Olig2 cKO mice showed increased vulnerability to social avoidance under the mild stress of social isolation. Together,these results indicate that developmental deficits in OL and myelin lead to cognitive impairment and increase the risk of phenotypes reminiscent of mental illnesses.
基金supported by the National Natural Science Foundation of China (81071084)the International Science &Technology Cooperation Program of China (2010DFB30820)the Natural Science Foundation of Chongqing Municipality, China(2010DBF30820)
文摘Schizophrenia is a mental disease that mainly affects young individuals （15 to 35 years old） but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile （3 weeks）, young-adult （6 weeks） and middle-aged （8 months）, were subjected to a 6-week diet containing 0.2% cuprizone （CPZ） to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated： （1） CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; （2） the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1- positive mature oligodendrocytes, and higher levels of astrocyte activation; and （3） CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-relatedvulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.
基金supported by the Ministry of Science and Technology of China(2021ZD0201700)the National Natural Science Foundation of China(31921003).
文摘Astrocytes(ASTs)and oligodendroglial lineage cells(OLGs)are major macroglial cells in the central nervous system.ASTs communicate with each other through connexin(Cx)and Cx-based network structures,both of which allow for quick transport of nutrients and signals.Moreover,ASTs interact with OLGs through connexin(Cx)-mediated networks to modulate various physiological processes in the brain.In this article,following a brief description of the infrastructural basis of the glial networks and exocrine factors by which ASTs and OLGs may crosstalk,we focus on recapitulating how the interactions between these two types of glial cells modulate myelination,and how the AST-OLG interactions are involved in protecting the integrity of the blood-brain barrier(BBB)and regulating synaptogenesis and neural activity.Recent studies further suggest that AST-OLG interactions are associated with myelin-related diseases,such as multiple sclerosis.A better understanding of the regulatory mechanisms underlying AST-OLG interactions may inspire the development of novel therapeutic strategies for related brain diseases.
基金by grants from the National Natural Science Foundation of China(32000723)Chongqing Education Commission Fund(CXQT19009)+3 种基金Chongqing Outstanding Young Investigator Fund(cstc2019jcyjjqx0001)the Natural Science Foundation of Chongqing(cstc2017jcyjAX0365)the Army Medical University Natural Science Fund(31041455)the Open Project Program of the Brain and Intelligence Research Key Laboratory of Chongqing Education Commission of China(BIR2019004).
文摘Exposure to chronic hypoxia is considered to be a risk factor for deficits in brain function in adults,but the underlying mechanisms remain largely unknown.Since active myelinogenesis persists in the adult central nervous system,here we aimed to investigate the impact of chronic hypoxia on myelination and the related functional consequences in adult mice.Using a transgenic approach to label newly-generated myelin sheaths(NG2-CreER^(TM);Tau-mGFP),we found that myelinogenesis was highly active in most brain regions,such as the motor cortex and corpus callosum.After exposure to hypoxia(10%oxygen)12 h per day for 4 weeks,myelinogenesis was largely inhibited in the 4-month old brain and the mice displayed motor coordination deficits revealed by the beam-walking test.To determine the relationship between the inhibited myelination and functional impairment,we induced oligoden-droglia-specific deletion of the transcription factor 01ig2 by tamoxifen(NG2-CreER^(TM);Tau-mGFP;Olig2 fl/fl)in adult mice to mimic the decreased myelinogenesis caused by hypoxia.The deletion of OHg2 inhibited myelinogenesis and consequently impaired motor coordination,suggesting that myelinogenesis is required for motor function in adult mice.To understand whether enhancing myelination could protect brain functions against hypoxia,we treated hypoxic mice with the myelination-enhancing drug-clemastine,which resulted in enhanced myelogenesis and improved motor coordination.Taken together,our data indicate that chronic hypoxia inhibits myelinogenesis and causes functional deficits in the brain and that enhancing myelinogenesis protects brain functions against hypoxia-related deficits.
基金This work was supported by the National Natural Science Foundation of China(82071779 and 81901626)the Science Fund for Creative Research Groups of Chongqing Municipal Education Commission of China,the grants from the Talent Foundation of Army Medical University(to Shuang-Shuang Dai)+1 种基金the Scientific Research Grant(ALJ22J003)the Chongqing Natural Science Foundation of China(CSTB2022NSCQ-MSX0177).
文摘Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood.Methods:Using the combined single-cell transcriptomics,metabolomics,and proteomics analysis from TBI patients and the TBI mouse model,we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests.We also characterized the underlying mechanisms both invitro and invivo through molecular simulations,signaling detections,gene expression regulation assessments[including dual-luciferase reporter and chromatin immunoprecipitation(ChIP)assays],primary cultures or co-cultures of neutrophils and oligodendrocytes,intracellular iron,and lipid hydroperoxide concentration measurements,as well as forkhead box protein O1(FOXO1)conditional knockout mice.Results:We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model.Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI,aggravating acute brain inflammatory damage and promoting late TBI-induced depression.In the acute stage,FOXO1 upregulated cytoplasmic Versican(VCAN)to interact with the apoptosis regulator B-cell lymphoma-2(BCL-2)-associated X protein(BAX),suppressing the mitochondrial translocation of BAX,which mediated the antiapoptotic effect companied with enhancing interleukin-6(IL-6)production of FOXO1high neutrophils.In the chronic stage,the“FOXO1-transferrin receptor(TFRC)”mechanism contributes to FOXO1high neutrophil ferroptosis,disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein,which contributes to the progression of late depression after TBI.Conclusions:FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI,which provides insight into the heterogeneity,reprogramming activity,and versatility of neutrophils in TBI.
基金the Chongqing Education Commission Fund(CXQT19009)and Chongqing Outstanding Young Investigator Fund Project(cstc2019jcyjjqx0001)the Open Project Program of the Brain and Intelligence Research Key Laboratory of Chongqing Education Commission of China(BIR2019002)+1 种基金the Chongqing Scientific and Technical Innovation Foundation of China(CSTCKJCXLJRC07)the National Natural Science Foundation of China(31970921).
文摘Increasing evidence has shown that astrocytes are implicated in regulating oligodendrocyte myelination,but the underlying mechanisms remain largely unknown.To understand whether microRNAs in astrocytes function in regulating oligodendroglial differentiation and myelination in the developing and adult CNS,we generated inducible astrocyte-specific Dicer conditional knockout mice(hGFAP-CreERT;Dicer fl/fl).By using a reporter mouse line(mT/mG),we confirmed that hGFAP-CreERT drives an efficient and astrocyte-specific recombination in the developing CNS,upon tamoxifen treatment from postnatal day 3(P3)to P7.The Dicer deletion in astrocytes resulted in inhibited oligodendroglial differentiation and myelination in the developing CNS of Dicer cKO mice at P10 and P14,and did not alter the densities of neurons or axons,indicating that Dicer in astrocytes is required for oligodendrocyte myelination.Consequently,the Dicer deletion in astrocytes at P3 resulted in impaired spatial memory and motor coordination at the age of 9 weeks.To understand whether Dicer in astrocytes is also required for remyelination,we induced Dicer deletion in 3-month-old mice and then injected lysolecithin into the corpus callosum to induce demyelination.The Dicer deletion in astrocytes blocked remyelination in the corpus callosum 14 days after induced demyelination.Together,our results indicate that Dicer in astrocytes is required for oligodendroglia myelination in both the developing and adult CNS.
基金supported by grants from the National Natural Science Foundation of China(31871075 and 32071015)the Open Project of Chongqing Key Laboratory of Neurobiology(cqsjsw202103 and cqsjsw202101)the Natural Science Foundation of Chongqing(cstc2020jcyj-msxmX0391).
文摘The anterior auditory field(AAF)is a core region of the auditory cortex and plays a vital role in discrimination tasks.However,the role of the AAF corticostriatal neurons in frequency discrimination remains unclear.Here,we used c-Fos staining,fiber photometry recording,and pharmacogenetic manipulation to investigate the function of the AAF corticostriatal neurons in a frequency discrimination task.c-Fos staining and fiber photometry recording revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task.Pharmacogenetic inhibition of AAF pyramidal neurons significantly impaired frequency discrimination.In addition,histological results revealed that AAF pyramidal neurons send strong projections to the striatum.Moreover,pharmacogenetic suppression of the striatal projections from pyramidal neurons in the AAF significantly disrupted the frequency discrimination.Collectively,our findings show that AAF pyramidal neurons,particularly the AAF–striatum projections,play a crucial role in frequency discrimination behavior.
基金supported by grants from National Natural Science Foundation of China(No.82073778,China)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-026,China)+1 种基金Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study(Z141102004414062,China)National Natural Science Foundation of China(No.82104106)。
文摘The extremely low bioavailability of oral paclitaxel(PTX)mainly due to the complicated gastrointestinal environment,the obstruction of intestinal mucus layer and epithelium barrier.Thus,it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously.In this work,a high-density PEGylation-based glycocholic acid-decorated micelles(PTX@GNPs)was constructed by a novel polymer,9-Fluorenylmethoxy carbonyl-poly ethylene glycocholic acid(Fmoc-PEG-GCA).The Fmoc motif in this polymer could encapsulate PTX viaπ-πstacking to form the core of micelles,and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG.Based on this versatile and flexible carriers,PTX@GNPs possess mucus trapping escape ability due to the flexible PEG,and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter.The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX,and exhibited similar antitumor efficacy to Taxol injection via intravenous route.In addition,oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX,which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.
基金supported by the National Basic Research Program of China(2009CB918300)the National Natural Science Foundation of China(31271189 and 81101009)
文摘A multiplexed targeted proteomic assay using a mTRAQ-MRM/MS-based approach was developed and assessed to systematically quantify the relative expressions of five candidate plasma apolipoproteins that have been previously shown to be dysregulated in neuropsychiatric disorders and cognitive dysfunction:apolipoprotein H(APOH),apolipoprotein J(APOJ),apolipoprotein A4(APOA4),apolipoprotein E(APOE),and apolipoprotein D(APOD).The peptides and transitions of each APO were carefully selected according to the tandem MS signals acquired on a TripleTOFTM 5600,followed by optimization of the declustering potential and collision energy voltages for transitions on a QTRAP 5500.Our results showed that the collision energies of mTRAQ-labeled peptides were approximately 15%–20%higher than corresponding non-labeled peptides.Through optimized transitions and parameters,we analyzed the relative abundances of the five APOs in human plasma with and without depletion of high abundant proteins.The results indicated that the MRM signals of four target APOs were significantly increased after depletion,while the MRM signal of one APO,APOD,was decreased.Furthermore,the relative abundances of the five target APOs in healthy human plasma were stable,and the ranking of these proteins according to their MS responses changed slightly.Therefore,we deduced that the rank order of the MS signals for these target proteins can be developed as a diagnostic signature for diseased plasma.
