查看更多>>摘要：Brain size abnormality is correlated with an increased frequency of autism spectrum disorder(ASD)in offspring.Genetic analysis indicates that heterozygous muta-tions of the WD repeat domain 62(WDR62)are associated with ASD.However,biological evidence is still lacking.Our study showed that Wdr62 knockout(KO)led to reduced brain size with impaired learning and memory,as well as ASD-like behaviors in mice.Interestingly,Wdr62 Nex-cKO mice(depletion of WDR62 in differentiated neurons)had a largely normal brain size but with aberrant social interac-tions and repetitive behaviors.WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cor-tical pyramidal neurons.Finally,we revealed that retinoic acid gavages significantly alleviated ASD-like behaviors in mice with WDR62 haploinsufficiency,probably by comple-menting the expression of ASD and synapse-related genes.Our findings provide a new perspective on the relationship between the microcephaly gene WDR62 and ASD etiology that will benefit clinical diagnosis and intervention of ASD.
查看更多>>摘要：The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorso-lateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.
查看更多>>摘要：Although sympathetic blockade is clinically used to treat pain,the underlying mechanisms remain unclear.We developed a localized microsympathectomy(mSYMPX),by cutting the grey rami entering the spinal nerves near the rodent lumbar dorsal root ganglia(DRG).In a chem-otherapy-induced peripheral neuropathy model,mSYMPX attenuated pain behaviors via DRG macrophages and the anti-inflammatory actions of transforming growth factor-β(TGF-β)and its receptor TGF-βR1.Here,we examined the role of TGF-β in sympathetic-mediated radiculopathy produced by local inflammation of the DRG(LID).Mice showed mechanical hypersensitivity and transcriptional and protein upregulation of TGF-β1 and TGF-βR1 three days after LID.Microsympathectomy prevented mechanical hypersensitivity and further upregulated Tgfb1 and Tgfbr1.Intrathecal delivery of TGF-β1 rapidly relieved the LID-induced mechanical hypersensitivity,and TGF-βR1 antago-nists rapidly unmasked the mechanical hypersensitivity after LID+mSYMPX.In situ hybridization showed that Tgfb1 was largely expressed in DRG macrophages,and Tgfbr1 in neurons.We suggest that TGF-β signaling is a general underlying mechanism of local sympathetic blockade.
查看更多>>摘要：Ischemic stroke is a major public health problem worldwide.Although the circadian clock is involved in the process of ischemic stroke,the exact mechanism of the cir-cadian clock in regulating angiogenesis after cerebral infarc-tion remains unclear.In the present study,we determined that environmental circadian disruption(ECD)increased the stroke severity and impaired angiogenesis in the rat middle cerebral artery occlusion model,by measuring the infarct volume,neurological tests,and angiogenesis-related protein.We further report that Bmal1 plays an irreplaceable role in angiogenesis.Overexpression of Bmal1 promoted tube-forming,migration,and wound healing,and upregulated the vascular endothelial growth factor(VEGF)and Notch path-way protein levels.This promoting effect was reversed by the Notch pathway inhibitor DAPT,according to the results of angiogenesis capacity and VEGF pathway protein level.In conclusion,our study reveals the intervention of ECD in angiogenesis in ischemic stroke and further identifies the exact mechanism by which Bmal1 regulates angiogenesis through the VEGF-Notchl pathway.
查看更多>>摘要：Females increase aggression for mating oppor-tunities and for acquiring reproductive resources.Although the close relationship between female aggression and mat-ing status is widely appreciated,whether and how female aggression is regulated by mating-related cues remains poorly understood.Here we report an interesting observa-tion that Drosophila virgin females initiate high-frequency attacks toward mated females.We identify 11-cis-vacce-nyl acetate(cVA),a male-derived pheromone transferred to females during mating,which promotes virgin female aggression.We subsequently reveal a cVA-responsive neural circuit consisting of four orders of neurons,including Or67d,DA1,aSP-g,and pC1 neurons,that mediate cVA-induced virgin female aggression.We also determine that aSP-g neurons release acetylcholine(ACh)to excite pC1 neurons via the nicotinic ACh receptor nAChRα7.Together,beyond revealing cVA as a mating-related inducer of virgin female aggression,our results identify a neural circuit linking the chemosensory perception of mating-related cues to aggres-sive behavior in Drosophila females.
查看更多>>摘要：L-dopa(1-3,4-dihydroxyphenylalanine)-induced dyskinesia(LID)is a debilitating complication of dopa-mine replacement therapy for Parkinson's disease.The potential contribution of striatal D2 receptor(D2R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear.In this study,we investigated the role of striatal D2R+neurons and downstream globus pal-lidus externa(Gpe)neurons in a rat model of LID.Intras-triatal administration of raclopride,a D2R antagonist,sig-nificantly inhibited dyskinetic behavior,while intrastriatal administration of pramipexole,a D2-like receptor agonist,yielded aggravation of dyskinesia in LID rats.Fiber pho-tometry revealed the overinhibition of striatal D2R+neurons and hyperactivity of downstream Gpe neurons during the dyskinetic phase of LID rats.In contrast,the striatal D2R+neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia.Consistent with the above findings,optogenetic activation of striatal D2R+ neurons or their projections in the Gpe was adequate to suppress most of the dyskinetic behaviors of LID rats.Our data demon-strate that the aberrant activity of striatal D2R+ neurons and downstream Gpe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.
查看更多>>摘要：Major depressive disorder(MDD)is a highly heterogeneous mental disorder,and its complex etiology and unclear mechanism are great obstacles to the diagnosis and treatment of the disease.Studies have shown that abnormal functions of the visual cortex have been reported in MDD patients,and the actions of several antidepressants coincide with improvements in the structure and synaptic functions of the visual cortex.In this review,we critically evaluate current evidence showing the involvement of the malfunc-tioning visual cortex in the pathophysiology and therapeutic process of depression.In addition,we discuss the molecular mechanisms of visual cortex dysfunction that may underlie the pathogenesis of MDD.Although the precise roles of visual cortex abnormalities in MDD remain uncertain,this undervalued brain region may become a novel area for the treatment of depressed patients.
查看更多>>摘要：In the central nervous system,nitric oxide(NO),a free gas with multitudinous bioactivities,is mainly pro-duced from the oxidation of L-arginine by neuronal nitric oxide synthase(nNOS).In the past 20 years,the studies in our group and other laboratories have suggested a signifi-cant involvement of nNOS in a variety of neurological and neuropsychiatric disorders.In particular,the interactions between the PDZ domain of nNOS and its adaptor proteins,including post-synaptic density 95,the carboxy-terminal PDZ ligand of nNOS,and the serotonin transporter,signifi-cantly influence the subcellular localization and functions of nNOS in the brain.The nNOS-mediated protein-protein interactions provide new attractive targets and guide the dis-covery of therapeutic drugs for neurological and neuropsy-chiatric disorders.Here,we summarize the work on the roles of nNOS and its association with multiple adaptor proteins on neurological and neuropsychiatric disorders.
万方数据
维普