查看更多>>摘要：Epilepsy is a common,chronic neurological disorder that has been associated with impaired neurode-velopment and immunity.The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism.Here,we first determined the expression pattern and distribu-tion of the CXCR5 gene in the mouse brain during differ-ent stages of development and the brain tissue of patients with epilepsy.Subsequently,we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylene-tetrazol-and kainic acid-induced seizures,whereas CXCR5 overexpression had the opposite effect.CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons.Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model,we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment.Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability,resulting in an increased number of seizures.Finally,our results suggested that CXCR5 deficiency triggers seizure-related electrical activ-ity through a previously unknown mechanism,namely,the disruption of neuronal polarity.
查看更多>>摘要：Autism spectrum disorder(ASD)is one of the common neurodevelopmental disorders in children.Its etiol-ogy and pathogenesis are poorly understood.Previous stud-ies have suggested potential changes in the complement and coagulation pathways in individuals with ASD.In this study,using multiple reactions monitoring proteomic technology,16 of the 33 proteins involved in this pathway were identi-fied as differentially-expressed proteins in plasma between children with ASD and controls.Among them,CFHR3,C4BPB,C4BPA,CFH,C9,SERPIND1,C8A,F9,and F11 were found to be altered in the plasma of children with ASD for the first time.SERPIND1 expression was positively cor-related with the CARS score.Using the machine learning method,we obtained a panel composed of 12 differentially-expressed proteins with diagnostic potential for ASD.We also reviewed the proteins changed in this pathway in the brain and blood of patients with ASD.The complement and coagulation pathways may be activated in the periph-eral blood of children with ASD and play a key role in the pathogenesis of ASD.
查看更多>>摘要：We previously identified a unique nucleus,the cerebrospinal fluid(CSF)-contacting nucleus.This study aims to understand its gene architecture and preliminarily suggest its functions.The results showed that there were about 19,666 genes in this nucleus,of which 913 were dis-tinct from the dorsal raphe nucleus(non-CSF contacting).The top 40 highly-expressed genes are mainly related to energy metabolism,protein synthesis,transport,secretion,and hydrolysis.The main neurotransmitter is 5-HT.The receptors of 5-HT and GABA are abundant.The channels for Cl-,Na+,K+,and Ca2+ are routinely expressed.The signal-ing molecules associated with the CaMK,JAK,and MAPK pathways were identified accurately.In particular,the chan-nels of transient receptor potential associated with nocicep-tors and the solute carrier superfamily members associated with cell membrane transport were significantly expressed.The relationship between the main genes of the nucleus and life activities is preliminarily verified.
查看更多>>摘要：Opioid use disorder(OUD)has become a con-siderable global public health challenge;however,potential medications for the management of OUD that are effective,safe,and nonaddictive are not available.Accumulating pre-clinical evidence indicates that antagonists of the dopamine D3 receptor(D3R)have effects on addiction in different animal models.We have previously reported that YQA14,a D3R antagonist,exhibits very high affinity and selectiv-ity for D3Rs over D2Rs,and is able to inhibit cocaine-or methamphetamine-induced reinforcement and reinstatement in self-administration tests.In the present study,our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-admin-istered rats,also attenuated heroin-induced reinstatement of drug-seeking behavior.On the other hand,YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice.Moreover,we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibit-ing morphine-induced up-regulation of dopaminergic neu-ron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber pho-tometry recording system.These findings suggest that D3R might play a very important role in opioid addiction,and YQA14 may have pharmacotherapeutic potential in attenu-ating opioid-induced addictive behaviors dependent on the dopamine system.
查看更多>>摘要：The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases,such as depression and anxiety.Meanwhile,the endocannabinoid system plays a crucial role in regu-lating emotions and mainly functions through the cannabi-noid type-1 receptor(CB1R),which is strongly expressed in the amygdala of non-human primates(NHPs).However,it remains largely unknown how the CB1Rs in the amyg-dala of NHPs regulate mental diseases.Here,we investi-gated the role of CB1R by knocking down the cannabinoid receptor 1(CNR1)gene encoding CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA.We found that CB1R knockdown in the amygdala induced anxiety-like behaviors,including disrupted night sleep,agitated psychomotor activity in new environments,and reduced social desire.Moreover,marmosets with CB1R-knockdown had up-regulated plasma cortisol levels.These results indicate that the knockdown of CB1Rs in the amygdala induces anxiety-like behaviors in marmosets,and this may be the mechanism underlying the regulation of anxiety by CB1Rs in the amygdala of NHPs.
查看更多>>摘要：Parvalbumin interneurons belong to the major types of GABAergic interneurons.Although the distribu-tion and pathological alterations of parvalbumin interneu-ron somata have been widely studied,the distribution and vulnerability of the neurites and fibers extending from par-valbumin interneurons have not been detailly interrogated.Through the Cre recombinase-reporter system,we visual-ized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain.We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions,among which the cortex and thalamus exhibited the most intense parvalbumin signals.In regions such as the stria-tum and optic tract,even long-range thick parvalbumin pro-jections were detected.Furthermore,in mouse models of temporal lobe epilepsy and Parkinson's disease,parvalbu-min fibers suffered both massive and subtle morphological alterations.Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.
查看更多>>摘要：Understanding the fundamental processes of human brain development and diseases is of great impor-tance for our health.However,existing research models such as non-human primate and mouse models remain limited due to their developmental discrepancies compared with humans.Over the past years,an emerging model,the"brain organoid"integrated from human pluripotent stem cells,has been developed to mimic developmental processes of the human brain and disease-associated phenotypes to some extent,making it possible to better understand the complex structures and functions of the human brain.In this review,we summarize recent advances in brain organoid technolo-gies and their applications in brain development and dis-eases,including neurodevelopmental,neurodegenerative,psychiatric diseases,and brain tumors.Finally,we also dis-cuss current limitations and the potential of brain organoids.
查看更多>>摘要：Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive lethal malignancy,characterized by late diagnosis,aggressive growth,and therapy resistance,leading to a poor overall prognosis.Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape.The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets.In this review,we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC,summarize the potential signaling pathways modulating the neuronal-cancer interaction,and discuss the current and future therapeutic possibilities for this condition.
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