查看更多>>摘要：Autism spectrum disorder(ASD)is a highly her-itable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hun-dreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic studies.Here,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.Using a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related genes.Importantly,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human brain.By further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ASD.Finally,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD patients.This work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.
查看更多>>摘要：The discovery of neuroglobin(Ngb),a brain-or neuron-specific member of the hemoglobin family,has revolutionized our understanding of brain oxygen metab-olism.Currently,how Ngb plays such a role remains far from clear.Here,we report a novel mechanism by which Ngb might facilitate neuronal oxygenation upon hypoxia or anemia.We found that Ngb was present in,co-localized to,and co-migrated with mitochondria in the cell body and neurites of neurons.Hypoxia induced a sudden and promi-nent migration of Ngb towards the cytoplasmic membrane(CM)or cell surface in living neurons,and this was accom-panied by the mitochondria.In vivo,hypotonic and anemic hypoxia induced a reversible Ngb migration toward the CM in cerebral cortical neurons in rat brains but did not alter the expression level of Ngb or its cytoplasm/mitochondria ratio.Knock-down of Ngb by RNA interference significantly diminished respiratory succinate dehydrogenase(SDH)and ATPase activity in neuronal N2a cells.Over-expression of Ngb enhanced SDH activity in N2a cells upon hypoxia.Mutation of Ngb at its oxygen-binding site(His64)signifi-cantly increased SDH activity and reduced ATPase activ-ity in N2a cells.Taken together,Ngb was physically and functionally linked to mitochondria.In response to an insuf-ficient oxygen supply,Ngb migrated towards the source of oxygen to facilitate neuronal oxygenation.This novel mecha-nism of neuronal respiration provides new insights into the understanding and treatment of neurological diseases such as stroke and Alzheimer's disease and diseases that cause hypoxia in the brain such as anemia.
查看更多>>摘要：Chronic cerebral hypoperfusion leads to white matter injury(WMI),which subsequently causes neurode-generation and even cognitive impairment.However,due to the lack of treatment specifically for WMI,novel recognized and effective therapeutic strategies are urgently needed.In this study,we found that honokiol and magnolol,two com-pounds derived from Magnolia officinalis,significantly facilitated the differentiation of primary oligodendrocyte precursor cells(OPCs)into mature oligodendrocytes,with a more prominent effect of the former compound.Moreover,our results demonstrated that honokiol treatment improved myelin injury,induced mature oligodendrocyte protein expression,attenuated cognitive decline,promoted oligoden-drocyte regeneration,and inhibited astrocytic activation in the bilateral carotid artery stenosis model.Mechanistically,honokiol increased the phosphorylation of serine/threonine kinase(Akt)and mammalian target of rapamycin(mTOR)by activating cannabinoid receptor 1 during OPC differentia-tion.Collectively,our study indicates that honokiol might serve as a potential treatment for WMI in chronic cerebral ischemia.
查看更多>>摘要：The histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit(EZH2)-medi-ated trimethylation of histone H3 lysine 27(H3K27me3)regulates neural stem cell proliferation and fate specificity through silencing different gene sets in the central nervous system.Here,we explored the function of EZH2 in early post-mitotic neurons by generating a neuron-specific Ezh2 conditional knockout mouse line.The results showed that a lack of neuronal EZH2 led to delayed neuronal migration,more complex dendritic arborization,and increased den-dritic spine density.Transcriptome analysis revealed that neuronal EZH2-regulated genes are related to neuronal mor-phogenesis.In particular,the gene encoding p21-activated kinase 3(Pak3)was identified as a target gene suppressed by EZH2 and H3K27me3,and expression of the dominant neg-ative Pak3 reversed Ezh2 knockout-induced higher dendritic spine density.Finally,the lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice.Our results demonstrated that neuronal EZH2 acts to control multiple steps of neuronal morphogenesis during development,and has long-lasting effects on cognitive function in adult mice.
查看更多>>摘要：Alzheimer's disease(AD)is associated with the impairment of white matter(WM)tracts.The current study aimed to verify the utility of WM as the neuroim-aging marker of AD with multisite diffusion tensor imag-ing datasets[321 patients with AD,265 patients with mild cognitive impairment(MCI),279 normal controls(NC)],a unified pipeline,and independent site cross-validation.Automated fiber quantification was used to extract diffu-sion profiles along tracts.Random-effects meta-analyses showed a reproducible degeneration pattern in which frac-tional anisotropy significantly decreased in the AD and MCI groups compared with NC.Machine learning models using tract-based features showed good generalizability among independent site cross-validation.The diffusion metrics of the altered regions and the AD probability predicted by the models were highly correlated with cognitive ability in the AD and MCI groups.We highlighted the reproducibility and generalizability of the degeneration pattern of WM tracts in AD.
查看更多>>摘要：The secondary motor cortex(M2)encodes choice-related information and plays an important role in cue-guided actions.M2 neurons innervate the dorsal stria-tum(DS),which also contributes to decision-making behav-ior,yet how M2 modulates signals in the DS to influence perceptual decision-making is unclear.Using mice perform-ing a visual Go/No-Go task,we showed that inactivating M2 projections to the DS impaired performance by increasing the false alarm(FA)rate to the reward-irrelevant No-Go stimulus.The choice signal of M2 neurons correlated with behavioral performance,and the inactivation of M2 neurons projecting to the DS reduced the choice signal in the DS.By measuring and manipulating the responses of direct or indirect pathway striatal neurons defined by M2 inputs,we found that the indirect pathway neurons exhibited a shorter response latency to the No-Go stimulus,and inactivating their early responses increased the FA rate.These results demonstrate that the M2-to-DS pathway is crucial for sup-pressing inappropriate responses in perceptual decision behavior.
查看更多>>摘要：Genetic tools,which can be used for the mor-phology study of specific neurons,pathway-selective con-nectome mapping,neuronal activity monitoring,and manip-ulation with a spatiotemporal resolution,have been widely applied to the understanding of complex neural circuit formation,interactions,and functions in rodents.Recently,similar genetic approaches have been tried in non-human primates(NHPs)in neuroscience studies for dissecting the neural circuits involved in sophisticated behaviors and clini-cal brain disorders,although they are still very preliminary.In this review,we introduce the progress made in the devel-opment and application of genetic tools for brain studies on NHPs.We also discuss the advantages and limitations of each approach and provide a perspective for using genetic tools to study the neural circuits of NHPs.
查看更多>>摘要：Respiration protocols have been developed to manipulate mental states,including their use for therapeu-tic purposes.In this systematic review,we discuss evidence that respiration may play a fundamental role in coordinating neural activity,behavior,and emotion.The main findings are:(1)respiration affects the neural activity of a wide vari-ety of regions in the brain;(2)respiration modulates differ-ent frequency ranges in the brain's dynamics;(3)different respiration protocols(spontaneous,hyperventilation,slow or resonance respiration)yield different neural and mental effects;and(4)the effects of respiration on the brain are related to concurrent modulation of biochemical(oxygen delivery,pH)and physiological(cerebral blood flow,heart rate variability)variables.We conclude that respiration may be an integral rhythm of the brain's neural activity.This provides an intimate connection of respiration with neuro-mental features like emotion.A respiratory-neuro-mental connection holds the promise for a brain-based therapeutic usage of respiration in mental disorders.
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