查看更多>>摘要：Mutations in genes encoding amyloid precursor protein(APP)and presenilins(PSs)cause familial forms of Alzheimer's disease(AD),a neurodegenerative disor-der strongly associated with aging.It is currently unknown whether and how AD risks affect early brain development,and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology.Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis.Among these lines,the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in study-ing amyloid plaque formation and amyloid β(Aβ)-induced neurodegeneration.We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons,and performed detailed synaptic physiological characterization of layer 5(L5)neurons from the prefrontal cortex(PFC)of 5XFAD and wild-type littermate controls.L5 PFC neurons from 5XFAD mice show early APP/Aβ immunolabeling.Whole-cell patch-clamp recording at an early post-weaning age(P22-30)revealed functional impairments;although 5XFAD PFC-L5 neurons exhibited similar membrane prop-erties,they were intrinsically less excitable.In addition,these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs.These functional disturbances were further corroborated by decreased den-dritic spine density and spine head volumes that indicated impaired synapse maturation.Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor sub-unit GluA1 and decreased synaptic NMDA receptor subu-nit GluN2A.Consistent with this,patch-clamp recording of the evoked L23＞L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio,and an increased level of AMPAR-lacking silent synapses.These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of corti-cal circuits,which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.
查看更多>>摘要：Accurate and efficient methods for identifying and tracking each animal in a group are needed to study complex behaviors and social interactions.Traditional tracking methods(e.g.,marking each animal with dye or surgically implanting microchips)can be invasive and may have an impact on the social behavior being measured.To overcome these shortcomings,video-based methods for tracking unmarked animals,such as fruit flies and zebrafish,have been developed.However,tracking individual mice in a group remains a challenging problem because of their flexible body and complicated interaction patterns.In this study,we report the development of a multi-object tracker for mice that uses the Faster region-based convolutional neural network(R-CNN)deep learning algorithm with geo-metric transformations in combination with multi-camera/multi-image fusion technology.The system successfully tracked every individual in groups of unmarked mice and was applied to investigate chasing behavior.The proposed system constitutes a step forward in the noninvasive tracking of individual mice engaged in social behavior.
查看更多>>摘要：Increased intestinal barrier permeability,leaky gut,has been reported in patients with autism.However,its contribution to the development of autism has not been determined.We selected dextran sulfate sodium(DSS)to disrupt and metformin to repair the intestinal barrier in BTBR T+tf/J autistic mice to test this hypothesis.DSS treat-ment resulted in a decreased affinity for social proximity;however,autistic behaviors in mice were improved after the administration of metformin.We found an increased affinity for social proximity/social memory and decreased repetitive and anxiety-related behaviors.The concentration of lipopol-ysaccharides in blood decreased after the administration of metformin.The expression levels of the key molecules in the toll-like receptor 4(TLR4)-myeloid differentiation factor 88(MyD88)-nuclear factor kappa B(NF-κB)pathway and their downstream inflammatory cytokines in the cerebral cortex were both repressed.Thus,"leaky gut"could be a trigger for the development of autism via activation of the lipopolysac-charide-mediated TLR4-MyD88-NF-KB pathway.
查看更多>>摘要：A decline in the activities of oxidative phos-phorylation(OXPHOS)complexes has been consistently reported in amyotrophic lateral sclerosis(ALS)patients and animal models of ALS,although the underlying molecular mechanisms are still elusive.Here,we report that receptor expression enhancing protein 1(REEP1)acts as an impor-tant regulator of complex Ⅳ assembly,which is pivotal to preserving motor neurons in SOD1G93A mice.We found the expression of REEP1 was greatly reduced in transgenic SOD1G93A mice with ALS.Moreover,forced expression of REEP1 in the spinal cord extended the lifespan,decelerated symptom progression,and improved the motor performance of SOD1G93A mice.The neuromuscular synaptic loss,glio-sis,and even motor neuron loss in SOD1G93A mice were alleviated by increased REEP1 through augmentation of mitochondrial function.Mechanistically,REEP1 associates with NDUFA4,and plays an important role in preserving the integrity of mitochondrial complex Ⅳ.Our findings offer insights into the pathogenic mechanism of REEP1 deficiency in neurodegenerative diseases and suggest a new therapeutic target for ALS.
查看更多>>摘要：Effective treatments for neuropathic pain are lacking due to our limited understanding of the mechanisms.The circRNAs are mainly enriched in the central nervous system.However,their function in various physiological and pathological conditions have yet to be determined.Here,we identified circFhit,an exon-intron circRNA expressed in GABAergic neurons,which reduced the inhibitory synap-tic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic pain.Moreover,we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R+neurons by promoting the expression of its parental gene Fhit in cis.Mechanistically,circFhit was directly bound to the intronic region of Fhit,and formed a circFhit/HNRNPK complex to promote Pol Ⅱphosphorylation and H2B monoubiquitination by recruit-ing CDK9 and RNF40 to the Fhit intron.In summary,we revealed that the exon-intron circFhit contributes to GABAe-rgic neuron-mediated NK1R+neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.
查看更多>>摘要：The anterior auditory field(AAF)is a core region of the auditory cortex and plays a vital role in dis-crimination tasks.However,the role of the AAF corticos-triatal neurons in frequency discrimination remains unclear.Here,we used c-Fos staining,fiber photometry recording,and pharmacogenetic manipulation to investigate the func-tion of the AAF corticostriatal neurons in a frequency dis-crimination task.c-Fos staining and fiber photometry record-ing revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task.Pharmacogenetic inhibition of AAF pyramidal neu-rons 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.
查看更多>>摘要：Major depressive disorder(MDD)is character-ized by emotion dysregulation.Whether implicit emotion regulation can compensate for this deficit remains unknown.In this study,we recruited 159 subjects who were healthy controls,had subclinical depression,or had MDD,and examined them under baseline,implicit,and explicit reap-praisal conditions.Explicit reappraisal led to the most nega-tive feelings and the largest parietal late positive potential(parietal LPP,an index of emotion intensity)in the MDD group compared to the other two groups;the group dif-ference was absent under the other two conditions.MDD patients showed larger regulatory effects in the LPP during implicit than explicit reappraisal,whereas healthy controls showed a reversed pattern.Furthermore,the frontal P3,an index of voluntary cognitive control,showed larger ampli-tudes in explicit reappraisal compared to baseline in the healthy and subclinical groups,but not in the MDD group,while implicit reappraisal did not increase P3 across groups.These findings suggest that implicit reappraisal is beneficial for clinical depression.
查看更多>>摘要：Evading or escaping from predators is one of the most crucial issues for survival across the animal king-dom.The timely detection of predators and the initiation of appropriate fight-or-flight responses are innate capabili-ties of the nervous system.Here we review recent progress in our understanding of innate visually-triggered defensive behaviors and the underlying neural circuit mechanisms,and a comparison among vinegar flies,zebrafish,and mice is included.This overview covers the anatomical and func-tional aspects of the neural circuits involved in this process,including visual threat processing and identification,the selection of appropriate behavioral responses,and the ini-tiation of these innate defensive behaviors.The emphasis of this review is on the early stages of this pathway,namely,threat identification from complex visual inputs and how behavioral choices are influenced by differences in visual threats.We also briefly cover how the innate defensive response is processed centrally.Based on these summaries,we discuss coding strategies for visual threats and propose a common prototypical pathway for rapid innate defensive responses.
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维普