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Chx10+V2a interneurons in spinal motor regulation and spinal cord injury

Neural Regeneration Research 2023年第5期18卷 933-939页

作者： Wen-Yuan Li Ling-Xiao Deng Feng-Guo Zhai Xiao-Yu Wang Zhi-Gang Li Ying Wang Institute of Neural Tissue Engineering Mudanjiang College of MedicineMudanjiangHeilongjiang ProvinceChina Spinal Cord and Brain Injury Research Group Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisINUSA Department of Pharmacy Mudanjiang College of MedicineMudanjiangHeilongjiang ProvinceChina Department of General Surgery Hongqi HospitalMudanjiang College of MedicineMudanjiangHeilongjiang ProvinceChina

Chx10-expressing V2 a(Chx10+V2 a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2 a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2 a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2 a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2 a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2 a interneurons also play an important role in rhythmic patterning maintenance, leftright alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2 a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2 a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2 a interneurons transplanted in spinal cord injury foci.

关键词： axons central nervous system central pattern generator Chx10 differentiation interneurons locomotion motor neurons propriospinal spinal cord injuries therapy transcription factor transplantation V2a neuron

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Selective Targeting of Perirhinal Cortex Projection to Hippocampal CA1 interneurons

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Neuroscience Bulletin 2019年第4期35卷 763-765页

作者： Xiang Li Yiding Li Junhui Zhang Xiaohui Zhang State Key Laboratory of Cognitive Neuroscience & Learning IDG/McGovern Institute for Brain Research Beijing Normal University Beijing 100875 China Department of Joint Surgery The 6th Hospital of Ningbo Ningbo 31500 China

Dear Editor,The perirhinal cortex (PER) is conceptually important in the recognition memory, especially in familiarity discrimination, whereas the hippocampus is important for association and recollection [1]. This no... 详细信息

关键词： Selective Targeting Perirhinal Cortex CA1 interneurons

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Parvalbumin interneurons in anterior cingu⁃late cortex regulate cognitive behaviors in methylazoxymethanol acetate model of schizophrenia

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中国药理学与毒理学杂志 2021年第9期35卷 666-667页

作者： ZHANG Xiao-qin XU Le YU Zhi-peng SHEN Hao-wei Department of Pharmacology School of MedicineNingbo UniversityNingbo 315211China Key Laboratory of Addiction Research of Zhejiang Province Ningbo 315010China

OBJECTIVE Cognitive dysfunc⁃tion is a core disturbance of schizophrenia,appear to emerge from impaired neural activity.The anterior cingulate cortex(ACC)is an integra⁃tion hub for higher-order thalamic inputs impor⁃tant for complex cognitive tasks such as learning and memory processes,attention and social interaction.Parvalbumin(PV)interneurons could filter information at pyramidal neurons of ACC,and the abnormal PV interneurons have been observed in both humans and animal models of schizophrenia.However,the mechanisms of PV interneurons in ACC regulating cognition in schizophrenia is poorly understood.METHODS The pregnant mice were injected with methyl⁃azoxymethanol acetate(MAM)on gestational day(GD)16 for the neurodevelopmental MAM model of schizophrenia in our study.We investi⁃gated the cognitive behaviors by a serious of tests such as pre-pulse inhibition,Y maze,novel object and novel location recognition and the intrinsic excitability of PV interneurons and inhibi⁃tory synaptic transmission onto pyramidal cells localized in layer 5 of ACC by whole-cell record⁃ings.Further,the PV interneurons were regulat⁃ed by designer receptor exclusively activated by a designer drug(DREADD)system and the D-serine,a co-agonist of N-methyl-D-aspartate(NMDA)receptors.RESULTS①MAM mice showed the cognitive deficits and hypo-excitability of PV interneurons in ACC.②Restoration of PV interneuron activity in ACC improved cognitive function in MAM mice.③Inhibition of PV interneu⁃ron activity in ACC was sufficient to cause cogni⁃tive dysfunction in control mice.④NMDA recep⁃tors of PV interneurons in ACC were impaired in MAM mice.⑤Deficits of NMDA receptor sig⁃naling specifically in PV interneurons and of cog⁃nitive behaviors in MAM mice were rescued by D-serine.CONCLUSION PV interneurons in ACC are closely related to cognitive function in the MAM model of schizophrenia and D-serine maybe a potential therapy for schizophrenia.

关键词： methylazoxymethanol acetate cognitive function parvalbumin interneurons D-serine

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Regulation of medial septum cholinergic neurons on activity of hippocampal CA1 interneurons

Regulation of medial septum cholinergic neurons on activity ...

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中国神经科学学会第十二届全国学术会议

作者： Yi-yao Zhang Long-nian Lin Key Laboratory of Brain Functional Genomics （Ministry of Education） Institute of Brain Functional Genomics School of Life Science East China Normal University

Hippocampal sharp-wave ripple complex during slow-wave sleep（SWS） plays a critical role in memory consolidation. Studies have shown that the content of hippocampal acetylcholine during SWS is much lower than that during active exploration. Anatomically, almost all the hippocampal cholinergic projections derive from medial septum（MS）. Recent studies have also shown that optogenetically activating MS cholinergic neurons can block hippocampal ripple oscillations. Meanwhile, the generation of hippocampal ripple oscillation is highly correlated with the firing patterns of particular hippocampal interneurons. In our experiment, we combine multi-channel in vivo recording with optogenetics to investigate the regulation mechanism of MS cholinergic neurons on hippocampal CA1 interneurons using chat-Ch R2 mice. We observe two distinctive responses of hippocampal interneurons to the light stimulation of MS cholinergic neurons. Type 1 interneurons（n=54） show decreased firing rate, while type 2 interneurons（n=29） display enhanced firing activity. In the class of type 1 interneurons, one sub-population of interneurons（n=12） shows a cluster of high frequency discharge（10-30 spikes） at each ripple event during SWS. The firing activity of these interneurons are phase-locked to ripple oscillation. The peak interspike interval（ISI） is at 8.2 ± 2.0 ms（98 Hz-161 Hz）, which is consistent with ripple frequency. We refer to these interneurons as "ripple-driving cell". Second sub-population of type 1 interneurons（n=15） shows strong phase-lock activity with theta, but not ripple oscillation.There is another sub-population of interneurons in contrast to ripple-driving cells. These neurons are active before and after ripple oscillations with significantly reduced firing rates at ripple peaks. The firing activity of such neurons is phase-locked with theta or gamma oscillation. Type 2 interneurons strongly increase their average firing rates from 8.55±5.26 Hz to 15.12±8 Hz（p＜0.05） along with the elevated content of hippocampal acetylcholine in

关键词： medial septum hippocampus acetylcholine interneurons sharp-wave ripple

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Foxg1 regulates the postnatal radial migration of cortical interneurons

Foxg1 regulates the postnatal radial migration of cortical I...

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中国神经科学学会第十二届全国学术会议

作者： Wei Shen Ru Ba Yan Su Yang Ni Dong Sheng Li-Juan Zhu Chunjie Zhao Key Laboratory of Developmental Genes and Human Diseases MOELife Science InstituteSoutheast University Department of Anatomy and Neuroscience School of Medicine Southeast University

Abnormalities in cortical interneurons are usually closely associated with neurological disorders such as epilepsy（Meyer et al., 2011）. Most patients with Foxg1 syndrome experience seizures, suggesting that Foxg1 has important roles in the development of cortical interneurons. According to our previous study, Foxg1 has significant functions in the tangential migration of cortical interneurons during embryonic development. Here, we explored its role in radial migration by deleting Foxg1 during postnatal development, which was achieved by crossing Foxg1 fl/fl mice with the Gad2-Cre ER line and treating the mice with tamoxifen. Ablation of Foxg1 resulted in impaired distributions of somatostatin-, calretinin-, and neuropeptide Y-positive interneurons in the cortex. Further investigations revealed that the migration capacity of cortical interneurons was significantly decreased, accompanied by a downregulation of C-X-C chemokine receptor 4（CXCR4） expression. Distal-less homeobox 1（Dlx1） expression was also decreased, resulting in the upregulation of Pak3 expression and ultimately the enhanced dendritic complexity of mutant interneurons, which may also be responsible for their decreased migration capacity. We further found that Foxg1 does not function upstream of KCC2 to regulate the termination of radial migration of cortical interneurons. Due to the imbalanced neural circuit, Foxg1 mutant mice showed increased seizure susceptibility in a pentylenetetrazole induction assay. Our work demonstrated that Foxg1 regulated the radial migration of cortical interneurons by preserving their migration capacity. These findings will improve our understanding of the radial migration of interneurons and help to elucidate the mechanisms underlying seizure symptoms in patients with Foxg1 syndrome.

关键词： interneurons radial migration Foxg1 CXCR4 Dlx1 zeizure

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Single Emxl-expressing neural stem cells give rise to both projection neurons and interneurons in vitro

Single Emxl-expressing neural stem cells give rise to both p...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yu-Qun CAI,Yue ZHANG,Zhen-Gang YANG~* Institutes of Brain Science and State Key Laboratory of Medical Neurobiology,Fudan University,Shanghai 200032, China

＜正＞There are two major subtypes of neurons in the brain:projection neurons and interneurons.During Drosophila nervous system development,a subpopulation of single neuroblasts（neural stem cells） can give rise to both projection neurons and interneurons.However,in mammalian brains,whether single neuroepithelial cells or radial glias（primary neural stem cells） can produce both projection neurons and interneurons remains largely unknown. Using fluorescence-activated cell sorting（FACS）,we cultured single Emxl-expressing neural stem cells derived from E10.5-11.5 mouse cortex.Two weeks after culturing in defined serum-free medium,multiple-immunostaining revealed that a subpopulation of single Emxl-expressing neural stem cells can produce both projection neurons and interneurons.The projection neurons in a single cell-derived clone express typical projection neuronal markers,such as Tbr1,Cux1,Ctip2,Foxp1 and Satb2,while interneurons in the same clone co-express Sp8 and calretinin.Thus, our preliminary results suggest that,during marine forebrain development,at least some projection neurons and interneurons share single multipotent progenitors.

关键词： projection neurons interneurons share single neural stem cells

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Hippocampus:Molecular,Cellular,and Circuit Features in Anxiety

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Neuroscience Bulletin 2023年第6期39卷 1009-1026页

作者： Hu-Jiang Shi Shuang Wang Xin-Ping Wang Rui-Xin Zhang Li-Juan Zhu Key Laboratory of Developmental Genes and Human Diseases MOEDepartment of Histology and EmbryologySchool of MedicineSoutheast UniversityNanjing210009China Shanghai Mental Health Center Shanghai Jiao Tong University School of MedicineShanghai201108China

Anxiety disorders are currently a major psychiatric and social problem,the mechanisms of which have been only partially elucidated.The hippocampus serves as a major target of stress mediators and is closely related to anxiety modulation.Yet so far,its complex anatomy has been a challenge for research on the mechanisms of anxiety regulation.Recent advances in imaging,virus tracking,and optogenetics/chemogenetics have permitted elucidation of the activity,connectivity,and function of specific cell types within the hippocampus and its connected brain regions,providing mechanistic insights into the elaborate organization of the hippocampal circuitry underlying anxiety.Studies of hippocampal neurotransmitter systems,including glutamatergic,GABAergic,cholinergic,dopaminergic,and serotonergic systems,have contributed to the interpretation of the underlying neural mechanisms of anxiety.Neuropeptides and neuroinflammatory factors are also involved in anxiety modulation.This review comprehensively summarizes the hippocampal mechanisms associated with anxiety modulation,based on molecular,cellular,and circuit properties,to provide tailored targets for future anxiety treatment.

关键词： Anxiety Hippocampus Excitatory neurons interneurons Neural circuit

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Genetic background of idiopathic neurodevelopmental delay patients with significant brain deviation volume

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Chinese Medical Journal 2023年第7期136卷 807-814页

作者： Xiang Chen Yuxi Chen Kai Yan Huiyao Chen Qian Qin Lin Yang Bo Liu Guoqiang Cheng Yun Cao Bingbing Wu Xinran Dong Zhongwei Qiao Wenhao Zhou Department of Neonatology Children’s Hospital of Fudan UniversityNational Children’s Medical CenterShanghai 201102China Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China Shanghai Key Laboratory of Birth Defects The Translational Medicine Center of Children Development and Disease of Fudan UniversityChildren’s Hospital of Fudan UniversityNational Children’s Medical CenterShanghai 201102China Department of Pediatric Endocrinology and Inherited Metabolic Diseases Children’s Hospital of Fudan UniversityNational Children’s Medical CenterShanghai 201102China Department of Radiology Children’s Hospital of Fudan UniversityNational Children’s Medical CenterShanghai 201102China State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Institutes of Brain ScienceFudan UniversityShanghai 200433China

Background:Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay(NDD),but its genetic basis has not been fully characterized.This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume(WBDV).Methods:We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years.We recruited only NDD patients without acquired etiologies or positive genetic results.Cranial magnetic resonance imaging(MRI)and clinical exome sequencing(2742 genes)data were acquired.A genetic burden test was performed,and the results were compared between patients with and without significant WBDV.Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development.Results:We recruited a total of 253 NDD patients.Among them,26 had significantly decreased WBDV(+2 SDs).NDD patients with significant WBDV had higher rates of motor development delay(49.8%[106/213]vs.75.0%[30/40],P=0.003)than patients without significant WBDV.Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV.Analyses of the literature further demonstrated that these genes were not randomly identified:burden genes were more related to the brain development than background genes(P=1.656e^(-9)).In seven human brain regions related to motor development,we observed burden genes had higher expression before 37-week gestational age than postnatal stages.Functional analyses found that burden genes were enriched in embryonic brain development,with positive regulation of synaptic growth at the neuromuscular junction,positive regulation of deoxyribonucleic acid templated transcription,and response to hormone,and these genes were shown to be expressed in neural progenitors.Based on single

关键词： Brain volume Burden genes Cranial Exome Transcriptome Gestational age Gene frequency Phenotype Magnetic resonance imaging Neuromuscular junction interneurons

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Lesions of mediodorsal thalamic nucleus reverse abnormal firing of the medial prefrontal cortex neurons in parkinsonian rats

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Neural Regeneration Research 2019年第9期14卷 1635-1642页

作者： Ling-Ling Fan Bo Deng Jun-Bao Yan Zhi-Hong Hu Ai-Hong Ren Dong-Wei Yang Department of Physiology Medical College Henan University of Science and Technology

The dysfunction of the medial prefrontal cortex is associated with affective disorders and non-motor features in Parkinson’s disease.However,the exact role of the mediodorsal thalamic nucleus in the function of the prefrontal cortex remains unclear.To study the possible effects of the mediodorsal thalamic nucleus on the neurological function of the medial prefrontal cortex,a model of Parkinson’s disease was established by injecting 8μg 6-hydroxydopamine into the substantia nigra compacta of rats.After 1 or 3 weeks,0.3μg ibotenic acid was injected into the mediodorsal thalamic nucleus of the midbrain.At 3 or 5 weeks after the initial injury,neuronal discharge in medial prefrontal cortex of rat brain was determined electrophysiologically.The numbers of dopamine-positive neurons and tyrosine hydroxylase immunoreactivity in substantia nigra compacta and ventral tegmental area were detected by immunohistochemical staining.Results demonstrated that after injury,the immunoreactivity of dopamine neurons and tyrosine hydroxylase decreased in the substantia nigra compacta and ventral tegmental areas of rats.Compared with normal medial prefrontal cortical neurons,at 3 and 5 weeks after substantia nigra compacta injury,the discharge frequency of pyramidal neurons increased and the discharge pattern of these neurons tended to be a burst-discharge,with an increased discharge interval.The discharge frequency of interneurons decreased and the discharge pattern also tended to be a burst-discharge,but the discharge interval was only higher at 3 weeks.At 3 weeks after the combined lesions,the discharge frequency,discharge pattern and discharge interval were restored to a normal level in pyramidal neurons and interneurons in medial prefrontal cortex.These findings have confirmed that mediodorsal thalamic nucleus is involved in regulating neuronal activities of the medial prefrontal cortex.The changes in the function of the mediodorsal thalamic nucleus may be associated with the abnormal discharge activity of the medial prefrontal co

关键词： nerve regeneration Parkinson's disease mediodorsal thalamic nucleus medial prefrontal cortex pyramidal neurons interneurons discharge neural regeneration

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Treadmill exercise improves hippocampal neural plasticity and relieves cognitive deficits in a mouse model of epilepsy

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Neural Regeneration Research 2024年第3期19卷 657-662页

作者： Hang Yu Mingting Shao Xi Luo Chaoqin Pang Kwok-Fai So Jiandong Yu Li Zhang Key Laboratory of CNS Regeneration(Ministry of Education) Guangdong-Hong Kong-Macao Institute of CNS RegenerationJinan UniversityGuangzhouGuangdong ProvinceChina State Key Laboratory of Brain and Cognitive Science Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong Special Administrative RegionChina Neuroscience and Neurorehabilitation Institute University of Health and Rehabilitation SciencesQingdaoShandong ProvinceChina Department of Neurosurgery The First Affiliated Hospital of Bengbu Medical CollegeBengbuShandong ProvinceChina School of Psychology Shanghai University of SportShanghaiChina

Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited.Although regular exercise effectively improves learning and memory functions across multiple neurological diseases,its application in patients with epilepsy remains controversial.Here,we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy.Cognitive assays confirmed the improvement of object and spatial memory after endurance training,and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise.Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons,probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier.In summary,this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.

关键词： blood-brain barrier cognition hippocampus interneurons long-term potentiation microglial cell neuroinflammation spatial memory temporal epilepsy treadmill exercise

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