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The endoplasmic reticulum membrane protein complex subunit Emc6 is essential for rhodopsin localization and photoreceptor cell survival

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genes & diseases 2024年第2期11卷 1035-1049页

作者： Kuanxiang Sun Lu Liu Xiaoyan Jiang Heting Wang Lin Wang Yeming Yang Wenjing Liu Lin Zhang Xiaohui Zhao Xianjun Zhu Health Management Center Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan 610072China key laboratory of Tibetan Medicine Research Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine ResearchNorthwest Institute of Plateau BiologyXiningQinghai 810008China The sichuan provincial key laboratory for Human disease gene study and Department of laboratory Medicine Center for Medical GeneticsSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan 610072China Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026) Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalChengduSichuan 610072China Department of Ophthalmology The First People's Hospital of ShangqiuShangqiuHenan 476000China

The endoplasmic reticulum(ER)membrane protein complex(EMC)is responsible for monitoring the biogenesis and synthetic quality of membrane proteins with tail-anchored or multiple transmembrane domains.The EMC subunit EMC6 is one of the core members of EMC and forms an enclosed hydrophilic vestibule in cooperation with EMC3.Despite studies demonstrating that deletion of EMC3 led to rhodopsin mislocalization in rod photoreceptors of mice,the precise mechanism leading to the failure of rhodopsin trafficking remains unclear.Here,we generated the first rod photoreceptor-specific knockout of Emc6(RKO)and cone photoreceptor-specific knockout of Emc6(CKO)mouse models.Deficiency of Emc6 in rod photoreceptors led to progressive shortening of outer segments(OS),impaired visual function,mislocalization and reduced expression of rhodopsin,and increased gliosis in rod photoreceptors.In addition,CKO mice displayed the progressive death of cone photoreceptors and abnormal localization of cone opsin protein.Subsequently,proteomics analysis of the RKO mouse retina illustrated that several cilium-related proteins,particularly anoctamin-2(ANO2)and transmembrane protein 67(TMEM67),were significantly down-regulated prior to OS degeneration.Detrimental rod photoreceptor cilia and mislocalized membrane disc proteins were evident in RKO mice.Our data revealed that in addition to monitoring the synthesis of rhodopsin-dominated membrane disc proteins,EMC6 also impacted rod photoreceptors'ciliogenesis by regulating the synthesis of membrane proteins associated with cilia,contributing to the mislocalization of membrane disc proteins.

关键词： ANO2 Cilium EMC6 ER membrane protein complex Mislocalization Photoreceptor degeneration TMEM67

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Effects of maternal methyl donor intake during pregnancy on ileum methylation and function in an intrauterine growth restriction pig model

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Journal of Animal Science and Biotechnology 2024年第3期15卷 1173-1189页

作者： Yan Lin Jiangnan Wu Yong Zhuo Bin Feng Zhengfeng Fang Shengyu Xu Jian Li Hua Zhao De Wu Lun Hua Lianqiang Che key laboratory of Animal disease‑Resistance Nutrition Animal Nutrition InstituteSichuan Agricultural UniversityChengdu 611130SichuanChina

Background Intrauterine growth retardation(IUGR)affects intestinal growth,morphology,and function,which leads to poor growth performance and high mortality.The present study explored whether maternal dietary methyl donor(MET)supplementation alleviates IUGR and enhances offspring’s growth performance by improving intestinal growth,function,and DNA methylation of the ileum in a porcine IUGR model.Methods Forty multiparous sows were allocated to the control or MET diet groups from mating until delivery.After farrowing,8 pairs of IUGR and normal birth weight piglets from 8 litters were selected for sampling before suckling colostrum.Results The results showed that maternal MET supplementation tended to decrease the IUGR incidence and increased the average weaning weight of piglets.Moreover,maternal MET supplementation significantly reduced the plasma concentrations of isoleucine,cysteine,urea,and total amino acids in sows and newborn pig-lets.It also increased lactase and sucrase activity in the jejunum of newborn piglets.MET addition resulted in lower ileal methionine synthase activity and increased betaine homocysteine S-methyltransferase activity in the ileum of newborn piglets.DNA methylation analysis of the ileum showed that MET supplementation increased the methyla-tion level of DNA CpG sites in the ileum of newborn piglets.Down-regulated differentially methylated genes were enriched in folic acid binding,insulin receptor signaling pathway,and endothelial cell proliferation.In contrast,up-regulated methylated genes were enriched in growth hormone receptor signaling pathway and nitric oxide biosyn-thetic process.Conclusions Maternal MET supplementation can reduce the incidence of IUGR and increase the weaning litter weight of piglets,which may be associated with better intestinal function and methylation status.

关键词： Ileum Intrauterine growth restriction Methyl donor Methylation Sows

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The m^(6)A reader YTHDC2 maintains visual function and retinal photoreceptor survival through modulating translation of PPEF2 and PDE6B

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Journal of genetics and Genomics 2024年第2期51卷 208-221页

作者： Yeming Yang Xiaoyan Jiang Junyao Chen Lu Liu Guo Liu Kuanxiang Sun Wenjing Liu Xianjun Zhu Qiuyue Guan The sichuan provincial key laboratory for Human disease gene study Center for Medical GeneticsSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan 610072China Department of Geriatrics Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan 610072China Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences(2019RU026) Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalChengduSichuan 610072China Qinghai key laboratory of Qinghai Tibet Plateau Biological Resources Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine ResearchNorthwest Institute of Plateau BiologyXiningQinghai 810008China Henan Eye Institute Henan Eye HospitalPeople's Hospital of Zhengzhou UniversityHenan Provincial People's HospitalZhengzhouHenan 450003China

Inherited retinal dystrophies (IRDs) are major causes of visual impairment and irreversible blindness worldwide, while the precise molecular and genetic mechanisms are still elusive. N6-methyladenosine (m^(6)A) modification is the most prevalent internal modification in eukaryotic mRNA. YTH domain containing 2 (YTHDC2), an m^(6)A reader protein, has recently been identified as a key player in germline development and human cancer. However, its contribution to retinal function remains unknown. Here, we explore the role of YTHDC2 in the visual function of retinal rod photoreceptors by generating rod-specific Ythdc2 knockout mice. Results show that Ythdc2 deficiency in rods causes diminished scotopic ERG responses and progressive retinal degeneration. Multi-omics analysis further identifies Ppef2 and Pde6b as the potential targets of YTHDC2 in the retina. Specifically, via its YTH domain, YTHDC2 recognizes and binds m^(6)A-modified Ppef2 mRNA at the coding sequence and Pde6b mRNA at the 5′-UTR, resulting in enhanced translation efficiency without affecting mRNA levels. Compromised translation efficiency of Ppef2 and Pde6b after YTHDC2 depletion ultimately leads to decreased protein levels in the retina, impaired retinal function, and progressive rod death. Collectively, our finding highlights the importance of YTHDC2 in visual function and photoreceptor survival, which provides an unreported elucidation of IRD pathogenesis via epitranscriptomics.

关键词： Epitranscriptomics N^(6)-methyladenosine(m^(6)A) Inherited retinal dystrophies YTHDC2 Retina function Photoreceptor degeneration

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Association analysis of genetic variants in critical patients with COVID-19 and validation in a Chinese population

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Virologica Sinica 2024年第2期39卷 347-350页

作者： Yi Yin Yi Zhang Lelin Sun Shuqiang Wang Yong Zeng Bo Gong Lulin Huang Yongquan He Zhenglin Yang Center for Natural Products Research Chengdu Institute of BiologyChinese Academy of SciencesChengdu610213China sichuan provincial key laboratory for Human disease gene study Center for Medical GeneticsDepartment of Laboratory MedicineSichuan Academy of Medical Sciences&Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengdu610072China Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences(2019RU026) Sichuan Academy of Medical Sciences&Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengdu610072China University of Chinese Academy of Sciences Beijing100049China Infectious disease Department Sichuan Academy of Medical Sciences&Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengdu610072China Department of Ophthalmology Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengdu610072China

Dear Editor,Genome-wide association studies(GWASs)have reported a genetic association between certain populations and the severity of COVID-19.In severe patients,changes in the locus 3p21.31(including SLC6A20,LZTFL1,CCR9,FYCO1,CXCR6,and XCR1)are associated with COVID-19 hospitalization(Ellinghaus et al.,2020).Moreover,variations in 9p34.2 region(including genes related to the ABO blood grouping)can affect both susceptibility and severity of COVID-19;in particular,individuals with blood group A may have an increased risk of COVID-19 infection,while those with blood group O may have a protective effect(Ellinghaus et al.,2020;Shelton et al.,2021).

关键词： patients protective

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Zinc glycine chelate ameliorates DSS‑induced intestinal barrier dysfunction via attenuating TLR4/NF‑κB pathway in meat ducks

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Journal of Animal Science and Biotechnology 2024年第2期15卷 765-778页

作者： Yaqi Chang Ke Wang Guangmang Liu Hua Zhao Xiaoling Chen Jingyi Cai Gang Jia Institute of Animal Nutrition Key Laboratory for Animal Disease‑Resistance Nutrition of ChinaMinistry of EducationSichuan Agricultural UniversityChengdu 611130SichuanChina

Background Zinc glycine chelate(Zn-Gly)has anti-inflammation and growth-promoting properties;however,the mechanism of Zn-Gly contribution to gut barrier function in Cherry Valley ducks during intestinal inflammation is unknown.Three-hundred 1-day-old ducks were divided into 5 groups(6 replicates and 10 ducks per replicate)in a completely randomized design:the control and dextran sulfate sodium(DSS)groups were fed a corn-soybean meal basal diet,and experimental groups received supplements of 70,120 or 170 mg/kg Zn in form of Zn-Gly.The DSS and treatment groups were given 2 mL of 0.45 g/mL DSS daily during d 15–21,and the control group received normal saline.The experiment lasted 21 d.Results Compared with DSS group,70,120 and 170 mg/kg Zn significantly increased body weight(BW),villus height and the ratio of villus to crypt,and significantly decreased the crypt depth of jejunum at 21 d.The number of goblet cells in jejunal villi in the Zn-Gly group was significantly increased by periodic acid-Schiff staining.Compared with control,the content of intestinal permeability marker D-lactic acid(D-LA)and fluxes of fluorescein isothiocyanate(FITC-D)in plasma of DSS group significantly increased,and 170 mg/kg Zn supplementation significantly decreased the D-LA content and FITC-D fluxes.Compared with control,contents of plasma,jejunum endotoxin and jejunum pro-inflammatory factors IL-1β,IL-6 and TNF-αwere significantly increased in DSS group,and were significantly decreased by 170 mg/kg Zn supplementation.Dietary Zn significantly increased the contents of anti-inflammatory factors IL-10,IL-22 and sIgA and IgG in jejunum.Real-time PCR and Western blot results showed that 170 mg/kg Zn supplementation significantly increased mRNA expression levels of CLDN-1 and expression of OCLN protein in jejunum,and decreased gene and protein expression of CLDN-2 compared with DSS group.The 120 mg/kg Zn significantly promoted the expressions of IL-22 and IgA.Dietary Zn-Gly supplementation significantly decreased pro-inflammatory genes IL-8

关键词： Cherry Valley ducks Growth performance Gut inflammation Intestinal barrier Zn-Gly

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Epileptic brain network mechanisms and neuroimaging techniques for the brain network

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Neural Regeneration Research 2024年第12期19卷 2637-2648页

作者： Yi Guo Zhonghua Lin Zhen Fan Xin Tian Department of Neurology Sichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan ProvinceChina sichuan provincial Center for Mental Health Sichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan ProvinceChina Department of Geriatrics Sichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan ProvinceChina Department of Neurology Chongqing Key Laboratory of NeurologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

Epilepsy can be defined as a dysfunction of the brain network,and each type of epilepsy involves different brain-network changes that are implicated diffe rently in the control and propagation of interictal or ictal discharges.Gaining more detailed information on brain network alterations can help us to further understand the mechanisms of epilepsy and pave the way for brain network-based precise therapeutic approaches in clinical practice.An increasing number of advanced neuroimaging techniques and electrophysiological techniques such as diffusion tensor imaging-based fiber tra ctography,diffusion kurtosis imaging-based fiber tractography,fiber ball imagingbased tra ctography,electroencephalography,functional magnetic resonance imaging,magnetoencephalography,positron emission tomography,molecular imaging,and functional ultrasound imaging have been extensively used to delineate epileptic networks.In this review,we summarize the relevant neuroimaging and neuroelectrophysiological techniques for assessing structural and functional brain networks in patients with epilepsy,and extensively analyze the imaging mechanisms,advantages,limitations,and clinical application ranges of each technique.A greater focus on emerging advanced technologies,new data analysis software,a combination of multiple techniques,and the construction of personalized virtual epilepsy models can provide a theoretical basis to better understand the brain network mechanisms of epilepsy and make surgical decisions.

关键词： electrophysiological techniques epilepsy functional brain network functional magnetic resonance imaging functional near-infrared spectroscopy machine leaning molecular imaging neuroimaging techniques structural brain network virtual epileptic models

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Zinc lactate alleviates oxidative stress by modulating crosstalk between constitutive androstane receptor signaling pathway and gut microbiota profile in weaned piglets

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Animal Nutrition 2024年第1期16卷 23-33页

作者： Wenjie Tang Xuan Xiang Houfu Wang Wentao Zhou Liuqin He Yulong Yin Tiejun Li College of Animal Science and Technology Hunan Agricultural University sichuan Academy of Animal Sciences Animal Breeding and Genetics Key Laboratory of Sichuan Province Livestock and Poultry Biological Products key laboratory of sichuan Province Sichuan Animtech Feed Co. Ltd Hunan provincial key laboratory of Animal Nutritional Physiology and Metabolic Process CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production Institute of Subtropical Agriculture Chinese Academy of Sciences College of Advanced Agricultural Science University of Chinese Academy of Sciences Hunan provincial key laboratory of Animal Intestinal Function and Regulation Laboratory of Animal Nutrition and Human Health College of Life Sciences Hunan Normal University

This study aimed to determine the regulatory mechanism of dietary zinc lactate (ZL) supplementation on intestinal oxidative stress damage in a paraquat (PQ)-induced piglet model. Twenty-eight piglets (mean body weight 9.51±0.23 kg) weaned at 28 d of age were randomly divided into control, ZL, PQ, and ZL+PQ groups (n=7 in each group). The ZL-supplemented diet had little effect on growth performance under normal physiological conditions. However, under PQ challenge, ZL supplementation significantly improved average daily gain (Pgenes and decreased inflammatory cytokine expression and secretion in PQinduced piglets. Furthermore, ZL treatment significantly inhibited the activation of constitutive androstane receptor (CAR) signaling (P<0.01) in PQ-induced piglets and altered the structure of the gut microbiota, especially by significantly increasing the abundance of beneficial gut microbes, including UCG＿002, Ruminococcus, Rikenellaceae＿RC9＿gut＿group, Christensenellaceae＿R＿7＿group, Treponema, unclassified＿Christensenellaceae, and unclassified＿Erysipelotrichaceae (P <0.05). These data reveal that pre-administration of ZL to piglets can suppress intestinal oxidative stress by improving antioxidant and anti-inflammatory capacity and regulating the crosstalk between CAR signaling and gut microbiota.

关键词： Zinc lactate Intestinal barrier Oxidative stress Inflammation Constitutive androstane receptor Gut microbiota

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Cryptic divergences and repeated hybridizations within the endangered “living fossil” dove tree(Davidia involucrata) revealed by whole genome resequencing

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Plant Diversity 2024年第2期46卷 169-180页

作者： Yumeng Ren Lushui Zhang Xuchen Yang Hao Lin Yupeng Sang Landi Feng Jianquan Liu Minghui Kang key laboratory of Bio-resource and Eco-environment of Ministry of Education College of Life SciencesSichuan UniversityChengdu 610065China State key laboratory of Herbage Improvement and Grassland Agro-ecosystem College of EcologyLanzhou UniversityLanzhou 730000China Guangdong provincial key laboratory of Plant Adaptation and Molecular Design Guangzhou Key Laboratory of Crop Gene EditingInnovative Center of Molecular Genetics and EvolutionSchool of Life SciencesGuangzhou UniversityGuangzhou 510006China

The identification and understanding of cryptic intraspecific evolutionary units(lineages) are crucial for planning effective conservation strategies aimed at preserving genetic diversity in endangered species.However, the factors driving the evolution and maintenance of these intraspecific lineages in most endangered species remain poorly understood. In this study, we conducted resequencing of 77 individuals from 22 natural populations of Davidia involucrata, a “living fossil” dove tree endemic to central and southwest China. Our analysis revealed the presence of three distinct local lineages within this endangered species, which emerged approximately 3.09 and 0.32 million years ago. These divergence events align well with the geographic and climatic oscillations that occurred across the distributional range.Additionally, we observed frequent hybridization events between the three lineages, resulting in the formation of hybrid populations in their adjacent as well as disjunct regions. These hybridizations likely arose from climate-driven population expansion and/or long-distance gene flow. Furthermore, we identified numerous environment-correlated gene variants across the total and many other genes that exhibited signals of positive evolution during the maintenance of two major local lineages. Our findings shed light on the highly dynamic evolution underlying the remarkably similar phenotype of this endangered species. Importantly, these results not only provide guidance for the development of conservation plans but also enhance our understanding of evolutionary past for this and other endangered species with similar histories.

关键词： Davidia involucrata Cryptic lineage Hybridization Population genomics Positive evolution

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Biomimetic“Gemini nanoimmunoregulators”orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1345-1361页

作者： Honglin Huang Ningxi Li Xiaodan Wei Qingzhi Li Junhan Guo Geng Yang Hong Yang Lulu Cai Yiyao Liu Chunhui Wu Department of Pharmacy Personalized Drug Therapy Key Laboratory of Sichuan ProvinceSichuan Provincial People’s Hospitaland School of Life Science and TechnologyUniversity of Electronic Science and Technology of ChinaChengdu 610054China TCM Regulating Metabolic diseases key laboratory of sichuan Province Hospital of Chengdu University of Traditional Chinese MedicineChengdu 610072China

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy.Here,a new type of spatiotemporal biomimetic“Gemini nanoimmunoregulators”was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death(ICD),tumor-associated macrophages(TAMs)phenotype reprogramming and programmed cell death ligand 1(PD-L1)degradation.The“Gemini nanoimmunoregulators”PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine(mPDA)as nanovectors to deliver metformin(Met)and toll-like receptor 7/8 agonist resiquimod(R848)to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane(RM)inlaid with T7or M2 peptides.mPDA/Met@RM-T7(abbreviated as PM@RM-T7)was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity.Meanwhile,PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion.Subsequently,mPDA/R848@RM-M2(abbreviated as PR@RM-M2)specifically recognized TAMs and reset the phenotype from M2 to M1 state,thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes.This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity,which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis.This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

关键词： Biomimetic immunoregulator Spatiotemporal delivery Targeted photothermal therapy Amplified immunogenic cell death Immunosuppressive tumor microenvironment PD-L1 degradation TAMs phenotype reversion Metastasis inhibition

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Morphological disruption and visual tuning alterations in the primary visual cortex in glaucoma(DBA/2J)mice

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Neural Regeneration Research 2024年第1期19卷 220-225页

作者： Yin Yang Zhaoxi Yang Maoxia Lv Ang Jia Junjun Li Baitao Liao Jing’an Chen Zhengzheng Wu Yi Shi Yang Xia Dezhong Yao Ke Chen Department of Ophthalmology Sichuan Provincial People’s HospitalMedical SchoolUniversity of Electronic Science and Technology of ChinaChengduSichuan ProvinceChina The Clinical Hospital of Chengdu Brain Science Institute MOE Key Lab for NeuroInformationSchool of Life Science and TechnologyUniversity of Electronic Science and Technology of ChinaChengduSichuan ProvinceChina Research Unit of NeuroInformation Chinese Academy of Medical SciencesChengduSichuan ProvinceChina Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical CollegeBeijingChina Health Management Center Sichuan Provincial Key Laboratory for Human Disease Gene StudySichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengduSichuan ProvinceChina Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences(2019RU026) Sichuan Academy of Medical SciencesChengduSichuan ProvinceChina School of Electrical Engineering Zhengzhou UniversityZhengzhouHenan ProvinceChina

Glaucoma is a leading cause of irreve rsible blindness wo rldwide,and previous studies have shown that,in addition to affecting the eyes,it also causes abnormalities in the brain.However,it is not yet clear how the primary visual cortex(V1)is altered in glaucoma.This study used DBA/2J mice as a model for spontaneous secondary glaucoma.The aim of the study was to compare the electrophysiological and histomorphological chara cteristics of neurons in the V1between 9-month-old DBA/2J mice and age-matched C57BL/6J mice.We conducted single-unit recordings in the V1 of light-anesthetized mice to measure the visually induced responses,including single-unit spiking and gamma band oscillations.The morphology of layerⅡ/Ⅲneurons was determined by neuronal nuclear antigen staining and Nissl staining of brain tissue sections.Eighty-seven neurons from eight DBA/2J mice and eighty-one neurons from eight C57BL/6J mice were examined.Compared with the C57BL/6J group,V1 neurons in the DBA/2J group exhibited weaker visual tuning and impaired spatial summation.Moreove r,fewer neuro ns were observed in the V1 of DBA/2J mice compared with C57BL/6J mice.These findings suggest that DBA/2J mice have fewer neurons in the VI compared with C57BL/6J mice,and that these neurons have impaired visual tuning.Our findings provide a better understanding of the pathological changes that occur in V1 neuron function and morphology in the DBA/2J mouse model.This study might offer some innovative perspectives regarding the treatment of glaucoma.

关键词： DBA/2J degeneration gamma band oscillations glaucoma primary visual cortex(V1) retina single-unit recording tuning curve

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