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Single-cell transcriptomic atlas of mouse cochlear aging

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Protein & Cell 2023年第3期14卷 180-201页

作者： Guoqiang Sun Yandong Zheng Xiaolong Fu Weiqi Zhang Jie Ren Shuai Ma Shuhui Sun Xiaojuan He QiaoranWang zhejun ji Fang Cheng KaowenYan Ziyi Liu Juan Carloszpisuaemonte Jing Qu Si Wang Renjie Chai Guang-Hui Liu State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Bioelectronics Jiangsu Province High-Tech Key Laboratory for Bio-Medical ResearchSchool of Life Sciences and TechnologySoutheast UniversityNanjing 211189China Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical University.Beijing100053China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital MedicalUniversityBeijing100053China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration CASBeijing 100101China China National Center for Bioinformation Beijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Gene Expression Laboratory Salk Institute for Biological StudiesLa JollaCA 92037USA Co-Innovation Center of Neuroregeneration Nantong UniversityNantong 226001China Shandong Provincial Hospital and School of Laboratory Animal Science Shandong First Medical UniversityJinan 250000China

Progressive functional deterioration in the cochlea is associated with age-related hearing loss(ARHL).However,the cellular and molecular basis underlying cochlear aging remains largely unknown.Here,we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging,in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points.Overall,our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging,highlights unexpected age-related transcriptional fluctuations in intermediate ceils localized in the stria vascularis(SV)and demonstrates that upregulation of endoplasmic reticulum(ER)chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging.Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related sVatrophyand hencedelay theprogressionofARHL.

关键词： single-cell transcriptomic atlas mouse cochlea aging

MicroRNAs in mouse and rat models of experimental epilepsy and potential therapeutic targets

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Neural Regeneration Research 2023年第10期18卷 2108-2118页

作者： Bridget Martinez Philip V.Peplow Department of Pharmacology University of Nevada-RenoRenoNVUSA Department of Medicine University of Nevada-RenoRenoNVUSA Department of Anatomy University of OtagoDunedinNew Zealand

Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals(mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p,-146a-5p,-10a-5p,-21a-3p,-27a-3p,-142a-5p,-212-3p,-431-5p, and-155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451,-10a-5p,-21a-5p,-27a-5p,-142a-5p,-431-5p,-155, and-134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p,-27a-3p,-155,-134,-181a, and-146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid.

关键词： epilepsy experimental models microRNA mouse rat seizures therapeutic targets

Altered Retinal Dopamine Levels in a Melatonin-proficient mouse Model of Form-deprivation Myopia

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Neuroscience Bulletin 2022年第9期38卷 992-1006页

作者： Kang-Wei Qian Yun-Yun Li Xiao-Hua Wu Xue Gong Ai-Lin Liu Wen-Hao Chen Zhe Yang Ling-Jie Cui Yun-Feng Liu Yuan-Yuan Ma Chen-Xi Yu Furong Huang Qiongsi Wang Xiangtian Zhou Jia Qu Yong-Mei Zhong Xiong-Li Yang Shi-Jun Weng State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Institutes of Brain ScienceFudan UniversityShanghai200032China Discipline of Neuroscience and Department of Anatomy and Physiology College of Basic Medical SciencesShanghai Jiao Tong University School of MedicineShanghai200025China School of Ophthalmology and Optometry and Eye Hospital Wenzhou Medical UniversityWenzhou325027China Department of Immunology School of Basic Medical SciencesAnhui Medical UniversityHefei230032China

Reduced levels of retinal dopamine,a key regulator of eye development,are associated with experimental myopia in various species,but are not seen in the myopic eyes of C57BL/6 mice,which are deficient in melatonin,a neurohormone having extensive interactions with dopamine.Here,we examined the relationship between form-deprivation myopia(FDM)and retinal dopamine levels in melatonin-proficient CBA/CaJ mice.We found that these mice exhibited a myopic refractive shift in form-deprived eyes,which was accompanied by altered retinal dopamine levels.When melatonin receptors were pharmacologically blocked,FDM could still be induced,but its magnitude was reduced,and retinal dopamine levels were no longer altered in FDM animals,indicating that melatonin-related changes in retinal dopamine levels contribute to FDM.Thus,FDM is mediated by both dopamine level-independent and melatonin-related dopamine level-dependent mechanisms in CBA/CaJ mice.The previously reported unaltered retinal dopamine levels in myopic C57BL/6 mice may be attributed to melatonin deficiency.

关键词： Myopia Refractive development Dopamine Melatonin mouse Retina

Morphological comparison and gonadotropins cell localization of mature female turbot and mouse pituitary

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Journal of Oceanology and Limnology 2023年第6期41卷 2418-2428页

作者： Yudong JIA Yunhong GAO Jinxing LIN Yellow Sea Fisheries Research Institute Chinese Academy of Fishery SciencesQingdao 266071China Shanghai Laboratory Animal Research Center Shanghai 201203China

Reproduction is subtlety regulated by the hypothalamic-pituitary-gonad(HPG)axis in vertebrates.Pituitary gland is the center of the HPG axis,while pituitary gonadotropins follicle stimulating hormone(FSH)and luteinizing hormone(LH)were identified the key elements of the HPG axis in teleost and mammal.Morphology,cell lines,and gonadotropins cell localization of female turbot and mouse pituitary were determined at mature stage to illustrate the anatomical difference and cell characteristics in this study.Results show that turbot pituitary is chicken heart-shaped,dorsoventral,located on the ventral surface of the diencephalon.The mouse pituitary is oval,located in the pituitary fossa of the sella turcica at the skull base.Two well-distinguished areas adenohypophysis(AH)and neurohypophysis(NH)in pituitary were identified in turbot and mouse.Turbot AH comprised the rostral pars distalis(RPD),proximal pars distalis(PPD),and pars intermedia(PI).NH was not pronounced and with finger-like protrusions into PPD.However,mouse AH only comprised the pars distalis(PD)and PI.NH distribution was semicircular.Three main types of cells(acidophilic,basophilic,and chromophobic cells)were distributed in the mouse PD region,whereas appeared in the turbot PPD,RPD,and PI.Moreover,the percentage of mouse chromophobic and basophilic cells was higher and lower than that of turbot,respectively.The diameter of the aforementioned three cells in the mouse was significantly higher than turbot.fshβ-and lhβ-immunoreactive signals were identified in turbot-distinct pituitary cells that primarily occupied the peripheral and central regions of AH.However,mouse fsh-and lh-immunoreactive cells were expressed in the same cells and present in the PD.These results demonstrate the significantly difference of pituitary morphology,cell lines and gonadotropins(fshβand lhβ)location in female turbot and mouse.These differences help for fully understand the evolution and endocrinological functions of pituitary.

关键词： turbot mouse pituitary gland cell line gonadotropins

mouse models of colorectal cancer: Past, present and future perspectives

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World Journal of Gastroenterology 2020年第13期26卷 1394-1426页

作者： Florian Bürtin Christina S Mullins Michael Linnebacher Department of General VisceralVascular and Transplantation SurgeryUniversity Medical Center RostockUniversity of RostockRostock 18057Germany Department of Thoracic Surgery University Medical Center RostockUniversity of RostockRostock 18057Germany Molecular Oncology and Immunotherapy Department of GeneralVisceralVascular and Transplantation SurgeryUniversity Medical Center RostockRostock 18057Germany

Colorectal cancer(CRC)is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union.While the incidence and mortality rates in western,high developed countries are declining,reflecting the success of screening programs and improved treatment regimen,a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development index.Despite a growing insight into the biology of CRC and many therapeutic improvements in the recent decades,preclinical in vivo models are still indispensable for the development of new treatment approaches.Since the development of carcinogen-induced rodent models for CRC more than 80 years ago,a plethora of animal models has been established to study colon cancer biology.Despite tenuous invasiveness and metastatic behavior,these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis.Genetically engineered mouse models(GEMM)mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited.Although the vast majority of CRC GEMM lack invasiveness,metastasis and tumor heterogeneity,they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses;thus,supporting development of new therapeutic avenues.Induction of metastatic disease by orthotopic injection of CRC cell lines is possible,but the so generated models lack genetic diversity and the number of suited cell lines is very limited.Patient-derived xenografts,in contrast,maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development–even in comparison to GEMM or cell line-based analyses.However,subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses.T

关键词： Colorectal cancer mouse models Patient-derived xenografts Carcinogen-induced models Genetically engineered mouse models Preclinical drug development

Effects and mechanism of Chinese medicine Jiawei Yupingfeng in a mouse model of allergic rhinitis

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Journal of Integrative Medicine 2021年第4期19卷 354-361页

作者： Hui Chen Wei Feng Ye Lu Yi Yang Zhong-hai Xin Man Li Li Xin Ying-di Gong Department of Otolaryngology Wangjing HospitalChina Academy of Chinese Medical SciencesBeijing 100102China

Objective: Chinese medicine has the potential to modulate allergic rhinitis(AR). There have been studies investigating the treatment efficacy of Yupingfeng San, alone or in combination with other ingredients, in AR, though few have studied the potential mechanisms of these drugs. In the present study, we measured the effects of Jiawei Yupingfeng(JWYPF), a traditional Chinese medicine formula, on mice with ovalbumin-induced AR and explored its underlying mechanism of action.Methods: Forty BALB/c mice were randomly divided into normal control, allergy control and two treatment groups of ten mice each. In the normal control group, mice were sensitized and challenged with saline. The mice in the allergy control and treatment groups were sensitized and challenged with ovalbumin and aluminum hydroxide gel. The treatments of JWYPF and Nasonex were administered intranasally in the AR mice for one week. Several signs of allergic inflammation, such as nasal eosinophils and inflammatory cytokines, were measured to determine the underlying mechanisms.Results: Mice in the JWYPF and Nasonex groups had significantly lower AR symptom scores than those in the allergy control group(the mean differences between JWYPF and the allergy control, and Nasonex and the allergy control were -2.00 ± 0.35 and -2.40 ± 0.32). After treatment with JWYPF and Nasonex, the levels of ovalbumin-specific Ig E and histamine were significantly reduced, as were the levels of interlukin-4 and transforming growth factor-b, while interferon-c levels were increased(all P < 0.0001,vs. allergy control). These two treatments also significantly inhibited eosinophil and mast cell infiltration into the nasal cavity but were not statistically different from one-another.Conclusion: JWYPF has a potential therapeutic effect on AR via adjusting the rebalance of T helper 1 and T helper 2.

关键词： Chinese medicine Jiawei Yupingfeng Allergic rhinitis mouse Inflammatory cytokines

The Schlager mouse as a model of altered retinal phenotype

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Neural Regeneration Research 2020年第3期15卷 512-518页

作者： Lakshini Y.Herat Aaron L.Magno Márcio G.Kiuchi Kristy L.Jackson Revathy Carnagarin Geoffrey A.Head Markus P.Schlaich Vance B.Matthews Dobney Hypertension Centre School of Biomedical Science-Royal Perth Hospital UnitUniversity of Western AustraliaPerthAustralia Research Centre Royal Perth HospitalPerthAustralia Dobney Hypertension Centre School of Medicine-Royal Perth Hospital UnitUniversity of Western AustraliaPerthAustralia Neuropharmacology Laboratory Baker Heart and Diabetes InstituteMelbourneAustralia Department of Cardiology and Department of Nephrology Royal Perth HospitalPerthAustralia

Hypertension is a risk factor for a large number of vision-threatening eye disorders.In this study,we investigated for the first time the retinal neural structure of the hypertensive BPH/2J mouse(Schlager mouse)and compared it to its control counterpart,the normotensive BPN/3J strain.The BPH/2J mouse is a selectively inbred mouse strain that develops chronic hypertension due to elevated sympathetic nervous system activity.When compared to the BPN/3J strain,the hypertensive BPH/2J mice showed a complete loss of outer layers of the neural retina at 21 weeks of age,which was indicative of a severe vision-threatening disease potentially caused by hypertension.To elucidate whether the retinal neural phenotype in the BPH/2J strain was attributed to increased BP,we investigated the neural retina of both BPN/3J and BPH/2J mice at 4 weeks of age.Our preliminary results showed for the first time that the BPH/2J strain develops severe retinal neural damage at a young age.Our findings suggest that the retinal phenotype in the BPH/2J mouse is possibly due to elevated blood pressure and may be contributed by an early onset spontaneous mutation which is yet to be identified or a congenital defect occurring in this strain.Further characterization of the BPH/2J mouse strain is likely to i)elucidate gene defects underlying retinal disease;ii)understand mechanisms leading to neural retinal disease and iii)permit testing of molecules for translational research to interfere with the progression of retinal disease.The animal experiments were performed with the approval of the Royal Perth Hospital Animal Ethics Committee(R535/17-18)on June 1,2017.

关键词： blood pressure eye hypertension mice neural regeneration retina Schlager mouse sympathetic nervous system

Whole-Brain Map of Long-Range Monosynaptic Inputs to Different Cell Types in the Amygdala of the mouse

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Neuroscience Bulletin 2020年第11期36卷 1381-1394页

作者： Jia-Yu Fu Xiao-Dan Yu Yi Zhu Shi-Ze Xie Meng-Yu Tang Bin Yu Xiao-Ming Li Center for Neuroscience and Department of Neurology of Second Affiliated Hospital Zhejiang University School of MedicineHangzhou 310058China NHC and CAMS Key Laboratory of Medical Neurobiology Center for Brain Science and Brain-Inspired IntelligenceGuangdong-Hong Kong-Macao Greater Bay AreaJoint Institute for Genetics and Genome Medicine between Zhejiang University and University of TorontoHangzhou 310058China

The amygdala,which is involved in various behaviors and emotions,is reported to connect with the whole brain.However,the long-range inputs of distinct cell types have not yet been defined.Here,we used a retrograde trans-synaptic rabies virus to generate a whole-brain map of inputs to the main cell types in the mouse amygdala.We identified 37 individual regions that projected to neurons expressing vesicular glutamate transporter 2,78 regions to parvalbumin-expressing neurons,104 regions to neurons expressing protein kinase C-δ,and 89 regions to somatostatin-expressing neurons.The amygdala received massive projections from the isocortex and striatum.Several nuclei,such as the caudate-putamen and the CA1 field of the hippocampus,exhibited input preferences to different cell types in the amygdala.Notably,we identified several novel input areas,including the substantia innominata and zona incerta.These findings provide anatomical evidence to help understand the precise connections and diverse functions of the amygdala.

关键词： Basolateral amygdala Central amygdala Rabies virus retrograde tracing Glutamatergic GABAergic mouse

Comparative proteomes change and possible role in different pathways of micro RNA-21a-5p in a mouse model of spinal cord injury

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Neural Regeneration Research 2020年第6期15卷 1102-1110页

作者： Almaghalsa-Ziad Mohammed Hong-Xia Du Hong-Liang Song Wei-Ming Gong Bin Ning Tang-Hong Jia Department of Spinal Surgery Jinan Central Hospital Affiliated to Shandong University

Our previous study found that microRNA-21 a-5 p(miR-21 a-5 p)knockdown could improve the recovery of motor function after spinal cord injury in a mouse model,but the precise molecular mechanism remains poorly understood.In this study,a modified Allen's weight drop was used to establish a mouse model of spinal cord injury.A proteomics approach was used to understand the role of differential protein expression with miR-21 a-5 p knockdown,using a mouse model of spinal cord injury without gene knockout as a negative control group.We found that after introducing miR-21 a-5 p knockdown,proteins that played an essential role in the regulation of inflammatory processes,cell protection against oxidative stress,cell redox homeostasis,and cell maintenance were upregulated compared with the negative control group.Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis identified enriched pathways in both groups,such as the oxidative phosphorylation pathway,which is relevant to Parkinson's disease,Huntington's disease,Alzheimer's disease,and cardiac muscle contraction.We also found that miR-21 a-5 p could be a potential biomarker for amyotrophic lateral sclerosis,as miR-21 a-5 p becomes deregulated in this pathway.These results indicate successful detection of some important proteins that play potential roles in spinal cord injury.Elucidating the relationship between these proteins and the recovery of spinal cord injury will provide a reference for future research of spinal cord injury biomarkers.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Shandong University of China on March 5,2014.

关键词： bioinformatics biomarker inflammation micro RNA mitochondria mouse pathway analysis proteomics spinal cord injury stathmin