Biology subjects

Wang, M.

Publications and source records attributed to Wang, M..

At least 757 records · Page 42Linked to original sources

bioRxiv2020

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieves a durable remission. SIRT5 is a member of the sirtuin family of protein deacylases that regulate metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we show that SIRT5 is required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 is required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf;Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we find that SIRT5 is required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably include MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a novel, druggable genotype-independent addiction in melanoma.

cancer biology↗

bioRxiv2020

BacAnt: the combination annotation server of antibiotic resistance gene, insertion sequences, integron, transposable elements for bacterial DNA sequences

Whole genome sequencing (WGS) of bacteria has become a routine method in diagnostic laboratories. One of the clinically most useful advantages of WGS is the ability to predict antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs) in bacterial sequences. This allows comprehensive investigations of such genetic features but can also be used for epidemiological studies. A plethora of software programs have been developed for the detailed annotation of bacterial DNA sequences, such as RAST (Rapid Annotation using Subsystem Technology), Resfinder, ISfinder, INTEGRALL and The Transposon Registry. Unfortunately, to this day, a reliable annotation tool of the combination of ARGs and MGEs is not available, and the generation of genbank files requires much manual input. Here, we present a new webserver which allows the annotation of ARGs, integrons, and transposable elements at the same time. The pipeline generates genbank files automatically, which are compatible with easyfig for comparative genomic analysis. Our BacAnt code and standalone software package are available at https://github.com/xthua/bacant with an accompanying web application at http://bacant.net. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/284273v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@262a07org.highwire.dtl.DTLVardef@1914001org.highwire.dtl.DTLVardef@101089corg.highwire.dtl.DTLVardef@dc5807_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2020

The Effect of Population Structure on Murine Genome-Wide Association Studies

Population structure (PS) has been shown to cause false positive signals in genome-wide association studies (GWAS). Since PS correction is routinely used in human GWAS, it was assumed that it also should be utilized for murine GWAS using inbred strains. Nevertheless, there are fundamental differences between murine and human GWAS, and the impact of PS on murine GWAS results has not been thoroughly investigated. To assess the impact of PS on murine GWAS, we examined 8223 datasets that characterized biomedical responses in panels of inbred mouse strains. Surprisingly, we found that the PS had a minimal impact on datasets characterizing responses in [≤]20 strains; and relatively little impact on the majority of datasets characterizing >20 strains. Moreover, there were examples where association signals within known causative genes could be rejected if PS correction methods were utilized. PS assessment should be carefully used and should be considered in conjunction with other criteria when assessing the candidate genes identified in GWAS using inbred mouse strains.

genetics↗

bioRxiv2020

Antibody Upstream Sequences Diversity and Its Biological Implications Revealed by Repertoire Sequencing

The sequence upstream of antibody variable region (Antibody Upstream Sequence, or AUS) consists of 5 untranslated region (5 UTR) and two leader regions, L-PART1 and L-PART2. The sequence variations in AUS affect the efficiency of PCR amplification, mRNA translation, and subsequent PCR-based antibody quantification as well as antibody engineering. Despite their importance, the diversity of AUSs has long been neglected. Utilizing the rapid amplification of cDNA ends (5RACE) and high-throughput antibody repertoire sequencing (Rep-Seq) technique, we acquired full-length AUSs for human, rhesus macaque (RM), cynomolgus macaque (CM), mouse, and rat. We designed a bioinformatics pipeline and discovered 2,957 unique AUSs, corresponding to 2,786 and 1,159 unique sequences for 5 UTR and leader, respectively. Comparing with the leader records in the international ImMunoGeneTics (IMGT), while 529 were identical, 313 were with single nucleotide polymorphisms (SNPs), 280 were totally new, and 37 updated the incomplete records. The diversity of AUSs impact on related antibody biology was also probed. Taken together, our findings would facilitate Rep-Seq primer design for capturing antibodies comprehensively and efficiently as well as provide a valuable resource for antibody engineering and the studies of antibody at the molecular level.

bioinformatics↗

bioRxiv2020

A Human Multi-Lineage Hepatic Organoid Model for Liver Fibrosis

BackgroundTo characterize fibrogenic mechanisms, genome engineering and a human hepatic organoid system was used to produce an in vitro model for human liver fibrosis. Methods and resultsHuman hepatic organoids that were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD) developed the key features of ARPKD liver pathology (abnormal bile ducts and hepatic fibrosis) in only 21 days. Second harmonic generation microscopy confirmed that the ARPKD mutation increased collagen abundance and thick collagen fiber production in hepatic organoids; and we demonstrated that these changes mirrored that occurring in ARPKD liver tissue. Transcriptomic and other analyses indicated that the ARPKD mutation generates cholangiocytes with increased TGF{beta}-associated pathway activation, which are actively involved in collagen fiber generation. The abnormal cholangiocytes promote the expansion of collagen-producing myofibroblasts with markedly increased PDGFR{beta} protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resembled that of myofibroblasts in liver tissue obtained from patients with commonly occurring acquired forms of liver fibrosis. The involvement of the PDGFRB pathway was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. ConclusionsBesides providing mechanistic insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies.

cell biology↗

bioRxiv2020

MyoD is a structure organizer for emergent property of 3D genome architecture in muscle cells

The genome is not a linear molecule of DNA randomly folded in the nucleus, but exists as an organized, three-dimensional (3D) dynamic architecture. Intriguingly, it is now clear that each cell type has a unique and characteristic 3D genome organization that functions in determining cell identity during development. A currently challenging basic question is how cell-type specific 3D genome structures are established during development. Herein, we analyzed 3D genome structures in primary myoblasts and myocytes from MyoD knockout (MKO) and wild type (WT) mice and discovered that MyoD, a pioneer transcription factor (TF), can function as a "genome organizer" that specifies the proper 3D genome architecture unique to muscle cell development. Importantly, we genetically demonstrate that H3K27ac is insufficient for establishing MyoD-induced chromatin loops in muscle cells. The establishment of MyoDs "architectural role" should have profound impacts on advancing understanding of other pioneer transcription factors in orchestrating lineage specific 3D genome organization during development in a potentially very large number of cell types in diverse organisms.

genomics↗

bioRxiv2020

The neural features in the precentral gyrus predict the severity of internet game disorder: results from the multi-voxel pattern analyses

ImportanceFinding the neural features that could predict internet gaming disorder severity is important in finding the targets for potential interventions using brain modulation methods. ObjectiveTo determine whether resting-state neural patterns can predict individual variations of internet gaming disorder by applying machine learning method and further investigate brain regions strongly related to IGD severity. DesignThe diagnostic study lasted from December 1, 2013, to November 20, 2019. The data were analyzed from December 31, 2019, to July 10, 2020. SettingThe resting-state fMRI data were collected at East China Normal University, Shanghai. ParticipantsA convenience sample consisting of 402 college students with diverse IGD severity Main Outcomes and MeasuresThe neural patterns were represented by regional homogeneity (ReHo) and the amplitude of low-frequency fluctuation (ALFF). Predictive model performance was assessed by Pearson correlation coefficient and standard mean squared error between the predicted and true IGD severity. The correlations between IGD severity and topological features (i.e., degree centrality (DC), betweenness centrality (BC), and nodal efficiency (NE)) of consensus highly weighted regions in predictive models were examined. ResultsThe final dataset consists of 402 college students (mean [SD] age, 21.43 [2.44] years; 239 [59.5%] male). The predictive models could significantly predict IGD severity (model based on ReHo: r = 0.11, p(r) = 0.030, SMSE = 3.73, p(SMSE) = 0.033; model based on ALFF: r=0.19, p(r) = 0.002, SMSE = 3.58, p(SMSE) = 0.002). The highly weighted brain regions that contributed to both predictive models were the right precentral gyrus and the left postcentral gyrus. Moreover, the topological properties of the right precentral gyrus were significantly correlated with IGD severity (DC: r = 0.16, p = 0.001; BC: r = 0.14, p = 0.005; NE: r = 0.15, p = 0.003) whereas no significant result was found for the left postcentral gyrus (DC: r = 0.02, p = 0.673; BC: r = 0.04, p = 0.432; NE: r = 0.02, p = 0.664). Conclusions and RelevanceThe machine learning models could significantly predict IGD severity from resting-state neural patterns at the individual level. The predictions of IGD severity deepen our understanding of the neural mechanism of IGD and have implications for clinical diagnosis of IGD. In addition, we propose precentral gyrus as a potential target for physiological treatment interventions for IGD. Key PointsO_ST_ABSQuestionC_ST_ABSCan machine learning algorithms predict internet gaming disorder (IGD) from resting-state neural patterns? FindingsThis diagnostic study collected resting-state fMRI data from 402 subjects with diverse IGD severity. We found that machine learning models based on resting-state neural patterns yielded significant predictions of IGD severity. In addition, the topological neural features of precentral gyrus, which is a consensus highly weighted region, is significantly correlated with IGD severity. MeaningThe study found that IGD is a distinctive disorder and its dependence severity could be predicted by brain features. The precentral gyrus and its connection with other brain regions could be view as targets for potential IGD intervention, especially using brain modulation methods.

neuroscience↗

bioRxiv2020

Longitudinal changes in brain metabolites in healthy subjects and patients with first episode psychosis (FEP): a 7-Tesla MRS study

Objective7 Tesla (T) longitudinal magnetic resonance spectroscopy (MRS) offers a precise measurment of metabolic levels in human brain via a non-invasive approach. Studying longitudinal changes in neurometabolites could help identify trait and state markers for diseases and understand inconsistent findings from different researchers due to differences in the age of study participants and duration of illness. This study is the first to report novel longitudinal patterns in young adulthood from both physiological and pathological viewpoints using 7T MRS. MethodsUtilizing a four-year longitudinal cohort with 38 first episode psychosis (FEP) patients (onset within 2 years) and 48 healthy controls (HC), the authors examined the annual percentage changes of 9 neurometabolites in 5 brain regions. ResultsBoth FEP patients and HC subjects were found to have significant longitudinal reductions in glutamate (Glu) in the anterior cingulate cortex (ACC). Only FEP patients were found to have a significant decrease over time in {gamma}-aminobutyric acid (GABA), N-acetyl aspartate (NAA), myo-inositol (mI), and total choline (tCho: phosphocholine plus glycerophosphocholine) in the ACC. Uniquely, glutathione (GSH) was found to have a near zero annual percentage change in both FEP patients and HC subjects in all 5 brain regions over a four-year timespan in young adulthood. ConclusionsGSH could be a trait marker for diagnostic applications at least in young adulthood. Glu, GABA, NAA, mI, and tCho in the ACC are associated with the patients status and could be state markers for mechanistic studies of psychotic disorders, including those for progressive pathological changes and medication effects in young adulthood.

neuroscience↗

bioRxiv2020

Fertility-LightGBM: A fertility-related protein prediction model by multi-information fusion and light gradient boosting machine

The identification of fertility-related proteins plays an essential part in understanding the embryogenesis of germ cell development. Since the traditional experimental methods are expensive and time-consuming to identify fertility-related proteins, the purposes of predicting protein functions from amino acid sequences appeared. In this paper, we propose a fertility-related protein prediction model. Firstly, the model combines protein physicochemical property information, evolutionary information and sequence information to construct the initial feature space ALL. Then, the least absolute shrinkage and selection operator (LASSO) is used to remove redundant features. Finally, light gradient boosting machine (LightGBM) is used as a classifier to predict. The 5-fold cross-validation accuracy of the training dataset is 88.5%, and the independent accuracy of the training dataset is 91.5%. The results show that our model is more competitive for the prediction of fertility-related proteins, which is helpful for the study of fertility diseases and related drug targets.

bioinformatics↗

bioRxiv2020

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer's-related mice

Microglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimers disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPTP301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E (Apoe) transcription was upregulated in MAPTP301S mice overexpressing TYROBP and transcription of genes previously associated with Apoe, including Axl, Ccl2, Tgf{beta} and Il6, was altered in both APP/PSEN1 and MAPTP301S mice overexpressing TYROBP. Lastly, Tyrobp and Apoe mRNAs were clearly increased in Trem2-null mice in microglia recruited around a cortical stab injury or amyloid-{beta} (A{beta}) deposits. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype.

neuroscience↗

bioRxiv2020

SARS-Cov-2-, HIV-1-, Ebola-neutralizing and anti-PD1 clones are predisposed

Antibody repertoire refers to the totality of the superbly diversified antibodies within an individual to cope with the vast array of possible pathogens. Despite this extreme diversity, antibodies of the same clonotype, namely public clones, have been discovered among individuals. Although some public clones could be explained by antibody convergence, public clones in naive repertoire or virus-neutralizing clones from not infected people were also discovered. All these findings indicated that public clones might not occur by random and they might exert essential functions. However, the frequencies and functions of public clones in a population have never been studied. Here, we integrated 2,449 Rep-seq datasets from 767 donors and discovered 5.07 million public clones - ~10% of the repertoire are public in population. We found 38 therapeutic clones out of 3,390 annotated public clones including anti-PD1 clones in healthy people. Moreover, we also revealed clones neutralizing SARS-CoV-2, Ebola, and HIV-1 viruses in healthy individuals. Our result demonstrated that these clones are predisposed in the human antibody repertoire and may exert critical functions during particular immunological stimuli and consequently benefit the donors. We also implemented RAPID - a Rep-seq Analysis Platform with Integrated Databases, which may serve as a useful tool for others in the field.

immunology↗

bioRxiv2020

Inducing highly physiologically relevant phenotypes of human vascular smooth muscle cells via 3D printing

Vascular smooth muscle cells (vSMCs) are one of the essential cell types in blood vessel walls. A significant vSMC phenotype characteristic is that they collectively wrap around the outer layer of the healthy blood vessels with spindle-like morphology and help maintain the vascular tones and regulate the blood flow. Both physiological and biomedical research are impeded by the standard 2D cell culture approaches which do not create in vivo like microenvironment. Here, we systematically investigated the vSMCs culturing within 3D printed geometrical constraints and on printed microfilaments. Based on these models, we demonstrate a simple bioprinting approach for fast manufacturing vessel architectures with micro-grooved surfaces for vSMCs alignment. We validated that the vSMCs cultured on the printed vessel with microfilaments (VWMF) present a more physiologically relevant morphological phenotype and gene expression profile, and they are considerably more active in wound healing and ischemia than conventional planarly cultured vSMCs.

bioengineering↗

bioRxiv2020

AD-linked R47H-TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans

The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimers disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

neuroscience↗

bioRxiv2020

A single-cell transcriptome atlas of the aging human and macaque retina

The human retina is a complex neural tissue that detects light and sends visual information to the brain. However, the molecular and cellular processes that underlie aging primate retina remain unclear. Here, we provide a comprehensive transcriptomic atlas based on 119,520 single cells of the foveal and peripheral retina of humans and macaques covering different ages. The molecular features of retinal cells differed between the two species, suggesting the distinct regional and species specializations of the human and macaque retinae. In addition, human retinal aging occurred in a region- and cell-type- specific manner. Aging of human retina exhibited a foveal to peripheral gradient. MYO9A- rods and a horizontal cell subtype were greatly reduced in aging retina, indicating their vulnerability to aging. Moreover, we generated a dataset showing the cell-type- and region- specific gene expression associated with 55 types of human retinal disease, which provides a foundation to understand the molecular and cellular mechanisms underlying human retinal diseases. Together, these datasets are valuable for understanding the molecular characteristics of primate retina, as well as the molecular regulation of aging progression and related diseases.

neuroscience↗

bioRxiv2020

Chromosome fusions shape an ancient UV sex chromosome system

Non-recombining sex chromosomes, like the mammalian Y, often lose genes and accumulate transposable elements, a process termed degeneration1,2. The correlation between suppressed recombination and degeneration is clear in animal XY systems1,2, but the absence of recombination is confounded with other asymmetries between the X and Y. In contrast, UV sex chromosomes, like those found in bryophytes, experience symmetrical population genetic conditions3,4. Here we test for degeneration in the bryophyte UV sex chromosome system through genomic comparisons with new female and male chromosome-scale reference genomes of the moss Ceratodon purpureus. We show that the moss sex chromosomes evolved over 300 million years ago and expanded via two chromosomal fusions. Although the sex chromosomes show signs of weaker purifying selection than autosomes, we find suppressed recombination alone is insufficient to drive gene loss on sex-specific chromosomes. Instead, the U and V sex chromosomes harbor thousands of broadly-expressed genes, including numerous key regulators of sexual development across land plants.

evolutionary biology↗

bioRxiv2020

The Evolution of Sex Chromosome Dosage Compensation in Animals

The evolution of sex chromosomes in the XY or ZW systems shall lead to gene expression dosage problems, as in at least one of the sexes, the sex-linked gene dose has been reduced by half. It has been proposed, most notably by Susumu Ohno for mammals, that the transcriptional output of the whole sex chromosome should be doubled for a complete dosage compensation. However, due to the variability of the existing methods to determine the transcriptional differences between Sex chromosomes and Autosomes (S:A ratios) in different studies, whether clade-specific results are comparable and whether there is a more general model to explain dosage compensation states remain unanswered. In this study, we collected more than 500 public RNA-seq datasets from multiple tissues and species in major clades (including mammals, birds, fishes, insects, and worms) and proposed a unified computational framework for unbiased and comparable measurement of the S:A ratios of multiple species. We also tested the evolution of dosage compensation more directly by assessing changes in the expression levels of the current sex-linked genes relative to those of the ancestral sex-linked genes. We found that in mammals and birds, the S:A ratio is approximately 0.5, while in insects, fishes and flatworms, the S:A ratio is approximately 1. Further analysis showed that the fraction of dosage-sensitive housekeeping genes on the sex chromosome is significantly correlated with the S:A ratio. In addition, the degree of degradation of the Y chromosome may be responsible for the change in the S:A ratio in mammals without a dosage-compensation mechanism. Our observations offer unequivocal support for the sex chromosome insensitivity hypothesis in animals and suggest that the dosage sensitivity states of sex chromosomes is a major factor underlying different evolutionary strategies of dosage compensation.

evolutionary biology↗

bioRxiv2020

Peopling of Tibet Plateau and multiple waves of admixture of Tibetans inferred from both modern and ancient genome-wide data

Archeologically attested human occupation on the Tibet Plateau (TP) can be traced back to 160 thousand years ago (kya, Xiahe) via archaic people and 30~40 kya via anatomically modern human in Nwya Devu. However, the past human movements and peopling of the TP keep in its infancy in the modern/ancient DNA studies. Here, we performed the first modern/ancient genomic meta-analysis among 3,017 Paleolithic to present-day eastern Eurasian genomes (2,444 modern individuals from 183 populations (including 98 Ü-Tsang/Ando/Kham Tibetans) and 573 ancients (including 161 Chinese ancients first meta-analyzed here)). Closer genetic connection between ancient-modern highland Tibetans and lowland island/coastal Neolithic northern East Asians was identified, reflecting the main ancestry of high-altitude Tibeto-Burman speakers originated from the ancestors of Houli/Yangshao/Longshan ancients in the middle and lower Yellow River basin, consistent with the common North-China origin of Sino-Tibetan language and dispersal pattern of millet farmers. Although the shared common northern East Asian lineage between Tibetans and lowland East Asians, we still identified genetic differentiation between Highlanders and lowland northern East Asians, the former harboring more deeply diverged Hoabinhian/Onge ancestry and the latter possessing more modern Neolithic southern East Asian and Siberian ancestry, which suggested the co-existence of Paleolithic and Neolithic ancestries in modern and Neolithic East Asian Highlanders. Tibetans from Ü-Tsang/Ando/Kham Tibetan regions showed strong population stratifications consistent with their cultural backgrounds and geographic terrains (showed as barriers for human movements): stronger Chokhopani affinity in Ü-Tsang Tibetans, more western Eurasian ancestry in Ando and greater Neolithic southern East Asian ancestry in Kham Tibetan. Modern combined ancient genomes documented multiple waves of human migrations in TP past: the first layer of local Hunter-Gatherer mixed with Qijia Farmer arose the Chokhopani-associated Proto-Tibetan-Burman, admixture with the additional genetic materials from the western Eurasian steppe, Yellow River and Yangtze River respectively gave rise to modern Ando, Ü-Tsang and Kham Tibetans.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2020

Biased Auditory Nerve Central Synaptopathy Exacerbates Age-related Hearing Loss

Sound information is transmitted from the cochlea to the brain by different subtypes of spiral ganglion neurons (SGN), which show varying degrees of vulnerbility under pathological conditions. It remains unclear how information from these SGNs reassemble among target neurons in the cochlear nucleus (CN) at the auditory nerve (AN) central synapses, and how different synapses change during hearing loss. Combining immunohistochemistry with electrophysiology, we investigated the giant endbulb of Held synapses and their postsynaptic bushy neurons in mice under normal hearing and age-related hearing loss (ARHL). We found that calretinin-expressing and non-calretinin-expressing endbulbs converge at continuously different ratios onto bushy neurons with varying physiological properties. Endbulbs degenerate during ARHL, and the degeneration is more severe in non-calretinin-expressing synapses, which correlates with a gradual decrease in neuronal subpopulation predominantly innervated by these inputs. Our findings suggest that biased AN central synaptopathy and shifted CN neuronal composition underlie reduced auditory input and altered central auditory processing during ARHL.

neuroscience↗