Biology subjects

Herb, B. R.

Publications and source records attributed to Herb, B. R..

10 recordsLinked to original sources

bioRxiv2026

A comparative single-cell transcriptomic atlas for diverse populations of vertebrate hair cells

Mechanosensitive hair cells vary widely in morphology and regenerative capacity across vertebrate organs and species. To investigate their underlying transcriptomic diversity, we integrated human, mouse, chicken, and zebrafish single-cell and single-nucleus RNA sequencing datasets and assembled a cross-species atlas of hair cells spanning organs, developmental stages, and species. Analysis of 29 hair cell populations, encompassing the major cochlear, vestibular, and lateral-line hair cell types, identified approximately 5,000 genes enriched in at least one hair cell population compared to supporting cells from the same organs. Unsupervised clustering of these hair cell-enriched (HCE) genes defined species-, organ-, and hair cell state-associated cohorts as well as broadly conserved hair cell-enriched programs. Using an AUC-based scoring framework, we further defined 884 pan hair cell-enriched (pan-HCE) genes with elevated expression in most developing and/or mature hair cell populations, including genes implicated in deafness, mechanotransduction, and synaptic transmission, along with genes not previously linked to hair cell function. Independent analysis of developing hair cells using the same metrics stratified pan-HCE genes based on when they are first enriched and identified an additional 97 genes that are transiently enriched. We used the pan- and developing HCE gene sets to assess transcriptional similarity between baseline hair cell states and hair cells produced during avian hair cell regeneration and in mouse cochlear organoids, as well as hair cell-like populations produced by fibroblast reprogramming. HCE gene sets with different developmental dynamics identified young vs. more mature hair cells when projected onto independent single-cell RNA sequencing datasets from developing zebrafish, mouse, and human. We provide a web-based resource of all HCE metrics and expression profiles, enabling future exploration of vertebrate hair cell gene expression across organs, species, and experimental contexts.

neuroscience↗

bioRxiv2026

STAPLE: automating spatial transcriptomics analysis and AI interpretation

Spatial transcriptomics workflows often span separate tools for cell typing, neighborhoods, and cell-cell communication, yielding fragmented outputs that hinder scalability, interpretation, and reproducibility. STAPLE systematizes analyses across distinct methods into a modular framework, unifying data structures and cross-tool interoperability. End-to-end analyses are performed unassisted with a single invocation, fostering rigorous, reproducible spatial transcriptomics analysis. Its novel, AI-enabled reporting layer synthesizes quantitative results into summaries of biological findings, facilitating analysis interpretation.

bioinformatics↗

bioRxiv2025

Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury

CNS has an overall higher level of lipids than all tissues except adipose and contains up to 25% of total body cholesterol. Recent data demonstrate a complex crosstalk between lipid metabolism and inflammation, suggesting potential contribution of the lipid-rich brain environment to neuroinflammation. While recent data support the importance of brain lipid environment to inflammatory changes observed in age related chronic neurodegenerative diseases, in vivo interactions between lipid environment, lipid metabolism and neuroinflammation in acute brain disease and injury remain poorly understood. Here we utilize a mouse model of traumatic brain injury (TBI) to demonstrate that acute neurotrauma leads to widespread lipid metabolism reprograming in all microglial and brain associated and infiltrating monocyte populations. Additionally, we identify unique microglial and monocyte populations with higher degree of lipid metabolism reprograming and pronounced accumulation of neutral storage lipids, including cholesteryl esters and triglycerides. These lipids accumulate not only in lipid droplets but also in the microglial and monocyte lysosomes and are associated with lysosomal dysfunction and inhibition of autophagy after TBI. Our data indicate that lipid accumulation in these cells is the result of altered lipid handling rather than lipid synthesis and is triggered by phagocytosis of lipid-rich myelin debris generated after TBI. Finally, we use mice with autophagy defects in microglia and monocytes to demonstrate that further inhibition of autophagy leads to more pronounced lipid metabolism reprograming and exacerbated cellular lipid accumulation. Our data suggest a pathological feedback loop, where lipid phagocytosis causes inhibition of autophagy-lysosomal function, which in turn exacerbates cellular lipid retention, reprograming and inflammation.

neuroscience↗

bioRxiv2024

Leptin Activated Hypothalamic BNC2 Neurons Acutely Suppress Food Intake

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism1. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons2. However, while AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect3-5. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that suppresses appetite on a rapid time scale. Here, we report the discovery of a novel population of leptin-target neurons expressing basonuclin 2 (Bnc2) that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is finely tuned by leptin, sensory food cues, and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action.

neuroscience↗

bioRxiv2023

Matrix and analysis metadata standards (MAMS) to facilitate harmonization and reproducibility of single-cell data

A large number of genomic and imaging datasets are being produced by consortia that seek to characterize healthy and disease tissues at single-cell resolution. While much effort has been devoted to capturing information related to biospecimen information and experimental procedures, the metadata standards that describe data matrices and the analysis workflows that produced them are relatively lacking. Detailed metadata schema related to data analysis are needed to facilitate sharing and interoperability across groups and to promote data provenance for reproducibility. To address this need, we developed the Matrix and Analysis Metadata Standards (MAMS) to serve as a resource for data coordinating centers and tool developers. We first curated several simple and complex "use cases" to characterize the types of featureobservation matrices (FOMs), annotations, and analysis metadata produced in different workflows. Based on these use cases, metadata fields were defined to describe the data contained within each matrix including those related to processing, modality, and subsets. Suggested terms were created for the majority of fields to aid in harmonization of metadata terms across groups. Additional provenance metadata fields were also defined to describe the software and workflows that produced each FOM. Finally, we developed a simple listlike schema that can be used to store MAMS information and implemented in multiple formats. Overall, MAMS can be used as a guide to harmonize analysis-related metadata which will ultimately facilitate integration of datasets across tools and consortia. MAMS specifications, use cases, and examples can be found at https://github.com/single-cell-mams/mams/.

bioinformatics↗

bioRxiv2022

The Neuroscience Multi-Omic Archive: A BRAIN Initiative resource for single-cell transcriptomic and epigenomic data from the mammalian brain

Scalable technologies to sequence the transcriptomes and epigenomes of single cells are transforming our understanding of cell types and cell states. The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative Cell Census Network (BICCN) is applying these technologies at unprecedented scale to map the cell types in the mammalian brain. In an effort to increase data FAIRness (Findable, Accessible, Interoperable, Reusable), the NIH has established repositories to make data generated by the BICCN and related BRAIN Initiative projects accessible to the broader research community. Here, we describe the Neuroscience Multi-Omic Archive (NeMO Archive; nemoarchive.org), which serves as the primary repository for genomics data from the BRAIN Initiative. Working closely with other BRAIN Initiative researchers, we have organized these data into a continually expanding, curated repository, which contains transcriptomic and epigenomic data from over 50 million brain cells, including single-cell genomic data from all of the major regions of the adult and prenatal human and mouse brains, as well as substantial single-cell genomic data from non-human primates. We make available several tools for accessing these data, including a searchable web portal, a cloud-computing interface for large-scale data processing (implemented on Terra, terra.bio), and a visualization and analysis platform, NeMO Analytics (nemoanalytics.org). KEY POINTSO_LIThe Neuroscience Multi-Omic Archive serves as the genomics data repository for the BRAIN Initiative. C_LIO_LIGenomic data from >50 million cells span all the major regions of the brains of humans and mice. C_LIO_LIWe provide a searchable web portal, a cloud-computing interface, and a data visualization platform. C_LI

genomics↗

bioRxiv2022

Early-childhood inflammation blunts the transcriptional maturation of cerebellar neurons

Inflammation early in life is a clinically established risk factor for autism spectrum disorders and schizophrenia, yet the impact of inflammation on human brain development is poorly understood. The cerebellum undergoes protracted postnatal maturation, making it especially susceptible to perturbations contributing to risk of neurodevelopmental disorders. Here, using single-cell genomics, we characterize the postnatal development of cerebellar neurons and glia in 1-5-year-old children, comparing those who died while experiencing inflammation vs. non-inflamed controls. Our analyses reveal that inflammation and postnatal maturation are associated with extensive, overlapping transcriptional changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons. Immunohistochemical analysis of a subset of these brains revealed no change to Purkinje neuron soma size but evidence for increased activation of microglia in those subjects experiencing inflammation. Maturation- and inflammation-associated genes were strongly enriched for those implicated in neurodevelopmental disorders. A gene regulatory network model integrating cell type-specific gene expression and chromatin accessibility identified seven temporally specific gene networks in Purkinje neurons and suggested that the effects of inflammation correspond to blunted cellular maturation. One Sentence SummaryPost-mortem cerebelli from children who perished under conditions that included inflammation exhibit transcriptomic changes consistent with blunted maturation of Purkinje neurons compared to those who succumbed to sudden accidental death.

genomics↗

bioRxiv2020

Evolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse

The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally conserved across mammals. Using high-throughput transcriptomic and epigenomic profiling of over 450,000 single nuclei in human, marmoset monkey, and mouse, we demonstrate a broadly conserved cellular makeup of this region, whose similarity mirrors evolutionary distance and is consistent between the transcriptome and epigenome. The core conserved molecular identity of neuronal and non-neuronal types allowed the generation of a cross-species consensus cell type classification and inference of conserved cell type properties across species. Despite overall conservation, many species specializations were apparent, including differences in cell type proportions, gene expression, DNA methylation, and chromatin state. Few cell type marker genes were conserved across species, providing a short list of candidate genes and regulatory mechanisms responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allowed the Patch-seq identification of layer 5 (L5) corticospinal Betz cells in non-human primate and human and characterization of their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell type diversity in M1 across mammals and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

neuroscience↗

bioRxiv2020

An integrated transcriptomic and epigenomic atlas of mouse primary motor cortex cell types

Single cell transcriptomics has transformed the characterization of brain cell identity by providing quantitative molecular signatures for large, unbiased samples of brain cell populations. With the proliferation of taxonomies based on individual datasets, a major challenge is to integrate and validate results toward defining biologically meaningful cell types. We used a battery of single-cell transcriptome and epigenome measurements generated by the BRAIN Initiative Cell Census Network (BICCN) to comprehensively assess the molecular signatures of cell types in the mouse primary motor cortex (MOp). We further developed computational and statistical methods to integrate these multimodal data and quantitatively validate the reproducibility of the cell types. The reference atlas, based on more than 600,000 high quality single-cell or -nucleus samples assayed by six molecular modalities, is a comprehensive molecular account of the diverse neuronal and non-neuronal cell types in MOp. Collectively, our study indicates that the mouse primary motor cortex contains over 55 neuronal cell types that are highly replicable across analysis methods, sequencing technologies, and modalities. We find many concordant multimodal markers for each cell type, as well as thousands of genes and gene regulatory elements with discrepant transcriptomic and epigenomic signatures. These data highlight the complex molecular regulation of brain cell types and will directly enable design of reagents to target specific MOp cell types for functional analysis.

neuroscience↗

bioRxiv2019

Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty

Age-related hearing impairment (ARHI), one of the most common medical conditions, is strongly heritable, yet its genetic causes remain largely unknown. We conducted a meta-analysis of GWAS summary statistics from multiple hearing-related traits in the UK Biobank (n = up to 323,978) and identified 31 genome-wide significant risk loci for self-reported hearing difficulty (p < 5e-8), of which 30 have not been reported previously in the peer-reviewed literature at genome-wide significance. We investigated the regulatory and cell specific expression for these loci by generating mRNA-seq, ATAC-seq, and single-cell RNA-seq from cells in the mouse cochlea. Risk-associated genes were most strongly enriched for expression in cochlear epithelial cells, as well as for genes related to sensory perception and known Mendelian deafness genes, supporting their relevance to auditory function. Regions of the human genome homologous to open chromatin in sensory epithelial cells from the mouse were strongly enriched for heritable risk for hearing difficulty, even after adjusting for baseline effects of evolutionary conservation and cell-type nonspecific regulatory regions. Epigenomic and statistical fine-mapping most strongly supported 50 putative risk genes. Of these, at least 39 were expressed robustly in mouse cochlea and 16 were enriched specifically in sensory hair cells. These results reveal new risk loci and risk genes for hearing difficulty and suggest an important role for altered gene regulation in the cochlear sensory epithelium.

genetics↗