A "retrodictive" analysis of the cortex is presented that reconstructs the proliferation history of neural stem cells from a static snapshot of tissue, providing a developmentally grounded coordinate system for comparison across samples and is expected to be a foundational framework for 3D neuropathological analysis.
Abstract
Single-cell-resolution mapping of the human brain is central to understanding the link between cellular-level phenotypes and disease. Tissue clearing and mesoscale imaging have facilitated organ-wide quantification of cell populations and are expected to drive the identification of pathological deficits in neurological disorders. However, mesoscopic comparison of human brain tissue remains challenging because of large variability in cortical folding patterns and heterogeneous cell distribution. Here, we present a “retrodictive” analysis of the cortex that reconstructs the proliferation history of neural stem cells from a static snapshot of tissue, providing a developmentally grounded coordinate system for comparison across samples. The analysis showed that most of the heterogeneity in cell distribution can be explained by the physical displacement caused by folding, which allows folding-induced variation to be removed and additionally reveals a possible mechanism of cortical folding. Together with a Bayesian framework, we estimated, with quantified uncertainty, the proliferation rate of a representative stem cell that summarizes the population of each cortical region. This analysis enables researchers to distill inter-individual differences down to stem cell properties and their distributions on the protomap. We anticipate our workflow to be a foundational framework for 3D neuropathological analysis, providing a common coordinate for the cortex-wide analysis of cells across individuals in development, aging, and disease.
Precise delineation of cortical layers is fundamental for understanding human brain organization, cell-type architecture, and disease-related tissue alterations. However, traditional anatomy-based methods often lack molecular resolution and suffer from inter-observer subjectivity. Here, we present gene expression-defined cortical layers (GD-Ls) using the BayesSpace algorithm, a high-resolution framework for cortical parcellation based on spatial transcriptomics. Compared with traditional anatomy-based approaches, GD-Ls more accurately resolve laminar boundaries and capture fine-scale laminar heterogeneity, including sublayer-like domains within L1, L3, and L6, as well as a molecularly distinct transition zone at the gray-white matter interface. Validation across diverse cortical lobes, multiple spatial platforms, and independent healthy postmortem datasets demonstrates that GD-Ls capture the intrinsic molecular architecture of the cortex irrespective of tissue source. Furthermore, cross-species analyses show that this framework is extensible to macaque and mouse cortices. Crucially, GD-Ls successfully identify subtle laminar disorganization and aberrant cellular and molecular signatures in pathologically altered tissues, which are often missed by conventional histology. Together, GD-Ls provide an objective and reproducible tool for standardized cortical mapping and for identifying early pathological signatures in the human brain. The source code is available on GitHub (https://github.com/YanrongWei/GD-Ls).
Yanrong Wei, Youzhe He, Yuyang Liu et al.· Genome Medicine· 0 citations
A comprehensive cerebrovascular cell atlas encompassing 314,535 transcriptomes is constructed that captures the arteriovenous axis and defines consensus cell states and identifies ensemble-specific susceptibilities and candidate therapeutic targets across neurological diseases, including small vessel disease and stroke.
Jerry C. Wang, Damian A Sanchez, Santhosh Arul et al.· Cell· 1 citation
The human hippocampus is a unique cortical structure central to brain function, plasticity, and disease. Unravelling its complex organization requires the integration of multiscale data, linking molecular features to mesoscale anatomy and macroscale functional patterns. Gene expression is a fundamental microscale phenotype, and its profiling can provide a reference description of how molecular features are distributed across the brain. Capitalizing on recent imaging-transcriptomic analyses, we introduce HippoGenes, a repository of fine-grained gene expression patterns across human hippocampal subregions. We leveraged spatial statistical models and hippocampal surface mapping to reconstruct dense transcriptomic maps from sparse post-mortem tissue samples of the Allen Human Brain Atlas, generating continuous expression estimates for thousands of genes aligned to a common surface-based coordinate system. We illustrate the utility of HippoGenes to (i) map medial-lateral and anterior-posterior transcriptomic gradients that align with subfield and tripartite subdivisions of the hippocampal formation, (ii) examine associations between gene expression and canonical microstructural and functional features of the hippocampus, and (iii) perform a molecular decoding of subregional alterations in neurological patients with hippocampal pathology. HippoGenes provides a framework for exploring the molecular organization of the hippocampus, opening avenues for multiscale integration in health and disease, and is openly available on https://hippogenes.readthedocs.io/.
A. Ngo, Sara Larivière, J. Royer et al.· bioRxiv· 0 citations
High-throughput single-cell omics of non-human primate brain tissue provides a powerful platform to investigate the molecular basis of brain aging. Here, we present a comprehensive transcriptomic and chromatin accessibility atlas of 2,955,873 nuclei from eight brain regions of 23 female cynomolgus macaques spanning the adult lifespan, including exceptionally old individuals. Our analyses reveal dynamic, cell-subtype- and region-specific age-related changes in core brain functions, including synaptic communication and axon myelination. We identify multicellular networks in the pons and medulla as a previously unrecognized hotspot of primate brain aging, highlighting white matter vulnerability as a central feature of aging. Integration with human brain aging and neurodegeneration datasets reveals both shared and divergent molecular mechanisms. We further define transcription factors and age-related chromatin remodeling programs linked to longevity and neurodegeneration. This spatiotemporal atlas establishes a foundational framework for understanding the cellular and regulatory architecture of primate brain aging and its links to disease.
Language is a defining trait of our species, and disruptions in language acquisition can have profound consequences to the individuals affected. Uncovering the neurodevelopmental basis of this complex trait requires detailed molecular and cellular insights into the neocortical areas that support linguistic abilities. Here we performed joint gene expression and chromatin accessibility profiling at single-nucleus resolution (10x Genomics Single cell Multiome) and spatial transcriptomic profiling (Xenium high-plex in situ spatial transcriptomics) of Broca’s area alongside adjacent motor cortical areas. We profiled individuals from different ancestries (European and African) and developmental stages (infancy, childhood, adolescence, and adulthood). We provide a high-resolution dissection of the cellular and molecular architecture of Broca’s and motor cortical areas across early life stages and anchor the trajectories to the cellular states found in the adult human brain. We identify distinct area- and stage-specific cellular signatures, including a prominent role of glia populations and interneuron subtypes contributing to cytoarchitectonic specializations. Using longitudinal single cell spatial transcriptomic profiling, we orthogonally validate our consensus cell taxonomy and spatially resolve layer enrichment of neuronal and astrocyte subtypes that distinguish Broca’s area and motor cortex. We also uncover cell type-specific molecular signatures that distinguish cell developmental trajectories in these cortical areas, including an early molecular code established by differential expression of cadherin genes that might contribute to area-specific intercellular communication. We also identify cell type-specific vulnerabilities to language- related neurodevelopmental and neuropsychiatric disorders, with selective susceptibility of particular somatostatin-positive interneuron subtypes to ASD/ADHD. Finally, evolutionary analysis of differentially accessible regions between Broca’s area and motor cortex suggests that genetic mutations that might have contributed to the emergence of linguistic abilities accumulated over the course of million years following the divergence of human and chimpanzee lineages. Together, our study provides a comprehensive molecular, cellular and spatial definition of Broca’s area and motor cortex, laying the groundwork for investigations into unique aspects of human cognition and related neurodevelopmental and neuropsychiatric disorders.
Juan Moriano, Tanzila Mukhtar, J. Lee et al.· bioRxiv· 0 citations
Human neurodevelopment is a continuous process that begins prenatally and extends into postnatal life. Current transcriptomic datasets are limited, fragmented across analytical frameworks, precluding comprehensive reconstruction of cellular trajectories linking developmental states to mature cell types. Here we present a consolidated cellular-resolution transcriptomic atlas of human brain development from the onset of neurogenesis to adulthood, covering ∼2.2 million cells from 156 donors across nine studies. All data were reprocessed from raw sequencing reads and annotated within a unified cell-type taxonomy, enabling reliable mapping across the lifespan. Cell types were highly replicable across heterogeneous datasets, enabling us to chart their maturation and cortical layer localization over time. We identify dynamic gene programs predictive of cell-type maturation, validate gene modules tracking known fate transitions, and leverage our atlas’ scale to characterize rare populations, including microglia. This resource establishes a standardized reference of human brain development and maturation gene modules for future comparisons across model systems, species, and disease states.
Sridevi Venkatesan, Patricia R. Nano, Jonathan M. Werner et al.· bioRxiv· 0 citations