Pereira, V. B. | Search bioRxiv

bioRxiv2026

A multimodal interrogation of Broca's area in the pediatric and adult human brain

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 Brocas 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 Brocas 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 Brocas 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 Brocas 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 Brocas area and motor cortex, laying the groundwork for investigations into unique aspects of human cognition and related neurodevelopmental and neuropsychiatric disorders.

neuroscience↗

bioRxiv2026

Spatial lung niches shape Pseudomonas aeruginosa persistence

Chronic Pseudomonas aeruginosa lung infection is a major cause of morbidity and mortality in people with pre-existing lung disease. Once established, infection is rarely eradicated and often persists despite prolonged antimicrobial therapy, but the underlying mechanisms remain poorly understood. To define how P. aeruginosa occupies and adapts to diseased lung tissue, we applied host-pathogen spatial transcriptomics to profile over 23 million lung cells from explanted and resected lungs from people with Cystic Fibrosis (CF) and chronic obstructive pulmonary disease (COPD), mapping bacterial niches and transcriptional states in situ. We found that P. aeruginosa adopted distinct niche-linked states across chronically infected human lung tissue. Bacterial burden was highest in airway lumens, but bacteria also occupied submucosal glands, parenchyma and, unexpectedly, blood vessel lumens in CF tissue. Within airway lumens, two coupled host-pathogen states emerged: an alginate-rich biofilm-like state linked to PI3-positive neutrophil inflammation and host chemical-sensing programmes; and a motile, quorum-sensing state with activated type 6 secretion linked to human ciliary stress, epithelial remodelling and proteolytic injury. Intravascular bacteria co-localised with neutrophils, fibrin and vascular-remodelling signatures, suggesting local breach of barrier integrity and subsequent immune containment. P. aeruginosa also displayed disease-specific cellular associations, with neutrophil-dominated interactions in CF and greater association with macrophages and dendritic cells in COPD. Together, these data reveal chronic P. aeruginosa infection as a spatially partitioned ecosystem in which anatomical microenvironments impose distinct bacterial lifestyles and host inflammatory states. This niche-resolved framework helps explain how persistent infection can diversify within a single lung and suggests that eradication therapies may need to target multiple anatomical and cellular niches to be effective.

immunology↗