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.
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.
Key links between peripheral protein dysregulation and neuronal function and behavior are revealed, offering new insights into systemic contributions to ASD pathophysiology and highlighting potential therapeutic targets for mitigating symptom severity.
Samia M. Ltaief, Safa Salim, Sadam Hussain et al.· Translational Psychiatry· 0 citations
Local brain age (LBA) is a spatially resolved biomarker of brain aging that captures regional deviations from chronological age, yet its genetic architecture in the subcortex remains unexplored. Here, we present the first genome-wide association study (GWAS) of subcortical LBA, estimated using a deep neural network applied to T1-weighted MRI scans from 41,957 cognitively normal participants in the UK Biobank. We computed LBA across 14 subcortical structures and identified 14 significant single-nucleotide polymorphisms (SNPs) across nine independent loci. These variants map to genes involved in cellular homeostasis, gene regulation, and synaptic and developmental signaling. A prominent signal emerged at the 17q21.31 haplotype, encompassing MAPT-related regulatory architecture, with significant associations across all subcortical regions. Across loci, we observed a recurring spatial pattern in which effect sizes are relatively larger in metabolically central structures such as the pallidum and thalamus compared to limbic regions. Together, these findings support a spatially structured pattern of genetic associations in subcortical brain aging. This work supports subcortical LBA as a genetically informed phenotype and provides a framework for linking common genetic variation to region-specific vulnerability and resilience in neurodegenerative disease.
Nicholas J. Kim, Ayati Mishra, Jeremy S Yu et al.· GeroScience· 0 citations
Stroke disrupts the brain's ability to process and integrate information over time, yet the underlying molecular mechanisms remain unclear. This study investigates post-stroke alterations in intrinsic neural timescales (INTs)-a measure of regional temporal integration-by combining resting-state fMRI, spatial transcriptomics, and PET-based neurochemical mapping. Fifty acute ischemic stroke patients (within 7 days of onset) and fifty matched healthy controls were examined. Voxel-wise and network-level analyses revealed significantly reduced INTs in temporoparietal and insular cortices, with pronounced network-level impairments in the visual and cerebellar systems. Using data from the Allen Human Brain Atlas, we identified gene expression patterns associated with these disruptions. Genes negatively associated with INT reductions were enriched for synaptic, mitochondrial, and neurodevelopmental pathways, while positively associated genes reflected immune signaling and nuclear transport. INT alterations also correlated with excitatory and inhibitory neuronal signatures and were spatially aligned with GABA-A receptor density. Importantly, INT reductions showed significant correlations with clinical assessments: whole-brain INT correlated negatively with NIHSS (r = -0.41) and positively with MoCA (r = 0.38) and FMA (r = 0.35); SMN INT correlated with FMA motor subscore (r = 0.44); and regional INT correlated with domain-specific NIHSS subscores (neglect: r = -0.42; language: r = -0.38). These findings position INT as a clinically meaningful systems-level correlate of stroke-induced dysfunction and highlight molecular pathways and neurotransmitter systems that may constrain temporal integration and recovery potential.
Shaogao Gui, Zhan-Xiang Hu, Yuan-Zhi He et al.· Brain Research· 0 citations
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