The integration of spatial transcriptomics and metabolic data from the cortical region of the brain identifies key genes associated with cognitive ability in pigs

Pigs are widely recognized for their advanced cognitive capabilities, making them a highly suitable animal model for studying human cognitive processes and neurological disorders. To elucidate the molecular underpinnings of cognition, we employed an innovative integrative approach combining spatial transcriptomics and metabolomics to construct a high-resolution, multi-dimensional map of the porcine prefrontal cortex. This map enables unprecedented precision in localising cognition-associated molecular events within complex neural tissues. With a focus on cortical layers III-V, we systematically characterised the spatial distributions of genes and metabolites, identifying CHGB as a key gene whose expression is closely associated with synaptic depolarization, cognitive performance, and neuropeptide secretion. Differential CHGB expression across cognitive groups was further validated through immunohistochemical analysis and Y-maze behavioural testing in stratified mice models. Additionally, we reconstructed a gene-metabolite regulatory network linked to cortical aerobic glycolysis, revealing a multi-layered architectural framework, comprising transcriptional, metabolic, and neurochemical tiers, that modulates cognitive function. As the first successful application of spatial multi-omics integration in a large gyrencephalic brain, this study establishes a novel paradigm for advancing research in cognition and neurodegenerative diseases.