Integrated spatial transcriptomic and metabolic profiling identifies molecular networks associated with cognitive performance in the porcine prefrontal cortex

Pigs possess advanced cognitive capabilities and provide a valuable large-animal model for studying human cognition and neurological disorders. To elucidate the molecular architecture underlying cognitive function, spatial transcriptomics and metabolomics were integrated to generate a high-resolution, multidimensional map of the porcine prefrontal cortex. This framework enabled precise localization of cognition-associated molecular programs within structurally complex neural tissue. Focusing on cortical layers III–V, the spatial distribution of transcripts and metabolites was systematically resolved, identifying CHGB as a cognition-linked gene associated with synaptic depolarization, cognitive performance, and neuropeptide secretion. Differential CHGB expression across cognitive groups was further validated through immunohistochemical analysis and Y-maze behavioral testing in stratified mouse models. Integrated gene-metabolite network reconstruction further implicated cortical aerobic glycolysis in cognitive regulation and revealed a layered molecular architecture that connected transcriptional activity, metabolic state, and neurochemical signaling. These findings provide the first spatially resolved multi-omics framework for a large gyrencephalic brain and establish a novel paradigm for advancing research in cognition-related mechanisms and neurodegenerative disease pathways.