Correlative analysis of metallomic gene expression and metal ion content within the mouse hippocampus

Brain metal homeostasis is essential for healthy neurological function, and disturbed brain metal homeostasis has deleterious consequences for neurodevelopment or cognitive outcome following injury or during disease. Specific regions of the brain (e.g. the hippocampus and subregions within) are known to be enriched with transition metals (i.e. ions of iron, copper, and zinc). Neither the physiological need for localized enrichment, nor the mechanisms driving the enrichment, however, are well understood. In this study we have applied a multimodal template, incorporating elemental mapping using X-ray fluorescence microscopy with spatial transcriptomics, to help reveal a molecular basis for metallomic heterogeneity across key subregions of the hippocampus. Our results reveal that significant differences in iron, zinc, and copper enrichment are associated with regional enrichment of specific transcripts related to metal transport, metal storage, and metal regulatory proteins. In addition to providing novel biological insight into the neurometallomic profile of the hippocampus, this study also provides an important template for others to integrate transcriptomics into multimodal workflows investigating the neurometallome.