Investigating transcriptomic changes during healthy development and aging provides insights into the molecular mechanisms that regulate the maturation of brain functions and drive age-related decline. Although it has been speculated that aging may represent a reversal of late-stage brain development, direct molecular comparisons between these two processes have remained limited. This study employs spatial transcriptomics to analyze the mouse brain at three key timepoints: postnatal day 21 (P21), 3 months (adult), and 28 months (aged), to identify region-specific differential gene expression dynamics. We identify widespread transcriptional changes across both brain development and aging, with all brain regions exhibiting distinct, region-specific gene expression dynamics that reflect divergent regulatory trajectories across the lifespan. During development, gene expression patterns were strongly enriched for neurogenesis, synaptic plasticity, and myelination, reflecting active circuit formation and white matter maturation. In contrast, aging was characterized by a decline in myelination-related gene expression and a pronounced increase in inflammatory and glial activation pathways, particularly within the hippocampus. While both development and aging involved changes in myelination-associated genes, the underlying mechanisms appear distinct: developmental upregulation supports circuit establishment and refinement, whereas aging-related downregulation may reflect secondary consequences of neuroinflammation and reactive gliosis. These findings underscore that, despite some overlap in affected pathways, neural maturation and age-related decline are driven by fundamentally different regulatory programs. These findings establish a novel spatial transcriptomic reference for brain development and aging, offering a valuable data resource for investigating neurodevelopmental and neurodegenerative mechanisms.

Background: Folate, an essential vitamin B9, is crucial for diverse biological processes, including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Objectives/Methods: Here, we employed a mouse model and spatial transcriptomic and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Results: Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Conclusions: Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation.