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Neurodevelopment emerges within a shifting landscape of nutrients and oxygen that shape metabolic states. Yet, the contribution of these metabolic states to the spatial and temporal patterning of the brain remains unresolved. Beyond providing energy and biosynthetic precursors, specific metabolic intermediates can influence cell fates through chromatin and post-translational modifications. 

This raises a fundamental question: can defined metabolic programs act as morphogenetic signals, encoding positional information that instructs neural induction, patterning, and lineage progression? To address this, we will construct the firstin vivo spatiotemporal metabolic atlas of the embryonic mouse brain, integrating spatial metabolomics with 13C isotope tracing to quantify nutrient utilizations and metabolic pathway activities across developmental windows. 

To mechanistically understand whether these metabolic signatures have instructive capacity, we will generate metabolically asymmetric 3D embryo-like models, namely assembloids, from mouse embryonic stem cells, engineered via targeted repression of metabolic enzymes or pre-conditioning with metabolites enriched in vivo. This will allow precise interrogation of how local metabolic perturbations influence neural induction, tube formation, regional specification, and cell fate determination within self-organizing tissue contexts. 

By integrating novel methodologies, quantitative in vivo mapping with mechanistic model systems, this proposal seeks to advance a framework in which metabolism is viewed not merely as supportive, but rather as an active determinant of neurodevelopmental architecture.