Deciphering molecular spatiotemporal information of brain cells by chemical labeling

Understanding the spatiotemporal dynamics of biomolecules in neurons is essential for deciphering brain functions, development, and diseases. Traditional biological labeling methods based on antigen-antibody recognition or nucleic acid hybridization are able to provide static snapshots of cell states. However, the morphological complexity of neurons and the rapid molecular dynamics at synapses render these static snapshots insufficient for deciphering the spatiotemporal dynamics of biomolecules in the brain. Recent advances in chemical labeling technologies, including covalent labeling, metabolic labeling, and proximity labeling, have enabled tracking of molecular spatiotemporal information of brain cells with unprecedented resolution. Covalent labeling methods, such as ligand-directed chemistry, offer covalent tagging of epigenetic modifications and biological components, revealing molecular landscapes. Metabolic labeling leverages modified biomolecule precursors to trace nucleic acid, protein, lipid, and glycan turnover, capturing dynamic synthesis processes. Proximity labeling, through enzymatic biotinylation, maps protein-protein interactions and subcellular proteomes with nanoscale precision. Despite their transformative potential, challenges remain in target universality, specificity, and minimizing cellular perturbation. Here, we highlight the principles, applications, and limitations of chemical labeling technologies. We also propose future directions to advance neuroscience toward decoding the molecular complexity of the brain.