Multimodal atlas of single neuron metabolic electrophysiological coupling uncovers circadian rewiring

Neuronal metabolism fundamentally modulates synaptic activity, yet how single-cell metabolic architecture aligns with electrophysiological diversity remains elusive. By integrating patch-clamp electrophysiology with single-neuron mass spectrometry (SNMS), we resolve metabolomic heterogeneity across suprachiasmatic nucleus (SCN) neurons, revealing six metabolic states with distinct synaptic dynamics, from lipid-enriched SCN1 exhibiting high-frequency presynaptic activity to quiescent SCN6. Pathway analysis linked metabolic state-specific signatures to sulfur metabolism, glutathione regulation, and citrate cycle dynamics. Machine learning and correlation networks mapped metabolites to functional parameters: histidine, carnitine, and creatinine regulated neuronal activity, validated by intracellular metabolite delivery experiments. Strikingly, light-dark cycles dynamically reconfigured most of the metabolite-postsynaptic current correlations, including light-induced taurine coupling to synaptic transmission. This multimodal platform establishes cellular metabolism as a tunable factor associated with neuronal heterogeneity and circadian plasticity, suggesting potential therapeutic avenues for circadian disorders.