Structured spike series specify gene expression patterns for olfactory circuit formation.

Neural circuits emerge through the interplay of genetic programming and activity-dependent process. During the development of mouse olfactory map, axons segregate into distinct glomeruli in an olfactory receptor (OR)-dependent manner. ORs generate a combinatorial code of axon-sorting molecules, whose expression is regulated by neural activity. However, how neural activity induces OR-specific expression patterns of axon-sorting molecules remains unclear. Here we revealed that the temporal patterns of spontaneous neuronal spikes were not spatially-organized, but were correlated with the OR types. Receptor substitution experiments demonstrated that ORs determine spontaneous activity patterns. Moreover, optogenetically differentiated patterns of neuronal activity induced specific expression of the corresponding axon-sorting molecules and regulated axonal segregation. Thus, OR-dependent temporal patterns of spontaneous activity play instructive roles in generating the combinatorial code of axon-sorting molecules during olfactory map formation.