Early-Life Odor Exposure Rewrites Innate Aversion through a Frizzled1-Regulated Critical Period

Animals are born with innate mechanisms to detect environmental danger, yet they must also learn to recognize their nest and caregivers through early-life experience. When an innately aversive stimulus becomes associated with the maternal environment, a fundamental conflict arises between hardwired predispositions and experience-dependent learning. How the brain resolves this conflict remains unknown. Here we show that in mice, exposure to aversive odors during the first postnatal week not only abolishes innate aversion but also converts these cues into safety signals. Remarkably, this altered response bears the hallmarks of innate perception and cannot be reversed by associative learning in adults, constituting a form of olfactory imprinting with lifelong consequences for social behavior. Mechanistically, early odor exposure reshapes axonal projections of neurons expressing the corresponding odorant receptors, thereby altering odor identity as encoded by olfactory glomerular activity patterns. This plasticity is restricted to a defined developmental critical period, after which the circuit changes become permanent. We find that this critical period coincides with a transient surge in activity of specific genetic regulatory networks in mature olfactory sensory neurons (mOSNs). Although these regulons are first engaged in neuronal progenitors, their activation in mOSNs does not alter neuronal identity. We identify the Wnt receptor Frizzled1 (Fzd1) as a key regulator of this critical period. Loss of Fzd1 selectively perturbs gene expression at the peak and termination of the critical period, prevents its closure, and abolishes odor imprinting. Genetic evidence indicates that Fzd1 expression at the onset of the critical period provides feedback to dampen regulon activity, thereby triggering a molecular cascade that irreversibly reduces plasticity. Together, these findings reveal a genetically controlled mechanism that stabilizes early-formed olfactory circuits, enabling innate aversive perception while permitting early-life experience to permanently redefine its valence. Overall design: WT and Fzd1cKO cells derived from olfactory epithelial tissue across different developmentally relevant timepoints is compared. scRNA-seq analysis was performed on samples to compare the effects of conditional Fzd1 knockout in mature olfactory sensory neurons, on broader neurodevelopment, and the maintenence of plasticity throughout an established olfactory critical period. (First postnatal week)