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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE319736 | GEO | 2026/02/18

REPOSITORIES: GEO

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Project description:Animals perform innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach and avoidance. The cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate olfactory behaviors of valence. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially express Slc17a6 and posterior neurons express Slc17a7. Activation of these respective cell types recapitulates appetitive and aversive valence behaviors, and chemogenetic inhibition reveals partial necessity for valence responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate negative and positive olfactory valence. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory valence responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This represents a novel circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct valence.

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

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