A nose-to-brain axis for spoiled food odor-triggered defensive responses in male mice

Rancid odors can trigger retching and aversion in humans that prevent consumption of spoiled food, and consequently metabolic dysregulation, but the underlying neural mechanisms remain unclear. Here, we show that exposure to 2-methylbutyric acid (2MBA) odor triggers such defensive responses in male mice, mediated by a nose-to-brain axis. 2MBA perception in olfactory epithelium activates neurons in olfactory bulb (OB) projecting to glutamatergic neurons in anterior piriform cortex (aPir^Glu), which in turn project to either the mediodorsal thalamic nucleus (MD), which innervates respiratory muscles to drive retching-like behaviors, or project to the nucleus accumbens (NAc) to drive aversion. Artificial inhibition of the nose→OB→aPir→MD^Glu→respiratory muscles circuit diminishes retching-like behaviors, but not aversion, while inhibiting the nose→OB→aPir→NAc circuit diminishes aversion, but not retching-like behaviors. These findings thus establish a nose-to-brain axis for rancid odor-triggered retching and aversion in male mice, advancing our understanding of sensory-motor integration and whole-body neural bases of defensive responses to odor.