Piriform cortex gates learned fear through a brain-spleen neuroimmune axis.

Maladaptive learned fear responses to stress underlie several debilitating neuropsychiatric disorders. Here, we identify a brain-to-spleen neural pathway that mediates learned fear through coordinated neuroimmune interactions. Using a chronic acquired olfactory stress (CAOS) model, we demonstrate that sustained enhancement of the piriform cortex (Pir) excitability contributes to the transformation of stress-associated olfactory inputs into learned fear-avoidance behavior. Through comprehensive neural tracing approaches, we mapped a functional tetrasynaptic circuit (Pir→ventral hippocampus CA1 subregion [vCA1]→CeM→DVC→spleen) regulating T helper 17 (Th17) cell-dependent fear responses. Single-nucleus RNA sequencing revealed that olfactomedin 3-expressing glutamatergic neurons in the Pir integrate olfactory stress inputs to activate this pathway. Importantly, targeted disruption of this circuit through either conditional knockdown of Olfm3 within Pir→vCA1 projecting glutamatergic neurons or chemogenetic inhibition of these projections eliminated CAOS-induced splenic Th17 cell expansion and fear avoidance. These findings provide fundamental insights into how learned fear becomes maladaptive by identifying a complete neural circuit linking olfactory perception to peripheral immunity.