This study investigated how the piriform cortex (Pir) drives maladaptive learned fear via a brain-to-spleen neuroimmune circuit, using a chronic acquired olfactory stress (CAOS) mouse model to map a tetrasynaptic pathway (Pir→vCA1→CeM→DVC→spleen) and its role in Th17 cell-dependent fear-avoidance behavior.
A tetrasynaptic circuit driven by olfactomedin 3 (Olfm3)-expressing glutamatergic neurons in the Pir was identified as the key mediator; conditional knockdown of *Olfm3* in Pir→vCA1 projecting neurons or chemogenetic inhibition of these projections **eliminated** CAOS-induced splenic Th17 cell expansion and fear-avoidance behavior.
The study was conducted in an animal model (CAOS); direct translational applicability to human neuropsychiatric disorders (e.g., PTSD, phobias) is not yet established. Full-text access was limited, so complete methodological details and effect sizes could not be verified.
While not yet clinically actionable, this work identifies the piriform cortex–spleen neuroimmune axis and Olfm3-expressing neurons as potential therapeutic targets for maladaptive fear disorders such as PTSD. Clinicians should watch for translational studies targeting this circuit or peripheral Th17 modulation in anxiety-spectrum conditions.
