ANTERIOR OLFACTORY NUCLEUS: AN INTRINSICALLY MECHANOSENSITIVE RELAY FOR OLFACTION

Mammalian olfaction depends on inhalation, suggesting that odor perception may arise from convergent processing of chemosensory (odor) and mechanosensory (airflow) information. While mechanosensation has been implicated in olfactory processing, its functional contribution remains poorly understood. Using single-molecule fluorescent in situ hybridization (smFISH), we detected expression of the mechanically gated ion channel Piezo2 throughout the olfactory system, with particularly high and developmentally enriched expression in neurons of the anterior olfactory nucleus (AON). Piezo2 fate mapping using Piezo2-Cre reporter mice revealed abundant Piezo2-lineage cells in the AON. To test whether AON neurons are intrinsically mechanosensitive, we established primary AON neuron cultures. Single-nucleus RNA sequencing identified Piezo2 and other mechanosensitive ion channels in specific neuronal clusters. Patch-clamp recordings demonstrated that mechanical stimulation via substrate deflection evoked robust mechanically activated (MA) currents, which were significantly more prevalent in tdTomato-positive neurons compared to tdTomato-negative neurons. To assess the functional relevance of AON mechanosensitivity in vivo, we used functional ultrasound imaging in anesthetized mice and observed AON activation in response to airflow-driven mechanical stimulation. Finally, a gain-of-function approach overexpressing STOML3, a modulator of mechanosensitivity in Piezo2+ cells within the AON, enhanced MA currents in vitro and impaired odor discrimination in vivo without altering AON structure or other behaviors (such as locomotion, anxiety). These findings demonstrate that AON neurons are intrinsically mechanosensitive and that proper tuning of mechanosensitivity is critical for processing novel olfactory stimuli.