A nose-to-brain circuit underlies anxiety regulation by nasal afferent frequency in mice.

Slow nasal breathing alleviates negative moods, but the precise nose-to-limbic pathways and their causal contributions remain unclear. Here, we identify a pathway in mice from olfactory sensory neurons (OSNs) in the nasal cavity to mitral cells in the olfactory bulb (OB), then to parvalbumin-positive (PV+) long-projecting interneurons in the perirhinal cortex (PRC), and subsequently to glutamatergic neurons in the posterior basolateral amygdala (pBLA), through which nasal afferent activity bidirectionally regulates anxiety in a frequency-dependent manner. Low-frequency nasal airflow or optogenetic OSN stimulation induced anxiolysis and increased PRC high-gamma power by activating PV+ neurons, whereas high-frequency had opposite effects. Chemogenetic silencing of the OB→PRCPV pathway eliminated the frequency-dependent regulation of anxiety-like behaviors driven by OSN stimulation. Selective activation or inhibition of the identified circuit generated opposing behavioral effects (anxiolytic vs. anxiogenic, respectively), paralleling the results of low- and high-frequency OSN stimulations. Strikingly, a 2-wk low-frequency nasal airflow/optogenetic OSN stimulation regimen ameliorated anxiety-like behaviors and restored PRC high-gamma activity in an anxiety model. This study reveals a nose-brain axis bidirectionally modulating anxiety via nasal afferent frequency, providing potential interventional strategies and targets for anxiety disorders.