A noradrenergic Ih-dependent pacemaker system drives sniffing

Abstract

Sniffs are rapid breaths generated to clear nasal passages, actively sample air for smelling, and, in infants, rouse from sleep. Rapid shifts between breathing at rest (eupnea) and sniffing point to generation of both behaviors by the core brainstem inspiratory oscillator, the preBotzinger Complex (preBotC). Eupneic rhythm generating mechanisms, when driven faster, are assumed to underlie higher frequency sniffing rhythms; however, the mechanisms governing sniffing have not been directly examined and remain unknown. Using head-fixed awake mice and rhythmically active medullary slices containing preBotC, we find that norepinephrine in preBotC elicits sniff bouts whose hyperpolarization-activated cyclic nucleotide-gated (HCN/Ih) channel-dependent rhythmogenic mechanisms are distinct from eupneic rhythm. These findings reveal how neuromodulation enables a single microcircuit to flexibly switch between distinct oscillatory modes, providing a mechanistic framework for rapid respiratory-related behavioral transitions and potential therapeutic targets for conditions affecting arousal and breathing.