In previous work mapping direct excitatory and inhibitory inputs to the respiratory rhythm–generating preBötzinger complex (preBötC), we identified several forebrain projections, including a prominent inhibitory input from the central amygdala (CeA). In epilepsy patients, electrical stimulation of the amygdala can elicit apnea without distress, implicating an inhibitory pathway to vital respiratory centers and raising the possibility of a mechanistic link to sudden unexpected death in epilepsy (SUDEP). We therefore hypothesized that, in mice, cell-type–specific activation of inhibitory CeA neurons—or selective stimulation of their axon terminals in the preBötC—would suppress breathing. To test this, we injected Cre-dependent channelrhodopsin into the CeA of Vgat-Cre mice and placed optical fibers either above the CeA or over the preBötC, allowing stimulation of Vgat+ CeA cell bodies or their preBötC-projecting terminals, respectively. Contrary to our prediction, activation of CeA cell bodies during awake whole-body plethysmography produced a slight increase, rather than a decrease, in breathing rate. Video analysis revealed that this effect was strongest when animals were initially calm and appeared secondary to a stimulation-evoked behavioral shift. Consistent with this, terminal stimulation in the preBötC did not affect breathing rate, indicating that the behavioral and respiratory effects arise from CeA neurons that do not project to the preBötC. Supporting this interpretation, open-field assays showed reduced locomotion during cell-body—but not terminal—stimulation.To separate direct respiratory effects from behaviorally driven ones, we repeated both stimulation conditions under anesthesia. Neither manipulation altered breathing rate. However, both increased the likelihood of sighs during or shortly after stimulation—a patterned inspiratory reconfiguration associated with affect, arousal, and physiological state. This shared effect of cell-body and terminal stimulation suggests that the inhibitory CeA→preBötC pathway contributes specifically to sigh modulation rather than apnea or overt respiratory suppression. Finally, Hargreaves testing revealed increased pain thresholds during stimulation in both awake and anesthetized animals.Together, these findings refine functional models of CeA–preBötC communication and motivate further exploration of forebrain inputs to respiratory circuits to determine how these pathways shape breathing across behavioral and physiological states. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Reilly et al. (Fri,) studied this question.