<p>During hibernation, golden-mantled ground squirrels (<i>Spermophilus lateralis</i>) breathe in distinct multi-breath episodes separated by prolonged periods of apnea. We hypothesized that vagal afferent feedback from pulmonary stretch receptors, and N-methyl-D-aspartate (NMDA) type glutamate receptor-mediated processes in the pons are instrumental in the production of this breathing pattern and analyzed the effects of disrupting vagal feedback, and blockade of NMDA type receptors by the non-competitive antagonist (+)-5-methyl-10,11-dihydro-5&#xa0;H-dibenzo[a, d]-cyclohepten-5,10-imine maleate (MK-801), on breathing pattern and ventilatory responses to hypoxia and hypercapnia in ground squirrels during natural hibernation. The hibernating squirrels breathed episodically and exhibited a robust ventilatory response to hypercapnia but not hypoxia. The breathing episode (not the individual breath) was the major regulated variable in the breathing pattern. Vagal blockade did not alter breathing on a breath-by-breath basis but did decrease the breaths per episode decreasing overall ventilation and abolished the hypercapnic ventilatory response. MK-801 increased the number of breaths per episode and the frequency of breathing during episodes but did not alter overall ventilation nor the hypercapnic ventilatory response. Combined treatment with MK-801 and vagal blockade abolished episodic breathing but also initiated arousal from hibernation. The data suggest that in golden-mantled ground squirrels hibernating at 5°C body temperature, vagal feedback and NMDA receptor mediated processes still modulate breathing. Whether they are responsible for clustering breaths into episodes is suggested but remains equivocal.</p>