Chemosensitive Phox2b-expressing neurons are crucial for hypercapnic ventilatory response in the nucleus tractus solitarius

Abstract

The nucleus tractus solitarius (NTS) neurons have been thought to function as central respiratory chemoreceptors. However, it remains unknown regarding the common molecular marker defined for these neurons. Here we ask whether paired-like homeobox 2b (Phox2b)-expressing NTS neurons are recruited in hypercapnic ventilatory response (HCVR) and whether these neurons exhibit intrinsic chemosensitivity. HCVR was assessed using whole body plethysmography and neuronal chemosensitivity was examined by patch clamp recordings in brainstem slices or dissociated neurons from Phox2b-EGFP transgenic mice. Injection of the neurotoxin substance P-saporin (SSP-SAP) into NTS destroyed Phox2b-expressing neurons. Minute ventilation and tidal volume were both reduced by 13% during exposure to 8% CO₂ in inspired air when ∼13% of the Phox2b-expressing neurons were eliminated. However, loss of ∼18% of these neurons was associated with considerable decreases in minute ventilation by ≥18% and in tidal volume by≥22% when challenged by ≥4% CO₂. In both cases, breathing frequency was unaffected. Most CO₂-activated neurons were immunoreactive to Phox2b. In brainstem slices, ∼43% of Phox2b-expressing neurons from Phox2b-EGFP mice displayed a sustained or transient increase in firing rate during physiological acidification (pH 7.0 or 8% CO₂). Such a response was also present in dissociated neurons in favor of an intrinsic property. In voltage clamp recordings, a background K⁺ channel-like current was found in a subgroup of Phox2b-expressing neurons. Thus, the respiratory deficits caused by injection of SSP-SAP into the NTS are attributable to proportional lesions of CO₂/H⁺-sensitive Phox2b-expressing neurons.

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