Identification of multiple hypoxia-independent triggers of upper airway long-term facilitation in a rat model of upper airway motor plasticity.

The respiratory control system can exhibit neuronal plasticity following exposures to repetitive respiratory challenges. For example, repeated obstructive apneas can trigger a form of respiratory plasticity that results in the enhancement of inspiratory hypoglossal (XII) motoneuron activity. This increase in respiratory motor output is known as hypoglossal long-term facilitation (hLTF). In adult male Sprague-Dawley rats, we demonstrate that hLTF can also be triggered in the absence of repeated apneas by intermittent optogenetic stimulation of locus coeruleus (LC) neurons, or through pharmacological activation of adenosine-A2a-receptors at the level of brainstem XII motor pool. Both our pharmacological and optogenetic approaches that trigger hLTF require noradrenergic signaling through activation of α1-noradrenergic receptors on hypoglossal motoneurons. We also use optical LC inhibition to reaffirm the importance of the LC in mediating apnea-induced hLTF. These results demonstrate that hLTF can be triggered by multiple hypoxia-independent stimuli, and for the first time, identify the LC as a key brainstem source for noradrenaline necessary for the expression of hLTF.