Multiple Hypoxia-Independent Triggers of Upper Airway Long-Term Facilitation

Abstract

The respiratory control system can augment respiratory output following repetitive challenges. For example, repeated airway obstructions can trigger a form of respiratory memory that strengthens inspiratory activity of hypoglossal (XII) motoneurons. This augmentation in respiratory motor output is known as long-term facilitation (LTF) and can be elicited by repeated apneas or bouts of hypoxia. We demonstrate that LTF can be triggered in the absence of repeated apneas or hypoxia by intermittently stimulating locus coeruleus (LC) neurons, or through pharmacological activation of the neurotrophic machinery in XII motoneurons. We used pharmacological and optogenetic approaches to elicit LTF and show that this is mediated by α1-adrenergic receptor-binding at the XII motor pool. We also use optical LC inhibition to reaffirm the importance of the LC in mediating apnea-induced LTF. Lastly, we show that neurotrophic signaling agonists or antagonists applied to XII motoneurons can also be used to elicit or prevent LTF expression, respectively, and acts co-operatively with noradrenaline. These results suggest LTF can be triggered by multiple hypoxia-independent triggers and is mediated by the release of noradrenaline from the LC onto α1-adrenergic receptors on XII motoneurons to trigger plasticity via activation of neurotrophic signaling cascades.