Brainstem Nuclei Associated with Mediating Apnea-Induced Respiratory Motor Plasticity

The respiratory control system is plastic. It has a working memory and is capable of retaining how respiratory stimuli affect breathing by regulating synaptic strength between respiratory neurons. For example, repeated airway obstructions trigger a form of respiratory plasticity that strengthens inspiratory activity of hypoglossal (XII) motoneurons. This form of respiratory plasticity is known as long-term facilitation (LTF) and requires noradrenaline released onto XII motoneurons. However, the brainstem regions responsible for this form of LTF remain unidentified. Here, we used electrophysiology, neuropharmacology and immunohistochemistry in adult rats to identify the brainstem regions involved in mediating LTF. First, we show that repeated airway obstructions induce LTF of XII motoneuron activity and that inactivation of the noradrenergic system prevents LTF. Second, we show that noradrenergic cells in the locus coeruleus (LC), which project to XII motoneurons, are recruited during LTF induction. Third, we show that targeted inactivation of noradrenergic LC cells during LTF induction prevents LTF. And lastly, we show that the nucleus tractus solitarius (NTS), which has known projections to the LC, is critical for LTF because its inactivation prevents LTF. Our results suggest that both the LC and NTS are involved in mediating apnea-induced LTF, and we hypothesize that a NTS → LC → XII circuit mechanism mediates this form of respiratory motor plasticity.