Noradrenergic input to hypoglossal motoneurons is mediated by interneurons located in prehypoglossal region

The genioglossus (GG) muscle of the tongue, innervated by hypoglossal motoneurons, plays a critical role in the pathophysiology of obstructive sleep apnea. The state-dependent activity of the hypoglossal motoneurons is largely maintained by excitatory noradrenergic drive. However, this drive was hypothesized to be mediated by unidentified perihypoglossal neurons. We used microinjections of phenylephrine or prazosin, α1-adrenoceptor agonist and antagonist, respectively, into the medullary reticular formation rostral to the hypoglossal nucleus to locate these neurons. The phenylephrine or prazosin was microinjected into the hypoglossal nucleus and into rostral medullary regions while recording spontaneous activity in GG and diaphragm muscles in anesthetized C57bl/6J mice. The microinjections of phenylephrine/prazosin elicited, respectively, excitatory/inhibitory responses in the GG muscle, which had minimal latencies when injected into a limited region just rostral to the hypoglossal nucleus, which we termed the "prehypoglossal region" (PHR). In isoflurane-anesthetized mice, phenylephrine injected into the PHR induced large increases in GG muscle activity (21.8 ± 3.5 vs. baseline 4.50 ± 0.86, arbitrary units). These phenylephrine-induced responses from the PHR were substantially stronger compared with those evoked from the hypoglossal nucleus (5.46 ± 1.3 vs. baseline 4.12 ± 0.73). However, in ketamine/xylazine-anesthetized mice, phenylephrine's ability to activate the GG muscle from the PHR was substantially blunted, which suggests that the ketamine-induced systemic antagonism of glutamatergic NMDA receptors may interfere with the response. Our findings suggest that the PHR contains interneurons that mediate the state-dependent noradrenergic drive to hypoglossal motoneurons, and that glutamate may be used as a mediator by PHR circuitry.NEW & NOTEWORTHY PHR interneurons that transmit noradrenergic drive to hypoglossal motoneurons are located just rostral to the hypoglossal nucleus. Under isoflurane anesthesia, phenylephrine-induced excitation of PHR interneurons induced a fivefold increase in the amplitude of spontaneous genioglossus (GG) muscle activity as compared with limited GG muscle responses from the hypoglossal nucleus. Ketamine/xylazine anesthesia blunted the phenylephrine-PHR-elicited GG muscle excitation, which suggests an involvement of NMDA receptors in the control of GG muscle by PHR circuitry.