Serotonergic neuromodulation of hypoglossal motor output to genioglossus muscle studied by in-vivo microdialysis

Breathing, in addition to being regulated by metabolism and CO2 production, is thought to be stimulated in the awake state by as yet undefined neural mechanisms, referred to as the "wakefulness stimulus". The studies in this thesis investigate the potential role of serotonin and medullary raphe neurons, the latter being the source of serotonergic afferents to respiratory premotor and motor neurons, as possible neural substrates for the "wakefulness stimulus" to breathing. Studies focus primarily on the role of serotonin at the hypoglossal motor nucleus which innervates the genioglossus muscle of the tongue. Understanding the control of this muscle is important as decreased genioglossus muscle activity in sleep can predispose to the common and serious condition of obstructive sleep apnea. The first objective was to develop an animal model to quantify the impact of chronic manipulation of neurotransmitters at the hypoglossal motor nucleus on genioglossus muscle activity across natural sleep and awake states. Additional studies were performed in anesthetized rats to complement the studies in conscious rats. The novel findings include: (1) Serotonin at the hypoglossal motor nucleus results in tonic and persistent enhancement of genioglossus muscle activity but responses are modulated by the prevailing sleep and awake states. (2) The effects of serotonin at the hypoglossal motor nucleus on tonic versus respiratory-related genioglossus activity depend on the concentration of applied serotonin. (3) Endogenous serotonin at the hypoglossal motor nucleus is required for full expression of genioglossus muscle responses to hypercapnia. (4) Endogenous serotonin at the hypoglossal motor nucleus plays a minimal role in the modulation of genioglossus muscle activity in freely behaving rats unless augmented by stimuli such as hypercapnia. (5) Serotonergic drive to the respiratory motor neurons is augmented by vagotomy in anesthetized rats. (6) Serotonergic neurons of the nucleus raphe obscurus impact genioglossus and diaphragm activities and diaphragm responses to hypercapnia in anesthetized, vagotomized rats but not across natural sleep and awake states.Previous studies in reduced animal preparations may have overestimated the role of serotonin in respiratory motor control as studies were performed in de-afferented (in-vitro) and vagotomized conditions in-vivo.