Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Abstract

The respiratory control system is not just reflexive, it is smart, it learns, and, in fact, it has a memory. The respiratory system listens to and carefully remembers how previous stimuli affect breathing. Respiratory memory is laid down by adjusting synaptic strength between respiratory neurons. For example, repeated hypoxic bouts trigger a form of respiratory memory that functions to strengthen the ability of respiratory motoneurons to trigger contraction of breathing muscles. This type of respiratory plasticity is known as long-term facilitation (LTF). Although chemical feedback, such as hypoxia, initiates LTF, it is unknown whether natural modulation of mechanical feedback (from vagal inputs) also causes motor plasticity. Here, we used reverse microdialysis, electrophysiology, neuropharmacology, and histology to determine whether episodic modulation of vagally mediated mechanical feedback is able to induce respiratory LTF in anesthetized adult rats. We show that repeated obstructive apneas disrupt vagal feedback and trigger LTF of hypoglossal motoneuron activity and genioglossus muscle tone. This same stimulus does not cause LTF of diaphragm activity. Hypoxic episodes do not cause apnea-induced LTF; instead, LTF is triggered by modulation of vagal feedback. Unlike hypoxia-induced respiratory plasticity, vagusinduced LTF does not require 5-HT 2 receptors but instead relies on activation of ␣1-adrenergic receptors on hypoglossal motoneurons. In summary, we identify a novel form of hypoxia-and 5-HT-independent respiratory motor plasticity that is triggered by physiological modulation of vagal feedback and is mediated by ␣1-adrenergic receptor activation on (or near) hypoglossal motoneurons.

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

“…Comparison of the above data for paralyzed and mechanically ventilated rats (Figures 2, 3, 5, and 6) vs. nonparalyzed and spontaneously breathing rats (Figure 7) showed that hLTF was effectively induced by repetitive no-lung-inflations (by stopping the ventilator or by airway occlusion) in both cases. This is consistent with the previous finding that repetitive interruption of vagally mediated lung volume feedback alone could induce hLTF (24). However, in spontaneously breathing rats (with vagi intact), GG activity also exhibited a significant tonic (respiratory phase-spanning) component during (but not before) airway obstruction ( Figure 7, B-D).…”

“…Because the hLTF so induced has been shown to be mediated mainly by repetitive interruption of lung volume feedback independently of 5-HT 2 receptors and without accompanying long-term facilitation of diaphragm activity (24), it was distinct from the 5-HT 2 receptor-dependent hLTF induced by repetitive hypoxia (30), although a minor contribution of the latter effect cannot be ruled out. Given that patients with OSA often experience only hypopnea (with partial airway obstruction and less severe resultant decreases in blood oxygen saturation and increases in hypoxic stimulation), the hLTF attained in this case may be weaker than that resulting from complete obstructive apnea, making this second-line motor defense against OSA even less effective during sleep.…”

“…To the extent that the present study has been aimed at primarily verifying the viability and sites of action of yohimbine therapy as a novel drug treatment of OSA, many underlying mechanistic details as discussed above remain to be clarified in the future (Figure 8). Another limitation of the present study is the necessary use of urethane anesthesia in order to avoid arousal during obstructive apnea in tracheostomized rats, which is typical of such studies (24). Unlike other anesthetics, urethane anesthesia retains the sleep-like alterations in brain state, GG activity, breathing pattern, and chemosensitivity similar to those seen during natural sleep in unanesthetized rats (29,62,63).…”

“…Rectal temperature was maintained at 36.5°C-37.5°C with a thermostatic heating pad. In all experiments, both vagus nerves were kept intact because repetitive interruption of vagal lung volume feedback was necessary for the induction of hLTF (24).…”

“…In particular, recent studies reveal that repetitive obstructive apnea per se may elicit persistent facilitation of rat GG activity, a form of vagally mediated neuroplasticity (referred to as hypoglossal long-term facilitation, hLTF) that requires the activation of α 1 -adrenoceptors on HMs for its expression (24). However, because hLTF is an effect rather than cause of OSA, its possible role in the pathogenesis of OSA has been poorly understood.…”