Similarities and differences in mechanisms of phrenic and hypoglossal motor facilitation

Abstract

Intermittent hypoxia-induced long-term facilitation (LTF) is variably expressed in the motor output of several inspiratory nerves, such as the phrenic and hypoglossal. Compared to phrenic LTF (pLTF), less is known about hypoglossal LTF (hLTF), although it is often assumed that cellular mechanisms are the same. While fundamental mechanisms appear to be similar, potentially important differences exist in the modulation of pLTF and hLTF. The primary objectives of this paper are to: 1) review similarities and differences in pLTF and hLTF, pointing out knowledge gaps, and 2) present new data suggesting that reduced respiratory neural activity elicits differential plasticity in phrenic and hypoglossal output (inactivity-induced phrenic and hypoglossal motor facilitation, iPMF and iHMF), suggesting that these motor pool specific differences are not unique to LTF. Differences in fundamental mechanisms or modulation of plasticity among motor pools may confer the capacity to mount a complex ventilatory response to specific challenges, particularly in motor pools with different “jobs” in the control of breathing.

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

“…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.…”

Decreased spinal synaptic inputs to phrenic motor neurons elicit localized inactivity-induced phrenic motor facilitation

“…On the other hand, following reversal of axon conduction block, phrenic amplitude did not eventually return to baseline, as would be expected from a true homeostatic form of plasticity, suggesting that iPMF is unidirectional or the “off” kinetic is considerably slower than the “on” response. In contrast to phrenic motor output, inactivity-induced plasticity in other respiratory motor pools (e.g., hypoglossal and intercostal) is reversed within the same time frame as its induction (Baker-Herman and Strey, 2011; Strey et al, 2013). Thus, in these motor pools, activation of counter mechanisms (i.e., the off response) may restore motor output to normal/baseline levels in a similar “on” versus “off” time frame.…”

“…Further, since central apnea reduces respiratory neural activity throughout the neuraxis, it is unknown if global (brainstem) versus local (spinal) mechanisms give rise to iPMF. Indeed, central apnea elicits facilitation in multiple respiratory-related motor pools, including phrenic (iPMF; Mahamed et al, 2011), hypoglossal (iHMF; Baker-Herman and Strey, 2011) and intercostal (iIMF; Strey et al, 2013), suggesting an input common to all signals (i.e., brainstem respiratory neurons) could give rise to inactivity-induced plasticity.…”

Adenosine 2A Receptor Inhibition Enhances Intermittent Hypoxia-Induced Diaphragm but Not Intercostal Long-Term Facilitation

“…On the other hand, the lack of enhanced AIH-induced T2 EIC LTF with A2A receptor inhibition demonstrates that this motor pool is not modulated by the same inhibitory, adenosinergic interaction. Thus, as with phrenic versus hypoglossal LTF, 24 there are both similarities and differences in factors modulating AIH-induced LTF among inspiratory motor pools.…”