Competing mechanisms of plasticity impair compensatory responses to repetitive apnoea

Abstract

Key pointsr Intermittent reductions in respiratory neural activity, a characteristic of many ventilatory disorders, leads to inadequate ventilation and arterial hypoxia. Both intermittent reductions in respiratory neural activity and intermittent hypoxia trigger compensatory enhancements in inspiratory output when experienced separately, forms of plasticity called inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively.r Reductions in respiratory neural activity that lead to moderate, but not mild, arterial hypoxia occludes plasticity expression, indicating that concurrent induction of iMF and LTF impairs plasticity through cross-talk inhibition of their respective signalling pathways.r Moderate hypoxia undermines iMF by enhancing NR2B-containing NMDA receptor signalling, which can be rescued by exogenous retinoic acid, a molecule necessary for iMF.r These data suggest that in ventilatory disorders characterized by reduced inspiratory motor output, such as sleep apnoea, endogenous mechanisms of compensatory plasticity may be impaired, and that exogenously activating respiratory plasticity may be a novel strategy to improve breathing.Abstract Many forms of sleep apnoea are characterized by recurrent reductions in respiratory neural activity, which leads to inadequate ventilation and arterial hypoxia. Both recurrent reductions in respiratory neural activity and hypoxia activate mechanisms of compensatory plasticity that augment inspiratory output and lower the threshold for apnoea, inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively. However, despite frequent concurrence of reduced respiratory neural activity and hypoxia, mechanisms that induce and regulate iMF and LTF have only been studied separately. Here, we demonstrate that recurrent reductions in respiratory neural activity ('neural apnoea') accompanied by cessations in ventilation that result in moderate (but not mild) hypoxaemia do not elicit increased inspiratory output, suggesting that concurrent induction of iMF and LTF occludes plasticity. A key role for NMDA receptor activation in impairing plasticity following concurrent neural apnoea and hypoxia is indicated since recurrent hypoxic neural apnoeas triggered increased phrenic inspiratory Daryl Fields is currently a neurosurgery resident at the University of Pittsburgh. He completed his medical degree and research doctorate at the University of Wisconsin Madison under the mentorship of Dr Tracy Baker, PhD. Daryl's research is focused on creating readily translatable therapies for movement control disorders: (1) development of animal models to better understand deficits in movement control and (2) development of pharmacological therapies for improved motor rehabilitation. He has contributed to the development of several novel research directions that continue to progress the field of motor control/rehabilitation. 3952 D. P. Fields and others J Physiol 597.15 output in rats in which spinal NR2B-containing ...

Pushing and pulling with no end in sight! The role of cross‐talk between different forms of respiratory plasticity in modifying sleep apnoea

“…Given that central sleep apnoea is characterized by periods of reduced or inactive motor activity, and mixed apnoeic events are characterized by motor inactivity at the onset of an event, the authors proposed that iMF may be initiated during sleep (Fields et al . ). Given that hypoxia typically accompanies motor inactivity, two forms of respiratory plasticity could theoretically be initiated in response to apnoeic events.…”

“…To test the hypothesis, a series of clever experiments using anaesthetized, neuromuscularly blocked, vagotomized and ventilated rats were employed (Fields et al . ). In one set of experiments, LTF of phrenic nerve activity was initiated by intermittent hypoxia, which was induced by ceasing mechanical ventilation five times for 25 s. In another series of experiments, iMF was initiated by eliminating motor activity by decreasing carbon dioxide levels five times for 25 s. Thereafter, the two perturbations were combined (i.e.…”

“…Although the separate stimuli initiated the two forms of plasticity as expected, there was no evidence of compensatory mechanisms when the two stimuli were combined (Fields et al . ). This observation is exciting and is tied in with our previous hypothesis, which suggested that increases in carbon dioxide levels are required for the manifestation of LTF (Harris et al .…”

“…Along these lines, in an article in this issue of The Journal of Physiology , Fields and colleagues () explored if initiation of competing forms of plasticity, induced by repetitive apnoea, prevents the induction of sustained increases in phrenic nerve activity. In addition to LTF induced by intermittent hypoxia, recurrent reductions in respiratory neural activity initiate another form of plasticity, known as inactivity‐induced inspiratory motor facilitation (iMF) (Streeter & Baker‐Herman, a ).…”

“…Thus, Fields et al . () hypothesized that the simultaneous initiation of LTF and iMF prevents the expression of compensatory modifications.…”