Unexpected benefits of intermittent hypoxia: enhanced respiratory and nonrespiratory motor function

Abstract

Intermittent hypoxia (IH) is most often thought of for its role in morbidity associated with sleep-disordered breathing, including central nervous system pathology. However, recent evidence suggests that the nervous system fights back in an attempt to minimize pathology by increasing the expression of growth/trophic factors that confer neuroprotection and neuroplasticity. For example, even modest ("low dose") IH elicits respiratory motor plasticity, increasing the strength of respiratory contractions and breathing. These low IH doses upregulate hypoxia-sensitive growth/trophic factors within respiratory motoneurons but do not elicit detectable pathologies such as hippocampal cell death, neuroinflammation, or systemic hypertension. Recent advances have been made toward understanding cellular mechanisms giving rise to IH-induced respiratory plasticity, and attempts have been made to harness the benefits of low-dose IH to treat respiratory insufficiency after cervical spinal injury. Our recent realization that IH also upregulates growth/trophic factors in nonrespiratory motoneurons and improves limb (or leg) function after incomplete chronic spinal injuries suggests that IH-induced plasticity is a general feature of motor systems. Collectively, available evidence suggests that low-dose IH may represent a safe and effective treatment to restore lost motor function in diverse clinical disorders that impair motor function.

FIGURE 1.

Varied exposures represent a dose of IH ranging from a few minutes per day to many hours per day over days to weeks Although high-dose IH still elicits functional benefits (35), it shifts the balance from net benefit to unacceptable pathology. Conceptually, nearly all IH doses elicit beneficial (“good”) effects, including neuroprotection and the induction of respiratory and somatic motor plasticity. These low-dose IH exposures do not elicit detectable pathology (“bad”), such as hypertension (128), hippocampal apoptosis, or reactive gliosis (68). Although high-dose IH still elicits functional benefits (35, 63a), it shifts the balance from net benefit to unacceptable pathology. Finding an optimal IH dose is key to developing effective therapies for clinical disorders that impair motor function, such as spinal injury or ALS.

FIGURE 2.

In the healthy CNS with no, or “low-dose” IH, microglia are in a “surveillance mode” that promotes neuron viability and function by releasing growth/trophic factors that confer neuro-protection and/or increase synaptic strength (i.e., plasticity) In contrast, high doses of IH, such as chronic IH, may activate microglia to a toxic, pro-inflammatory phenotype that triggers neuronal apoptosis and undermines synaptic plasticity.

FIGURE 3.

Low-dose IH elicits spinal respiratory motor plasticity For example, a single presentation of acute intermittent hypoxia (AIH: 3–10 episodes, 5-min duration, 5-min intervals) elicits phrenic (and diaphragm), long-term facilitation (3, 118). Similar, but greater relative effects are observed in the inspiratory intercostal nerves/muscles (34a). These forms of respiratory motor plasticity can be harnessed to recover lost breathing capacity by exposing rats with cervical spinal injuries to daily AIH (7 days; Ref. 68). Similar motor plasticity is also observed in limb function (68, 119), demonstrating that IH elicits plasticity in diverse motor systems. Understanding mechanisms giving rise to respiratory motor plasticity may guide development of novel therapies to treat motor impairment in diverse clinical disorders, including spinal cord injury and ALS.

FIGURE 4.

Working model of convergent pathways to long-lasting phrenic motor facilitation (pMF) The “Q” pathway (left; purple) is elicited by intermittent activation of Gq-coupled metabotropic receptors (e.g., 5-HT2 or α1), followed by PKC activation, new BDNF synthesis, TrkB activation, and activation of ERK MAP kinases (pERK; Ref. 27). The mechanism whereby pERK elicits pMF remains unknown but may involve changes in respiratory motoneuron excitability and/or synaptic strength. The “S” pathway (right; green) is elicited by Gs-coupled metabotropic receptors (e.g., 5-HT7 and A2A), PKA activation, new synthesis of an immature TrkB isoform, and downstream signaling via Akt phosphorylation/activation (pAkt; Ref. 38). The mechanism whereby pAkt elicits pMF remains unknown but may involve changes in respiratory motoneuron excitability and/or synaptic strength. Although important details distinguish them, the BDNF/TrkB system plays a critical role in both the Q and S pathways to pMF. Other hypoxia-sensitive growth/trophic factors elicit pMF via ERK- and Akt-dependent mechanisms, including VEGF (V pathway) and EPO (E pathway). The biological significance of diverse cellular cascades to pMF remains unclear, but they may impart adaptability as an animal copes with diverse stimuli that differ in (for example) severity, pattern, or cumulative duration (89). Regardless, the existence of so many hypoxia-induced pathways gives many options as we attempt to devise repetitive AIH protocols for therapeutic benefit.

FIGURE 5.

Hypothetical mechanism of motor plasticity following rAIH in rats and humans with chronic spinal injuries Based on our increasing understanding of cellular mechanisms giving rise to AIH-induced phrenic motor facilitation (FIGURE 4) and daily AIH (7 days)-induced changes in key molecules within respiratory and nonrespiratory motor nuclei (68), we propose that a common mechanism underlies plasticity in both respiratory and nonrespiratory motoneurons. By enhancing synaptic inputs to motoneurons, rAIH amplifies whatever the relevant behavior is for that specific motor pool, including breathing (68), forelimb function during ladder walking (68), or ankle strength (119). In specific, we propose that rAIH elicits intermittent serotonin (5-HT) release within the respective motor nuclei, activating postsynaptic serotonin receptors and initiating new BDNF synthesis (4). BDNF-dependent activation of its high-affinity receptor tyrosine kinase TrkB subsequently strengthens spared synaptic pathways to motoneurons, improving motor function after spinal injury. Since the combination of SCI and rAIH increases TrkB phosphorylation and activation more than either stimulus alone (68), rAIH may be particularly effective after chronic spinal injury. Thus rAIH is safe, easy to administer, triggers spinal plasticity, and may be an effective therapeutic approach to enhance motor function in persons with chronic spinal injuries.