Synergy between Acute Intermittent Hypoxia and Task-Specific Training

Abstract

Acute intermittent hypoxia (AIH) and task-specific training (TST) synergistically improve motor function after spinal cord injury; however, mechanisms underlying this synergistic relation are unknown. We propose a hypothetical working model of neural network and cellular elements to explain AIH-TST synergy. Our goal is to forecast experiments necessary to advance our understanding and optimize the neurotherapeutic potential of AIH-TST.

Figure 1:. Neural Network Model.

Postulated neural circuits activated by acute intermittent hypoxia (AIH) and task-specific training (TST). Hypoxia stimulates carotid body (CB) chemoreceptors and their chemoafferent neurons, activating second order medullary neurons in the nucleus tractus solitarii (NTS). These second order neurons project to the central pattern generator (CPG) of the ventral respiratory column (signified by an oscillator and integral sign). Either direct (NTS) or indirect projections from ventral respiratory group neurons activate serotonergic neurons of the caudal raphe nuclei. Descending projections to spinal motor nuclei and subsequent serotonin release initiate and orchestrate plasticity in phrenic (PMn) and limb (LMn) motor neurons. During TST, primary motor cortex (M1) neurons with direct projections to PMn, LMn and/or their pre-motor neurons are activated; although they could activate raphe and spinal CPG neurons, we do not postulate that those relay projections play a major role in TST-induced motor plasticity. Dashed lines indicate unknown pathways.

Figure 2:. Cellular Model.

Postulated intracellular signaling cascades giving rise to AIH- and TST-induced motor plasticity. In A: AIH-activated cellular cascades (elevated BDNF) and increased motor neuron output (bottom trace). Serotonin release and receptor activation are the major drivers of the AIH-induced cellular cascade. In B: TST-activated cellular cascades (elevated BDNF) and increased motor neuron output (bottom trace). In this case, BDNF synthesis is not quite as high (signified as less bold) and motor output is not elevated as strongly versus AIH. We postulate that serotonin plays a less prominent role, and that the more relevant cascade is activity-dependent increases in intracellular calcium and CaMK activation – an alternate mechanism of increased BDNF synthesis; this activity driven effect would occur exclusively in neurons relevant to TST. In C: Combined AIH-TST converges both mechanisms, but only in neurons activated during TST. Thus, BDNF and motor activity in these task-relevant neurons are greater than that elicited by either treatment alone. Abbreviations: AIH = acute intermittent hypoxia; BDNF = brain-derived neurotrophic factor; CaMK = Ca²⁺-calmodulin-dependent protein kinase; TrkB = tyrosine kinase B; TST = task-specific training.

Figure 3:. Working Hypothetical Model of Motor Plasticity.

With a postulated sigmoid BDNF dose-response curve, AIH and TST each elicit modest plasticity when delivered alone. However, combined AIH-TST elicits greater elevations in BDNF (but only within task-relevant neurons), increasing plasticity and improving motor function more than the combined value predicted from each alone. Abbreviations: AIH = acute intermittent hypoxia; BDNF = brain-derived neurotrophic factor; TrkB = tyrosine kinase B; TST = task-specific training.