Plasticity in respiratory motor neurons in response to reduced synaptic inputs: A form of homeostatic plasticity in respiratory control?

Abstract

For most individuals, the respiratory control system produces a remarkably stable and coordinated motor output-recognizable as a breath-from birth until death. Very little is understood regarding the processes by which the respiratory control system maintains network stability in the presence of changing physiological demands and network properties that occur throughout life. An emerging principle of neuroscience is that neural activity is sensed and adjusted locally to assure that neurons continue to operate in an optimal range, yet to date, it is unknown whether such homeostatic plasticity is a feature of the neurons controlling breathing. Here, we review the evidence that local mechanisms sense and respond to perturbations in respiratory neural activity, with a focus on plasticity in respiratory motor neurons. We discuss whether these forms of plasticity represent homeostatic plasticity in respiratory control. We present new analyses demonstrating that reductions in synaptic inputs to phrenic motor neurons elicit a compensatory enhancement of phrenic inspiratory motor output, a form of plasticity termed inactivity-induced phrenic motor facilitation (iPMF), that is proportional to the magnitude of activity deprivation. Although the physiological role of iPMF is not understood, we hypothesize that it has an important role in protecting the drive to breathe during conditions of prolonged or intermittent reductions in respiratory neural activity, such as following spinal cord injury or during central sleep apnea.

Keywords: Activity; Central sleep apnea; Control of breathing; Homeostatic plasticity; Hypoxia; Motor neuron; Phrenic; Plasticity; Respiratory; Spinal injury; iPMF.

Figure 1. Reduced respiratory neural activity elicits rebound increases in phrenic burst amplitude

Compressed phrenic neurograms (~60 min recording) depicting baseline, a 30 min neural hypopnea (top) or 5, brief (~1 min) hypopneas separated by 5 min (bottom). Enhanced phrenic amplitude after neural hypopnea indicates iPMF.

Figure 2. iPMF magnitude is proportional to the magnitude of phrenic activity deprivation

Descending synaptic inputs to phrenic motor neurons on one side of the spinal cord were reversibly impaired with intraspinal procaine injections into the C2 ventrolateral funiculus in anesthetized, ventilated rats (Streeter and Baker-Herman, 2014a). Linear regression analysis indicates a significant relationship between the average decrease in phrenic motor output during axon conduction block and the resulting increase in phrenic burst amplitude (i.e., iPMF) observed 15 min following reversal of conduction block. These data indicate that iPMF magnitude is proportional to the degree of phrenic activity deprivation.