Are All Motoneurons Created Equal in the Eyes of REM Sleep and the Mechanisms of Muscle Atonia?

Abstract

A-receptor antagonists into the V nucleus. Authors challenge the concept established in the 60s 2 and entrenched in the 80s primarily with the intracellular recording studies of Morales, Chase and Soja 3-8 that the muscle atonia of REM sleep is produced by a common, brainstem-derived, REM or active-sleep specific, postsynaptic, glycine-mediated inhibition of somatic motoneurons. The nervous system employs two main mechanisms to reduce activity. The first is through active GABA or glycinergic inhibition and the second is via disfacilitation, the withdrawal of excitatory input. As already mentioned, Brooks and Peever 1 have challenged the prevailing view that for most motoneurons active inhibition underlies REM atonia. This view is based primarily on the analysis of lumbar and V motoneurons, of which the latter were examined by Brooks and Peever, and is often extrapolated to all motoneurons that show REM sleep specific reductions in excitability. 9 Is there evidence of any exceptions to this standard? The best candidates are respiratory motoneu-rons. First, many muscles innervated by these motoneurons do not experience complete atonia; most of us continue to breathe, albeit somewhat erratically, during active sleep without becoming hypoxic. Their activity is, never-the-less, reduced in REM with different respiratory motoneurons showing a gradation in their sensitivity to REM sleep atonia. Phrenic motoneurons that drive the diaphragm (the main inspiratory pump muscle in mammals) are least sensitive, while expiratory pharyngeal (va-gal), and XII motoneurons (controlling upper airway muscles) are the most suppressed. 9 Significant effort has focused on understanding the mechanis-tic basis of the variable inhibition within respiratory motoneu-ron pools. Not only is this an important question of basic neu-rophysiology, it is of great interest from a clinical perspective due to the growing prevalence of sleep disordered breathing in human populations. 10 Sleep disordered breathing, which includes obstructive sleep apnea, manifests in part due to a differential suppression of airway compared to diaphragm muscle tone during sleep, especially REM sleep. 11 This gradation in sensitivity to REM sleep atonia could reflect variability in the magnitude of the REM-specific glycinergic inhibition. Indeed the proposal that all motoneurons, regardless of how they are categorized (re-spiratory and non-respiratory, spinal and cranial, antigravity) are controlled by a single common mechanism is appealing in its simplicity. Nevertheless, a substantial body of work by Leszek Kubin and colleagues 9 using the carbachol model of REM-sleep atonia, and more recently by Richard Horner 12,13 using a preparation developed to enable delivery of drugs via microdialysis in unrestrained rats (from which the one used by Brooks and Peever was derived) suggest that the depression of XII activity, and by extrapolation perhaps all respiratory motoneurons, is primarily due to disfacilitation rather than glycinergic inhibition. 14-20 The basic approach, like that used by Brooks and Peever, is to deliver an antagonist to the motoneuron pool and assess whether the magnitude of the REM-sleep induced atonia (measured at the relevant nerve for the carbachol model or muscle in freely moving rats) is influenced by the absence of that modulatory system. An altered atonia is taken as evidence that the modulator in question contributes. Debate about the relative roles of disfa-cilitation vs active inhibition in producing the REM-sleep ato-nia of respiratory muscles continues. In light of recent advances with these two models, however, the debate has expanded and in fact shifted to focus on which modulatory systems underlie the disfacilitation 13,15,17,18 (more on this to follow). In contrast, and counter to the statement by Brooks and Peev-er, the fact that active sleep-specific glycinergic inhibition underlies the muscle atonia of nonrespiratory muscles, especially lumbar and V, has not been seriously debated for some time. In fact, until the study by Brooks and Peever in V motoneurons, 1 this view and the data supporting it have not been challenged. Thus, the provocative statement by Brooks and Peever, based on the analysis of V muscle output, that the role of synaptic inhibition in REM sleep atonia requires revisiting has attracted a lot of attention. Not only does it propose that glycinergic inhibition is not the sole modulator of the REM sleep atonia in V motoneurons, it suggests that inhibition is not involved and that an as yet unidentified mechanism, presumably involving disfacilitation, is solely responsible. What is the basis for rejecting the long-standing focus on inhibitory processes? First, what are the weaknesses in the data CritiCal topiCs Forum Are All Motoneurons Created Equal in the Eyes of REM Sleep and the Mechanisms of Muscle Atonia? Commentary on Brooks PL and Peever JH. Glycinergic and GABA A-mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia. J Neurosci 2008;28:3535-45.