A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol

Abstract

. A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol. J Appl Physiol 93: 1448-1456, 2002. First published June 14, 2002 10.1152/japplphysiol.00225.2002The A5 noradrenergic neurons are considered important for cardiorespiratory regulation. We hypothesized that A5 cells are silenced during rapid eye movement (REM) sleep, thereby contributing to cardiorespiratory changes and suppression of hypoglossal (XII) motoneuronal activity. We used an anesthetized, paralyzed, and artificially ventilated rat in which pontine microinjections of carbachol trigger signs of REM sleep, including hippocampal theta rhythm, motor suppression, and silencing of locus coeruleus neurons. All 16 putative noradrenergic A5 cells recorded were strongly suppressed when the REM sleep-like episodes were elicited and also after intravenous clonidine. Antidromic mapping showed that none of six neurons tested projected to the XII nucleus, whereas three of five projected to the nucleus of the solitary tract and two of four to the rostral ventrolateral medulla. Bilateral microinjections of clonidine into the A5 regions did not alter XII nerve activity. These data suggest that A5 neurons are silenced during natural REM sleep. This will lead to decreased norepinephrine release and may alter synaptic transmission in the nucleus of the solitary tract and rostral ventrolateral medulla without, however, a detectable impact on XII motoneurons. hypoglossal motoneurons; norepinephrine; nucleus of the solitary tract; pons; rapid eye movement sleep THE NOREPINEPHRINE-CONTAINING neurons of the A5 group, located in the ventrolateral pons between the root of the facial nerve and the superior olive, are considered important regulators of cardiorespiratory function (reviewed in Refs. 11,24,25,45,46). They have extensive axonal projections that include cardiorespiratory and motor regions of the brain stem and spinal cord (1,8,9,23,36). Through these projections, they may control, among others, sympathetic and respiratory outputs and, via projection to the hypoglossal (XII) motor nucleus, may mediate noradrenergic excitation of XII motoneurons (5,22,27,40,49). XII motoneurons are of particular interest because they innervate the genioglossus muscle of the tongue, an important airway dilator. Its decreased activity during sleep contributes, in predisposed individuals, to the pathophysiology of the obstructive sleep apnea syndrome (34).The noradrenergic neurons of the locus coeruleus (LC) and the sub-LC region show a robust relationship of their firing frequency with the sleep-wake cycle: the highest activity occurs during wakefulness, and the lowest during the rapid eye movement (REM) stage of sleep (6,43). Consistent with these findings, the extracellular level of norepinephrine is reduced in the XII nucleus during the motor atonia produced by electrical stimulation of the pontine reticular formation region implicated in the triggering of REM sleep (35). The noradrenergic cells of the A5 group may be similarly modulated with the sleep-wa...

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

“…In contrast, baseline GG activity was not significantly affected after focal injection of clonidine at the bilateral A5 region ( Figure 7D), in agreement with similar findings in vagotomized rats reported previously (33). Despite the lack of effect on baseline GG activity, however, clonidine injection at the bilateral A5 region still markedly suppressed hLTF both during and after the obstructive apnea episodes as with injection at bilateral A7 ( Figure 7D).…”

“…Because endogenous inhibition of HMs is generally most prominent in REM sleep when central noradrenergic activity is lowest, we speculate that inhibitory inputs to HMs may be inversely gated by endogenous noradrenergic drive (or directly gated by α 2 -adrenoceptor activity), perhaps in a manner similar to that seen in some brain systems (40)(41)(42). Furthermore, given that central noradrenergic neurons are generally presumed silent during REM sleep (33,43), it is surprising that systemic yohimbine alone was sufficient to reactivate central noradrenergic drive during both cholinergic-induced REM-lime sleep and spontaneous REM sleep (Figure 3) when the α 2 -autoreceptors were supposedly already quiescent. We speculate that inhibition of A7 and A5 neurons during REM sleep may be mediated by the activation of α 2 -adrenoceptors expressed on these neurons in response to inputs from other (extrapontine) noradrenergic or adrenergic cell groups that are active during REM sleep.…”

Fos expression in pontomedullary catecholaminergic cells following rapid eye movement sleep-like episodes elicited by pontine carbachol in urethane-anesthetized rats

“…We determined that the presence and amount of REMS-like state produced during about 2 h (140 min) prior to animal's sacrifice had a higher impact on Fos levels in pontomedullary TH neurons than any longer periods, and that there was no correlation between the amount of carbachol injected into the pons and Fos expression in any CA group. Considering that, in most central neurons, Fos expression increases with the level of activity, these results are consistent with prior evidence that SubC and A5 cells cease firing during REM sleep (Reiner, 1986;Fenik et al, 2002) and suggest, for the first time, that pontine A7 and medullary A2/C2 neurons also have reduced activity during REMS, whereas A1/C1 cells do not have this feature. …”

“…They also had a strong positive correlation between the time elapsed after last REMS-like episode and Fos expression ( Table 1). The decreased Fos expression in A7 NE neurons in association with REMS-like state provides the first evidence that these neurons may have reduced or abolished activity during REMS, as it is typical of LC (Aston-Jones and Bloom, 1981), SubC (Reiner, 1986) and at least some A5 neurons (Fenik et al, 2002).The results with A2/C2 neurons were less unequivocal than those with A7 neurons. There was only a trend for negative correlation between the total duration of REMS-like state and percentage of Fos-positive neurons, but the positive correlation with the time elapsed after the last REMS-like episode was highly significant.…”

Effect of chronic intermittent hypoxia on noradrenergic activation of hypoglossal motoneurons

“…In OSA patients, these muscles play an important role in the maintenance of upper airway patency (46) and have sleep-wake state-dependent activity that is maximal during wakefulness, reduced during non-rapid eye movement (REM) sleep, and minimal during REM sleep (10,23,32,44,58). This activity pattern is importantly driven by pontomedullary noradrenergic and serotonergic neurons; these neurons have axonal projections to the XII and other orofacial motor nuclei (3,27,43), and their activity is maximal during wakefulness and lowest or absent during REM sleep (4,13,42,54). Indeed, data indicate that XII motoneurons are under a tonic noradrenergic excitatory drive in anesthetized and unanesthetized rats (7,15) and that intermittent noradrenergic stimulation of XII motoneurons in vitro elicits their prolonged activation, similar to that elicited in vivo under anesthesia by acute intermittent hypoxia (36,45).…”