Abstract
When rapid eye movement (REM) sleep occurs, noradrenergic cells become silent, with the abolition of activity in locus coeruleus (LC) neurons seen as a key event permissive for the occurrence of REM sleep. However, it is not known whether silencing of other than LC noradrenergic neurons contributes to the generation of REM sleep. In urethane-anesthetized rats, stereotyped REM sleep-like episodes can be repeatedly elicited by injections of the cholinergic agonist, carbachol, into a discrete region of the dorsomedial pons. We used this preparation to test whether inhibition of ventrolateral pontine noradrenergic A5 neurons only, or together with LC neurons, also can elicit REM sleep-like effects. To silence noradrenergic cells, we sequentially injected the α2-adrenergic agonist clonidine (20–40 nl, 0.75 mM) into both A5 regions and then the LC. In two rats, successful bilateral clonidine injections into the A5 region elicited the characteristic REM sleep-like episodes (hippocampal theta rhythm, suppression of hypoglossal nerve activity, reduced respiratory rate). In five rats, bilateral clonidine injections into the A5 region and then into one LC triggered REM sleep-like episodes, and in two rats injections into both A5 and then both LC were needed to elicit the effect. In contrast, in three rats, uni- or bilateral clonidine injections only into the LC had no effect, and clonidine injections placed in another six rats outside of the A5 and/or LC regions were without effect. The REM sleep-like episodes elicited by clonidine had similar magnitude of suppression of hypoglossal nerve activity (by 75%), similar pattern of hippocampal changes, and similar durations (2.5–5.3 min) to the episodes triggered in the same preparation by carbachol injections into the dorsomedial pontine reticular formation. Thus, silencing of A5 cells may importantly enable the occurrence of REM sleep-like episodes, at least under anesthesia. This is a new role for noradrenergic A5 neurons.
Highlights
The rapid eye movement (REM) stage of sleep is a state characterized by wake-like cortical and hippocampal activation that occurs in the absence of awareness of the external environment, with tonic suppression of motor activity, random twitches of distal muscles, REMs, and distinct variability of breathing and blood pressure (Aserinsky and Kleitman, 1953)
Based on these data and the studies showing that muscarinic cholinergic agonists delivered to the dorsomedial pontine tegmentum trigger a REM sleep-like state (Silberman et al, 1980; Baghdoyan et al, 1984; Kimura et al, 1990), a reciprocal model of the generation of REM sleep has been proposed that had as its key feature direct or indirect mutually inhibitory interactions between brainstem aminergic and cholinergic neurons (McCarley and Hobson, 1975)
REM SLEEP-LIKE EPISODES ELICITED BY CLONIDINE INJECTED INTO THE A5 REGIONS, OR A5 REGIONS FOLLOWED BY locus coeruleus (LC) Figure 1 shows brain sections from one rat in which injections were placed in all four sites, A5 bilaterally, and LC bilaterally, with the sites marked by deposits of Pontamine sky blue included in the clonidine solution
Summary
The rapid eye movement (REM) stage of sleep is a state characterized by wake-like cortical and hippocampal activation that occurs in the absence of awareness of the external environment, with tonic suppression of motor activity, random twitches of distal muscles, REMs, and distinct variability of breathing and blood pressure (Aserinsky and Kleitman, 1953). Single cell recordings from noradrenergic neurons of the locus coeruleus (LC) and serotonergic neurons of the dorsal raphe nucleus revealed that REM sleep is associated with the silencing of these cells (McGinty and Harper, 1976; Trulson and Jacobs, 1979; Aston-Jones and Bloom, 1981) and concurrent activation of a subset of dorsal pontine cholinergic neurons (El Mansari et al, 1989; Steriade et al, 1990; Kayama et al, 1992; Thakkar et al, 1998) Based on these data and the studies showing that muscarinic cholinergic agonists delivered to the dorsomedial pontine tegmentum trigger a REM sleep-like state (Silberman et al, 1980; Baghdoyan et al, 1984; Kimura et al, 1990), a reciprocal model of the generation of REM sleep has been proposed that had as its key feature direct or indirect mutually inhibitory interactions between brainstem aminergic and cholinergic neurons (McCarley and Hobson, 1975). Lesions of the LC had only small and transient effects on the amount and pattern of REM sleep (Roussel et al, 1976; Webster and Jones, 1988; Blanco-Centurion et al, 2004), suggesting that the www.frontiersin.org
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