Noradrenergic neurons expressing Fos during waking and paradoxical sleep deprivation in the rat
Introduction
Central noradrenergic (NA)-synthetizing neurons are classically recognized as integral parts of the systems that maintain wakefulness (W) and contribute to the inhibition of paradoxical sleep (PS) (Jones, 2005, Jouvet, 1969, Luppi et al., 2006, Sakai et al., 1981). Indeed, enhancing NA transmission with monoamine oxidase inhibitors (such as clorgyline and pargyline) or reuptake blockers (such as imipramine and desimipramine) promotes W and suppresses PS in humans as well as in animals (Cohen et al., 1982, Gervasoni et al., 2002, Jones, 1991, Jouvet, 1969, Mendelson et al., 1982, Nishino and Mignot, 1997, Ross et al., 1995).
Due to their compact organization, at least in the rat, the NA locus coeruleus (LC) cells were extensively recorded across the sleep-wake cycle. It was found that their unit activity is tightly linked to W, since they discharge tonically during this state, decrease their firing rate during slow-wave sleep and become silent during PS (Aston-Jones and Bloom, 1981b, Gervasoni et al., 1998). In contrast, the activity in relation to the sleep-waking cycle of the other brainstem NA cell groups is not known. The present work was undertaken in order to fill this gap by comprehensively examining the distribution of the NA neurons activated when enhancing W or suppressing PS in the rat.
To achieve this goal, we took advantage of the elevated expression of the immediate-early gene c-fos in neurons after a stimulation (Dragunow and Faull, 1989, Kovacs, 1998, Morgan and Curran, 1991), a method widely used to map neurons activated in different experimental situations. The immunohistochemical detection of the protein Fos has been successfully used to localize the brainstem neurons active during PS and/or W (Maloney et al., 1999, Maloney et al., 2000, Shiromani et al., 1995, Verret et al., 2003, Verret et al., 2005, Verret et al., 2006, Yamuy et al., 1993). In the present work, rats either remained awake by placing them in a novel environment (NEv) or were specifically deprived of PS, with some of them allowed to recover from this deprivation. The expression of the protein Fos in NA neurons was visualized by dual immunostaining combining Fos and tyrosine hydroxylase (TH) immunohistochemistry. The NA A1–A7 groups were examined. This work has already appeared in abstract form (Léger et al., 2006, Léger et al., 2007).
Section snippets
Animals
OFA adult male rats (250–350 g) (Charles River France, L’Arbresle, France) were used in this study. Four series of three animals were submitted to the protocol consisting of a selective deprivation/recovery of PS. Four additional animals were submitted to the NEv protocol to maintain them awake. All experiments were performed according to the European Community Council Directive (86/609/EEC). The protocol was approved by our Institutional Animal Care and Use Committee (BH 2006-09).
Novel environment and PS deprivation-recovery protocols
The NEv
Results
The distribution of the 3 categories of labeled neurons (Fos-IR, TH-IR and Fos/TH-IR) is illustrated in Fig. 1, Fig. 2, Fig. 3. The localization and numbers of Fos-IR neurons in the PSC, PSD and PSR groups was similar to that previously described (2005; 2006). These numbers, compared between (Verret et al., 2005) and the present study, were not significantly different for any of the seven nuclei analyzed (P < 0.05). The distribution of the double-labeled neurons was homogeneous inside the NA
Discussion
In the present study, we found that up to 38% of the brainstem NA neurons were immunoreactive to Fos after both alert W or PS deprivation, excepting those within LC showing a strong activation only after alert W. In addition, NA neurons from all brainstem groups did not show Fos labeling in control condition or after PS recovery period.
Conclusion
The present results suggest that the A1/C1, A2 and to a lesser degree A5 NA cell groups are responsible for the PS inhibition during PS deprivation. In contrast, the LC would play no role in this inhibition. Studies with local infusions of alpha-1 and alpha-2 agonists or antagonists, and retrograde tracing combined with Fos and TH immunostainings will be necessary to determine whether NA innervation from medullary NA cell groups in PS-controlling areas (sublaterodorsal nucleus, ventrolateral
Acknowledgements
This work was supported by CNRS (CNRS UMR5167) and Université de Lyon, Université Lyon 1. Warm thanks are due to Damien Gervasoni and Pascal Ravassard for their help in the statistical analysis. Thanks are also due to Paul Herman for revising the English language.
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Present address: Douglas Institute Research Center, McGill University, 6875 Bd LaSalle, Verdun, Québec, Canada H4H 1R3.