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This Article Full Text Full Text (PDF) All Versions of this Article: 582/2/553    most recent jphysiol.2007.127613v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lu, J. W. Articles by Kubin, L. Search for Related Content PubMed PubMed Citation Articles by Lu, J. W. Articles by Kubin, L. Related Collections Neuroscience

¹ Department of Animal Biology, School of Veterinary Medicine and Centre for Sleep and Respiratory Neurobiology, University of Pennsylvania, Philadelphia, PA 19104-6046, USA

Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABA_A receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABA_A receptor antagonist, bicuculline (20 nl, 1 mM), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABA_A receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABA_A receptor-expressing PF neurones may cause narcolepsy/cataplexy.

(Received 2 January 2007; accepted after revision 3 May 2007; first published online 10 May 2007)
Corresponding author L. Kubin: Department of Animal Biology 209E/VET, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104–6046, USA. Email: lkubin{at}vet.upenn.edu