Abstract
SummaryThe lateral habenula has been widely studied for its contribution in generating reward-related behaviors [1, 2]. We have found that this nucleus plays an unexpected role in the sedative actions of the general anesthetic propofol. The lateral habenula is a glutamatergic, excitatory hub that projects to multiple targets throughout the brain, including GABAergic and aminergic nuclei that control arousal [3, 4, 5]. When glutamate release from the lateral habenula in mice was genetically blocked, the ability of propofol to induce sedation was greatly diminished. In addition to this reduced sensitivity to propofol, blocking output from the lateral habenula caused natural non-rapid eye movement (NREM) sleep to become highly fragmented, especially during the rest (“lights on”) period. This fragmentation was largely reversed by the dual orexinergic antagonist almorexant. We conclude that the glutamatergic output from the lateral habenula is permissive for the sedative actions of propofol and is also necessary for the consolidation of natural sleep.
Highlights
IntroductionDuring the sedation produced by systemically administered GABAergic general anesthetics, as well as by the a2 adrenergic agonist dexmedetomidine, cFOS expression increases in sleeppromoting neurons and decreases in arousal-promoting neurons [14, 20, 21]
We have found that this nucleus plays an unexpected role in the sedative actions of the general anesthetic propofol
We conclude that the glutamatergic output from the lateral habenula is permissive for the sedative actions of propofol and is necessary for the consolidation of natural sleep
Summary
During the sedation produced by systemically administered GABAergic general anesthetics, as well as by the a2 adrenergic agonist dexmedetomidine, cFOS expression increases in sleeppromoting neurons and decreases in arousal-promoting neurons [14, 20, 21]. A comprehensive study [22] surveyed cFOS expression throughout the brain in response to a variety of sedatives and compared these changes with those observed during the natural sleep-wake cycle. One remarkable observation in this and a subsequent report [23] was that sedative agents induced marked cFOS expression in the lateral habenula (LHb). Because cFOS expression marks neuronal excitation, we have investigated whether the sedative actions of propofol require neurons of the LHb to be excited
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