The role of sleep-active neuronal nuclei in volatile anesthetic response

General anesthetics are among the most important drugs in modern medicine, yet the mechanisms by which this diverse class of compounds converge to produce a singular effect remains a mystery. The state of hypnosis produced by general anesthetics is similar in many ways to natural sleep, prompting researchers to hypothesize that the endogenous neural circuits governing sleep and wake may also be functional targets for anesthetic drugs. Of particular interest are the roles that the median preoptic (MnPO) and ventrolateral preoptic (VLPO) nuclei of the hypothalamus might play in generation and maintenance of hypnosis given that subsets of cells in these regions are among the few parts of the brain that are more active during sleep than wake. This thesis combined both in vivo and ex vivo approaches to examine the extent to which a variety of volatile anesthetics activate the MnPO and the VLPO. Transcription of the immediate early gene c-Fos increased specifically in the GABAergic neurons of the VLPO in the presence of several volatile anesthetics, but not in the presence of the non-immobilizer F6. The MnPO, on the other hand, showed an indirectly mediated increase in overall c-Fos expression after exposure to isoflurane and F6, but not halothane. Further experiments utilized electrophysiology, electroencephalogram, and behavioral assays to determine how pharmacological and genetic manipulation of VLPO activity affects anesthetic response in mice. Individual VLPO neurons that were directly activated by isoflurane were in turn inhibited by the α2-adrenergic agonist dexmedetomidine. When injected directly into the VLPO of live, anesthetized mice, dexmedetomidine increased behavioral measures of wakefulness but did not alter cortical activity. These results suggest that the VLPO may be a partial functional target for some general anesthetics, further supporting the notion that different anesthetics may target a variety of sleep/wake nuclei to precipitate hypnosis