Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis
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Background Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep.Results Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, whereas neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance.Conclusions Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties.
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Acute VLPO lesions produce resistance to anesthetic effects, supporting a role for VLPO in induction of general anesthesia.
“acute lesions of VLPO confer resistance to anesthetic effects, arguing for a role for VLPO in the induction of general anesthesia [99, 101].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [99]
VLPO metabolic activation, measured by c-Fos, is associated with various sedative-hypnotic drugs.
“identified the metabolic activation of VLPO—as determined by c-Fos expression, a marker of antecedent cellular activity—in association with a variety of sedative-hypnotic drugs [98–100].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [99]
The shared circuits hypothesis between sleep and anesthesia has been replicated across invertebrates to mammals.
“This shared circuits hypothesis has been replicated across divergent species spanning invertebrates to mammals [54, 58, 82, 98, 99, 101].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [99]
Except for ketamine, systemic hypnotic doses of every general anesthetic examined recruit sleep-promoting VLPO neurons.
“with the exception of ketamine, systemic delivery of hypnotic doses of every general anesthetic examined recruits sleep-promoting neurons in the VLPO [98–102]”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [99]
Sleep-promoting VLPO neurons are depolarized by isoflurane and other anesthetics.
“sleep-promoting VLPO neurons were depolarized by isoflurane and other anesthetics [99, 102].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [99]
General anesthetics coopt warm-sensing and sleep-active preoptic neurons to produce hypnosis and central body cooling.
“Recent work suggests that general anesthetics coopt such “dual purpose” warm-sensing and sleep-active subsets of neurons both to elicit hypnosis and to drive central cooling of body temperature, which occurs during anesthetics states [99, 103, 110].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [99]
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- Authors
- Moore, J. T., Chen, J., Han, B., Meng, Q. C., Veasey, S. C., Beck, S. G., & Kelz, M. B.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Kelz, Max B.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 22
- Issue
- 21
- Pages
- 2008-2016
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC3628836
- OpenAlex
- W2085138535
- Cited by
- 171
- References
- 47
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 12 · 2023: 18 · 2022: 11 · 2021: 15 · 2020: 20 · 2019: 14 · 2018: 16 · 2017: 12 · 2016: 11 · 2015: 8 · 2014: 11 · 2013: 7 · 2012: 3
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL007953, R01HL079588, T32HL007953)
- National Institute of Mental Health (R01MH075047, RC1MH089800, MH075047, P01MH048125, R21MH099488)
- National Institute of General Medical Sciences (K08GM077357, GM077357, GM088156, R01GM088156)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- volatile anesthetics, loss of consciousness, ventrolateral preoptic nucleus, isoflurane, halothane, sleep-promoting neurons, neuronal depolarization, c-fos, anesthetic resistance
- MeSH terms
- Anesthetics, Animals, Halothane, Hypnosis, Anesthetic, Hypnotics and Sedatives, Isoflurane, Neurons, Potassium, Preoptic Area, Sleep, Unconsciousness, Proto-Oncogene Proteins c-fos, Mice
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