# Neuronal Basis Underlying Volatile Anesthetic Induced Hypnosis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $479,669

## Abstract

PROJECT SUMMARY
Although much progress has been made deciphering the effects of anesthetics upon individual ion channels,
identification of the neural substrates upon which anesthetics act to produce their behavioral effects remains
challenging. Of the key components that characterize the anesthetized state, we focus on volatile anesthetic-
induced hypnosis, defined as a lack of awareness to non-noxious stimuli. Understanding how anesthetics
produce hypnosis has become more than a central question for neuroscience, as multiple reports over the past
decade suggest that existing general anesthetics may annually harm a subset of the 40 million US patients
who require anesthesia. One hypothetical alternative to anesthetic-induced unconsciousness is to generate a
state of reversible physiological unconsciousness, such as sleep, in which the patient is locked out of access to
the state of wakefulness yet recoups restorative benefits of natural sleep. In our original award period, we
discovered that volatile anesthetics do directly depolarize a subset of sleep-promoting, preoptic anterior
hypothalamic (POAH) neurons. Our lab and others have also shown that every tested general anesthetic
(except for ketamine) depolarizes ventrolateral preoptic (VLPO) neurons. However, the exact degree of overlap
among neurons triggering endogenous sleep and those activated by anesthetic exposure as well as precise
consequences of anesthetic “hijacking” of endogenous sleep circuitry remain unknown. The central hypothesis
of this renewal is that volatile anesthetics will impart a portion of their hypnotic properties by enhancing activity
in endogenous POAH neurons, but that key differences in neuronal activation will distinguish endogenous
NREM sleep from anesthetic hypnosis. In Aim 1, we will use a novel genetically encoded calcium detector to
permanently mark sleep-active POAH neurons in vivo and subsequently determine the exact fraction that is
also depolarized by volatile anesthetics. Similarly, we will determine the fraction of anesthetic-depolarized
POAH neurons that active during NREM and REM sleep. In Aim 2, we will employ groundbreaking in vivo
endoscopic microscopy to visualize and determine real time neuronal activity of POAH neurons as mice cycle
naturally across wakefulness, NREM, and REM sleep as well as in these same POAH neurons during a
carefully titrated volatile anesthetic exposure. Finally, in Aim 3 we will modulate in vivo activity of sleep-active
POAH neurons achieving precise control through neuronal circuit labeling and by recently discovered tissue
specific expression markers that distinguish sleep-active neurons from state-indifferent or wake-active
neighbors. Conditional expression of virally driven “designer receptors exclusively activated by designer
drugs” (DREADDs) will permit us to depolarize or hyperpolarize POAH neurons to determine the ensuing
effects of activating or inhibiting sleep-active POAH neurons upon the stability of the anesthe...

## Key facts

- **NIH application ID:** 10224841
- **Project number:** 5R01GM088156-09
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Max Kelz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $479,669
- **Award type:** 5
- **Project period:** 2010-04-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224841

## Citation

> US National Institutes of Health, RePORTER application 10224841, Neuronal Basis Underlying Volatile Anesthetic Induced Hypnosis (5R01GM088156-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10224841. Licensed CC0.

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