The Neural Circuits Underlying General Anesthesia and Sleep

Abstract

General anesthesia is characterized by loss of consciousness, amnesia, analgesia, and immobility. Important molecular targets of general anesthetics have been identified, but the neural circuits underlying the discrete end points of general anesthesia remain incompletely understood. General anesthesia and natural sleep share the common feature of reversible unconsciousness, and recent developments in neuroscience have enabled elegant studies that investigate the brain nuclei and neural circuits underlying this important end point. A common approach to measure cortical activity across the brain is electroencephalogram (EEG), which can reflect local neuronal activity as well as connectivity among brain regions. The EEG oscillations observed during general anesthesia depend greatly on the anesthetic agent as well as dosing, and only some resemble those observed during sleep. For example, the EEG oscillations during dexmedetomidine sedation are similar to those of stage 2 nonrapid eye movement (NREM) sleep, but high doses of propofol and ether anesthetics produce burst suppression, a pattern that is never observed during natural sleep. Sleep is primarily driven by withdrawal of subcortical excitation to the cortex, but anesthetics can directly act at both subcortical and cortical targets. While some anesthetics appear to activate specific sleep-active regions to induce unconsciousness, not all sleep-active regions play a significant role in anesthesia. Anesthetics also inhibit cortical neurons, and it is likely that each class of anesthetic drugs produces a distinct combination of subcortical and cortical effects that lead to unconsciousness. Conversely, arousal circuits that promote wakefulness are involved in anesthetic emergence and activating them can induce emergence and accelerate recovery of consciousness. Modern neuroscience techniques that enable the manipulation of specific neural circuits have led to new insights into the neural circuitry underlying general anesthesia and sleep. In the coming years, we will continue to better understand the mechanisms that generate these distinct states of reversible unconsciousness.

Rapid thalamocortical network switching mediated by cortical synchronization underlies propofol-induced EEG signatures: a biophysical model

“…Thus, loss of ACh may be a major contributor to propofol-induced loss of consciousness. The fact that our model requires neuromodulatory changes to produce propofol oscillations and their coupling suggests that the effects of propofol on the brainstem may be critical for its oscillatory phenomena, which is supported by active experimental research on propofol and other anesthetics (Moody et al 2021; Minert, Yatziv, and Devor 2017; Minert, Baron, and Devor 2020; Muindi et al 2016; Vlasov et al 2021). Since the transition from trough-max to peak-max is associated with only lowering ACh in our model, we predict that a smaller dose of physostigmine may promote less peak-max.…”

Historical and Modern Evidence for the Role of Reward Circuitry in Emergence

“…Importantly, the state of general anesthesia, a drug-induced reversible coma, is distinct from natural sleep (see comprehensive reviews on this topic 57,140 ). While insight into brain reward circuitry is gained from studies of sleep arousal, the same mechanisms should not be expected to correlate directly with emergence from anesthesia.…”

Relevance of Cortical and Hippocampal Interneuron Functional Diversity to General Anesthetic Mechanisms: A Narrative Review

“…The role of SST + interneurons in endogenous sleep circuits raises the possibility that they also operate in overlapping anesthesia/sleep circuits (Funk et al, 2017 ; Moody et al, 2021 ). In the basal forebrain, select SST + interneuron activation potentiates propofol and isoflurane hypnosis, with a comparably smaller contribution from PV + interneurons (Cai et al, 2021 ).…”