Activation of GABAergic Neurons in the Rostromedial Tegmental Nucleus and Other Brainstem Regions Promotes Sedation and Facilitates Sevoflurane Anesthesia in Mice

Vlasov, Ksenia; Pei, JunZhu; Nehs, Christa J; Guidera, Jennifer A.; Zhang, Edlyn R.; Kenny, Jonathan D.; Houle, Timothy T.; Brenner, Gary J.; Taylor, Norman E.; Solt, Ken

doi:10.1213/ane.0000000000005387

Cited by 16 publications

(8 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Discussionmentioning

confidence: 74%

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

Soplata

McCarthy

Adam

et al. 2022

Preprint

View full text Add to dashboard Cite

The anesthetic propofol produces prominent oscillatory signatures on the EEG. Despite the strong correlation between oscillations and the anesthetic state, the fundamental mechanisms of this unconsciousness remain unknown. On the EEG, propofol elicits alpha oscillations (8-14 Hz), slow oscillations (0.5-2.0 Hz), and dose-dependent phase-amplitude coupling (PAC) between these rhythms. A low enough dose causes "trough-max" PAC, where alpha oscillation amplitude is consistently maximal during slow troughs; this occurs at the same time as arousable unconsciousness. A high enough dose causes consistent "peak-max" PAC, where alpha amplitude is maximal during the slow peak, at the same time as unarousable unconsciousness. Much of the anesthetic state is dominated by a mixture of both states. Using thalamocortical Hodgkin-Huxley simulations, we show that, in addition to propofol effects on GABAA synapses and thalamocortical H-currents, propofol-induced changes to neuromodulation may generate LFP oscillations and their dose-dependent coupling. We show this for acetylcholine specifically, though other neuromodulators may produce the same effects. We find that LFP- and EEG- relevant synapses of local thalamocortical circuits stochastically display either trough-max or peak-max PAC on any given slow cycle. Trough-max PAC signals are present only in thalamocortical synaptic currents, and not identifiable via membrane potentials alone. PAC preference depends critically on the neuromodulatory state, which is dose-dependent: high doses are associated with statistically more peak-max than trough-max, and vice-versa. This is caused by increased cortical synchronization at higher doses. Our results have important consequences for analyzing LFP/EEG data, in that local network trough- or peak-max may only be seen on a cycle-by-cycle basis, and not when averaging. We hypothesize that this increased cortical synchronization leads to an inability to process signals in a flexible manner needed for awake cognition.

show abstract

Section: Discussionmentioning

confidence: 74%

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

Soplata

McCarthy

Adam

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Activation of dopaminergic neurons in the VTA induce arousal under general anesthesia [31]. Activation of the RMTg, a structure with dense inhibitory projections to VTA dopamine and glutamate neurons, enhances general anesthesia [58]. Dopamine release from the VTA onto D1R-expressing neurons in the NAc [38,40 ▪▪ ,41 ▪▪ ] and OT [46] (mesolimbic pathway) or the Prl (mesocortical pathway) [47 ▪ ] has been shown to induce emergence from general anesthesia in rodent studies.…”

Section: Discussionmentioning

confidence: 99%

Modulating anesthetic emergence with pathway-selective dopamine signaling

Vincent

Solt

2023

Current Opinion in Anaesthesiology

Self Cite

View full text Add to dashboard Cite

Purpose of review To summarize the recent preclinical findings investigating dopaminergic circuits for their involvement in reversing anesthetic-induced unconsciousness. Recent findings The release of dopamine from the ventral tegmental area onto dopamine D1 receptor-expressing neurons in the nucleus accumbens promotes emergence following general anesthesia. Two relevant targets of dopamine D1 receptor-expressing neurons in the nucleus accumbens include the lateral hypothalamus and ventral pallidum. Activating mesocortical dopaminergic projections from the ventral tegmental area to the prelimbic cortex has also been shown to hasten emergence from general anesthesia. In contrast, the nigrostriatal dopamine pathway is not involved in regulating anesthetic emergence. The role of the tuberoinfundibular endocrine dopamine pathway remains to be tested; however, recent studies have identified an important function of neuroendocrine signaling on modulating general anesthesia. Summary Potential avenues for accelerating anesthetic emergence may be found through targeting specific arousal-promoting pathways in the brain. Accumulating evidence from rodent studies manipulating cell type- and circuit-specific signaling pathways have identified dopamine as a potent modulator of general anesthesia. Specifically, dopamine signaling along the mesolimbic and mesocortical pathways plays a fundamental role in regulating consciousness.

show abstract

“…The concentration of sevoflurane sufficient to induce LORR decreased after the activation of RMTg neurons compared with inactivation. This remains an important subject for future research (Vlasov et al, 2021 ).…”

Section: Brain Areas and Circuitsmentioning

confidence: 99%

Brain areas modulation in consciousness during sevoflurane anesthesia

Jie

Cai

Chen

et al. 2022

Front. Integr. Neurosci.

View full text Add to dashboard Cite

Sevoflurane is presently one of the most used inhaled anesthetics worldwide. However, the mechanisms through which sevoflurane acts and the areas of the brain associated with changes in consciousness during anesthesia remain important and complex research questions. Sevoflurane is generally regarded as a volatile anesthetic that blindly targets neuronal (and sometimes astrocyte) GABAA receptors. This review focuses on the brain areas of sevoflurane action and their relation to changes in consciousness during anesthesia. We cover 20 years of history, from the bench to the bedside, and include perspectives on functional magnetic resonance, electroencephalogram, and pharmacological experiments. We review the interactions and neurotransmitters involved in brain circuits during sevoflurane anesthesia, improving the effectiveness and accuracy of sevoflurane’s future application and shedding light on the mechanisms behind human consciousness.

show abstract

Activation of GABAergic Neurons in the Rostromedial Tegmental Nucleus and Other Brainstem Regions Promotes Sedation and Facilitates Sevoflurane Anesthesia in Mice

Cited by 16 publications

References 17 publications

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

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

Modulating anesthetic emergence with pathway-selective dopamine signaling

Brain areas modulation in consciousness during sevoflurane anesthesia

Contact Info

Product

Resources

About