A Neural Circuit from the Paraventricular Thalamus to the Bed Nucleus of the Stria Terminalis for the Regulation of States of Consciousness during Sevoflurane Anesthesia in Mice

Abstract

Background The neural circuitry underlying sevoflurane-induced modulation of consciousness is poorly understood. We hypothesized that the paraventricular thalamus-bed nucleus of the stria terminalis pathway plays an important role in regulating states of consciousness during sevoflurane anesthesia. Methods Rabies-virus-based transsynaptic tracing techniques were employed to reveal the neural pathway from the paraventricular thalamus to the bed nucleus of the stria terminalis. We investigated the role of this pathway in sevoflurane anesthesia induction, maintenance and emergence using chemogenetic and optogenetic methods combined with cortical electroencephalogram (EEG) recordings. Both male and female mice were used in our study. Results Both GABAergic and glutamatergic neurons in the bed nucleus of the stria terminalis receive paraventricular thalamus glutamatergic projections. Chemogenetic inhibition of paraventricular thalamus glutamatergic neurons prolonged the sevoflurane anesthesia emergence time (mean ± SD, hM4D-CNO vs. mCherry-CNO, 281 ± 88 vs. 172 ± 48 s, p < 0.001, n = 24) and decreased the induction time (101 ± 32 vs. 136 ± 34 s, p = 0.002, n = 24) as well as the EC50 for the loss or recovery of the righting reflex under sevoflurane anesthesia (mean [95% confidence interval]; MACLORR, 1.16 [1.12 to 1.20] vs. 1.49 [1.46 to 1.53] vol%, p < 0.001, n = 20; MACRORR, 0.95 [0.86 to 1.03] vs. 1.34 [1.29 to 1.40] vol%, p < 0.001, n = 20). Similar results were observed during suppression of the paraventricular thalamus- bed nucleus stria terminalis pathway. Optogenetic activation of this pathway produced the opposite effects. Additionally, transient stimulation of this pathway efficiently induced behavioral arousal during continuous steady-state general anesthesia with sevoflurane and reduced the depth of anesthesia during sevoflurane-induced burst suppression. Conclusions In mice, axonal projections from the paraventricular thalamic neurons to the bed nucleus of the stria terminalis contribute to regulating states of consciousness during sevoflurane anesthesia.

In VivoPhotoadduction of Anesthetic Ligands in Mouse Brain Markedly Extends Sedation and Hypnosis

“…While we chose to photoadduct in the rostral pons as proof of principle in studying systemic effects of local CNS anesthetic photolabel adduction, this same approach could be extended to multiple other brain regions previously shown to be involved in arousal and as targets for anesthetic effects. Numerous and disparately located CNS centers, including other areas of the pons, medulla, midbrain, hypothalamus, basal forebrain, thalamus, and cortex, have been demonstrated to be critical for anesthetic action or emergence from anesthesia ( Devor and Zalkind, 2001 ; Abulafia et al, 2009 ; Luo and Leung, 2009 ; Moore et al, 2012 ; Solt et al, 2014 ; Z. Zhang et al, 2015 ; Gelegen et al, 2018 ; Pal et al, 2018 ; Gao et al, 2019 ; Wang et al, 2019 ; J. Y. Li et al, 2022 ). Our results confirm that in vivo photoadduction produces local therapeutic-level concentrations of drug in ROIs.…”

Study of the Association of Single Nucleotide Polymorphisms in Candidate Genes With Sevoflurane

“…The sensitive SNPs associated with sedative and cardiovascular effects of sevoflurane are not identical, possibly due to the different mechanisms by which sevoflurane exerts these 2 effects. Sevoflurane acts on multiple parts of the central nervous system, including the reticular ascending activation system in the brain, the thalamus, and so on, to exert a sedative effect 27,28 . However, the main centers that control cardiovascular activity are the spinal cord and brain stem.…”

“…Sevoflurane acts on multiple parts of the central nervous system, including the reticular ascending activation system in the brain, the thalamus, and so on, to exert a sedative effect. 27,28 However, the main centers that control cardiovascular activity are the spinal cord and brain stem.…”

Brain areas modulation in consciousness during sevoflurane anesthesia

“…Additionally, there is mounting proof that glial cells are involved and that sevoflurane acts on their GABA A receptors (Woll et al, 2018;Chung et al, 2022), thereby influencing their function. (2022) ↑indicated that the time is increasing, the EEG power increased or the c-Fos positive cells was increased. ↓indicated that the tme is decreasing or the EEG power decreased.…”

“…After the inhibition of the PVT-BNST pathway, the time to LORR is reduced during sevoflurane anesthesia and the dose-response curve is shifted to the left. Optogenetic activation of the PVT-BNST showed the opposite trend (Li et al, 2022 ).…”