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

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.