Background

Stimulation of the paraventricular thalamus has been found to enhance anesthesia recovery; however, the underlying molecular mechanism by which general anesthetics modulate paraventricular thalamus is unclear. This study aimed to test the hypothesis that the sodium leak channel (NALCN) maintains neuronal activity in the paraventricular thalamus to resist anesthetic effects of sevoflurane in mice.

Methods

Chemogenetic and optogenetic manipulations, in vivo multiple-channel recordings, and electroencephalogram recordings were used to investigate the role of paraventricular thalamus neuronal activity in sevoflurane anesthesia. Virus-mediated knockdown and/or overexpression was applied to determine how NALCN influenced excitability of paraventricular thalamus glutamatergic neurons under sevoflurane. Viral tracers and local field potentials were used to explore the downstream pathway.

Results

Single neuronal spikes in the paraventricular thalamus were suppressed by sevoflurane anesthesia and recovered during emergence. Optogenetic activation of paraventricular thalamus glutamatergic neurons shortened the emergence period from sevoflurane anesthesia, while chemogenetic inhibition had the opposite effect. Knockdown of the NALCN in the paraventricular thalamus delayed the emergence from sevoflurane anesthesia (recovery time: from 24 ± 14 to 64 ± 19 s, P < 0.001; concentration for recovery of the righting reflex: from 1.13% ± 0.10% to 0.97% ± 0.13%, P < 0.01). As expected, the overexpression of the NALCN in the paraventricular thalamus produced the opposite effects. At the circuit level, knockdown of the NALCN in the paraventricular thalamus decreased the neuronal activity of the nucleus accumbens, as indicated by the local field potential and decreased single neuronal spikes in the nucleus accumbens. Additionally, the effects of NALCN knockdown in the paraventricular thalamus on sevoflurane actions were reversed by optical stimulation of the nucleus accumbens.

Conclusions

Activity of the NALCN maintains the excitability of paraventricular thalamus glutamatergic neurons to resist the anesthetic effects of sevoflurane in mice.

Editor’s Perspective
What We Already Know about This Topic
  • The paraventricular thalamus is involved in wakefulness, and there is evidence that activities of paraventricular thalamus neurons may play a role in the sedative effects of general anesthetics.
  • Conductance of the sodium leak channel (NALCN), which regulates neuronal excitability, has been shown to be enhanced by volatile anesthetics.
What This Article Tells Us That Is New
  • The hypothesis that the NALCN maintains neuronal activity in the paraventricular thalamus to resist the anesthetic effects of sevoflurane was tested in mice. Induction of and recovery from sevoflurane anesthesia were assessed by measuring loss of righting reflex and recovery of righting reflex, respectively.
  • Expression of c-Fos, a marker of neuronal activity, in the paraventricular thalamus was decreased by exposure to 2% sevoflurane for 2 h and increased 2 h after anesthesia recovery.
  • Chemogenetic inhibition of paraventricular thalamus neurons accelerated induction of anesthesia and delayed recovery from it, as did knockdown of NALCN in paraventricular thalamus glutamatergic neurons.
  • Optogenetic activation of paraventricular thalamus neurons delayed induction of anesthesia and accelerated recovery from it.