Activity of the Sodium Leak Channel Maintains the Excitability of Paraventricular Thalamus Glutamatergic Neurons to Resist Anesthetic Effects of Sevoflurane in Mice

Anesthesiology. 2024 Jul 1;141(1):56-74. doi: 10.1097/ALN.0000000000005015.


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.

MeSH terms

  • Anesthetics, Inhalation* / pharmacology
  • Animals
  • Glutamic Acid / metabolism
  • Glutamic Acid / pharmacology
  • Ion Channels
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Midline Thalamic Nuclei* / drug effects
  • Midline Thalamic Nuclei* / physiology
  • Neurons* / drug effects
  • Neurons* / physiology
  • Sevoflurane* / pharmacology
  • Sodium Channels / drug effects
  • Sodium Channels / physiology


  • Sevoflurane
  • Anesthetics, Inhalation
  • NALCN protein, mouse
  • Sodium Channels
  • Glutamic Acid
  • Ion Channels
  • Membrane Proteins