Excitatory Pathways from the Lateral Habenula Enable Propofol-Induced Sedation

Abstract

SummaryThe lateral habenula has been widely studied for its contribution in generating reward-related behaviors [1, 2]. We have found that this nucleus plays an unexpected role in the sedative actions of the general anesthetic propofol. The lateral habenula is a glutamatergic, excitatory hub that projects to multiple targets throughout the brain, including GABAergic and aminergic nuclei that control arousal [3, 4, 5]. When glutamate release from the lateral habenula in mice was genetically blocked, the ability of propofol to induce sedation was greatly diminished. In addition to this reduced sensitivity to propofol, blocking output from the lateral habenula caused natural non-rapid eye movement (NREM) sleep to become highly fragmented, especially during the rest (“lights on”) period. This fragmentation was largely reversed by the dual orexinergic antagonist almorexant. We conclude that the glutamatergic output from the lateral habenula is permissive for the sedative actions of propofol and is also necessary for the consolidation of natural sleep.

Activation of Preoptic GABAergic or Glutamatergic Neurons Modulates Sleep-Wake Architecture, but Not Anesthetic State Transitions

“…It is also important to consider other subcortical nodes that are not classically considered critical for sleep regulation but might play a more relevant role in general anesthetic mechanisms. For example, recent and noteworthy studies showed that glutamatergic neurons in the lateral habenula facilitate the hypnotic effect of the intravenous anesthetic propofol [24], and neuroendocrine cells within the supraoptic nucleus promote NREM sleep and facilitate general anesthesia [25]. These studies, in conjunction with our complementary findings, should prompt the field to consider exploring additional brain regions and nuclei beyond those classically known to regulate sleep and wakefulness.…”

Intraoperative ketamine for prevention of depressive symptoms after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial

“…32 However, recent work has also shown that excitation of glutamatergic neurones in the lateral habenula, which is metabolically activated by many anaesthetics, 33 is critical for propofol sedation and unconsciousness. 34 Thus, administration of ketamine during prolonged general anaesthesiadas was studied in the PODCAST trialdmight create unfavourable neural conditions for anti-depressant effects at both cortical and subcortical levels.…”

Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep

“…CC-BY-NC 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted October 20, 2020. ; https://doi.org/10.1101/2020.10.19.345728 doi: bioRxiv preprint 14 fragmentation effect mostly occurring during the "lights-on" sleep phase (Gelegen et al, 2018).…”