Hypothalamic thermoregulatory neurons divergently modulate isoflurane anesthesia via temperature dependent and independent mechanisms.

Perioperative hypothermia is common clinically. The neural mechanisms underlying general anesthesia and the hypothermia it induces remain elusive. We found that lower core temperature (Tcore) deepened anesthesia and delayed emergence, which showed a logarithmic relationship below 31.9°C. Chemogenetic activation of brain-derived neurotrophic factor in the lateral preoptic area (LPOBDNF) neurons before isoflurane administration lowered Tcore and increased isoflurane induced burst-suppression ratio (BSR), δ power, and recovery time, while its optogenetic activation during isoflurane did not change Tcore and anesthesia depth. Conversely, chemogenetic activation of dorsomedial hypothalamus glutamatergic (DMHVglut2) neurons increased Tcore, attenuated anesthesia depth and promoted recovery. Stage-specific optogenetic activation of DMHVglut2 neurons and its downstream raphe pallidus (RPa) projection during isoflurane exposure induced cortical activation without Tcore alteration. Our study indicates that LPOBDNF neurons modulate isoflurane anesthesia primarily through temperature-dependent mechanism, while DMHVglut2 neurons and the DMHVglut2 to RPa pathway have a temperature-independent function in modulating isoflurane anesthesia.