Circuits for anesthesia, unawareness, OIRD, sleep and memory replay: MHb→IPN→PAG + DRN + MRN→claustrum→cortex.

Mu-opioid activation of the medial habenula-interpeduncular nucleus circuit slows respiration and suppresses arousal, linking opioid-induced respiratory depression and prenatal nicotine exposure to sudden infant death syndrome. The same circuit, when activated during slow wave sleep, promotes memory replay, synaptogenesis, and immune defense while inhibiting theta states and REM sleep. Ketamine and hallucinogens may produce their anesthetic, anxiolytic, and antidepressant effects by activating this circuit via 5-HT2a receptors in the interpeduncular nucleus, claustrum, and infralimbic cortex, increasing safety signaling and cognitive flexibility.

Study at a glance

Abstract

Opiates are fast pain relievers that can cause respiratory arrest.I show new mechanisms how mu-opioids and high prenatal nicotine cause respiratory slowdownlinked to slow wave sleep. Mu-opioids activate the medial habenula which activates theinterpeduncular nucleus. The MHb-IPN system decreases respiration and alarm/arousal response tohypercapnia by projections to PAG, DRN, MRN and LPO→RMTg→vPAG. The same MHb-IPNcircuit that causes respiratory slowdown, likely causes ventilatory deficits in mammalian neonates,known as sudden infant death syndrome (SIDS), linked to high fetal nicotine intake.Natural slowdown of respiration and heart rate is caused by slow wave sleep, when body is notmoving. The MHb and rostromedial tegmental nucleus are known for high amount of mu-opioidreceptors. Both were claimed to be activated by the MHb→IPN→MRN circuit that activatesserotonin release, promotes slow SWS, rest, immune defense, recovery, sharp wave ripples, corticalspindles, replay of temporaly, spatialy and relationally bound memories, synaptogenesis and BDNFlinked growth, but inhibits theta states, arousal, alert wakefulness, awareness and REM sleep linkedcircuits (Vadovičová, 2015).This updated circuit model explains role of the MHb→IPN→MRN→hippocampus + claustrum→cortical slow wave activity (SWA) in anesthesia, memory replay, loss of awareness, SWS and intheta states suppression. I propose new mechanisms for anesthetic ketamine and hallucinogenseffect: activation of the IPN→MRN→claustrum→cortical SWA circuit by the 5-HT2a IPN andclaustrum receptors. I show why are ketamine and hallucinogens anxiolytic and antidepressant, andhow activation of 5-HT2a receptors in vACC/infralimbic cortex increases the safety, well-beingsignal, and cognitive flexibility.