Mechanisms for anesthesia, unawareness, OIRD, sleep and memory replay: MHb→IPN→ PAG + DRN + MRN→claustrum→ cortical slow-waves.

My findings show what causes loss of awareness, anesthesia, memory replay, opioid induced respiratory depression (OIRD), and slow wave sleep. Opiates are fast pain relievers and anesthetics that can cause respiratory arrest. I found how mu-opioids and anesthetics by activating medial habenula (MHb) and/or interpeduncular nucleus (IPN) induce unawareness and slowdown respiration. Using DTI method I observed that human hippocampus is connected to MHb via posterior septum, while amygdala via anteromedial BNST. MHb projected to pineal gland and contralateral MHb (Vadovičová, 2014). MHb has dense mu-opioid receptors (Gardon and Faget, 2014) and strong projections to IPN. Herkenham (1981) found that MHb and IPN increase their glucose intake during anesthesia. The question is: What is the MHb-IPN circuit doing?

I found that it causes slow-wave sleep (SWS), memory replay, sharp-wave ripples, spindles, hippocampo-cortical replay of temporally, spatially and relationally bound information, serotonin-BDNF-linked growth, synaptogenesis, rest and recovery, by activating median raphe (MRN) serotonin, and by inhibiting the theta state circuit, new memories encoding, awareness, arousal, alert wakefulness, and REM sleep (Vadovičová, 2015). SWS circuit causes also natural slowdown of respiration and heart rate, while it inhibits locomotion and arousal.

This extended circuit model added role of the dentate gyrus→posterior septum→MHb→IPN →MRN→hippocampus + basal forebrain + claustrum→cortical slow-wave activity (SWA) in memory replay, ripples, loss of awareness, anesthesia, and SWS. It proposes new neural mechanism for anesthetic ketamine, nitrous oxide, and phencyclidine effects: activation of the IPN→MRN→claustrum→cortical SWA circuit by the 5-HT2a receptors in the IPN and claustrum. My brain/circuit model shows why are ketamine and psychedelics anxiolytic and antidepressant. How they by activating the 5-HT2a receptors in vACC/infralimbic cortex increase safety, well-being signal, socializing, and cognitive flexibility, and attenuate fear, worries, anger, impulsivity, self-defence, and wanting. This model claims that mu-opioids, acetylcholine, nicotine, endocannabinoids, adenosine, GLP-1RA, and substance P activate the MHb-IPN-MRN circuit which promotes rest, recovery, repair, serotonin→BDNF→proteins production, spines/synapses growth, and anti-inflammatory state.