Sleep
Inactivation of the DREAM complex mimics the molecular benefits of sleep
Resisting sleep deprivation by breaking the link between sleep and circadian rhythms
Mitochondrial origins of the pressure to sleep (see also mitochondria)
Development of short sleeper phenotype after brain surgery: Development of a short sleeper phenotype after third ventriculostomy in a patient with ependymal cysts -- "Beyond presumably lowered overall supratentorial brain pressure, thalamic and hypothalamic structures near the intervention site might be responsible for the changed regulation of sleep homeostasis and circadian regulation. Due to their exposed location and the proximity to the third ventricle, decompression of the wake-promoting histaminergic neurons in the tuberomammillary nucleus might be involved or alternatively altered expression of genes regulating circadian rhythm and sleep homeostasis."
The evolution of sleep is inevitable
"Being awake day and night forces an organism to adapt to both light and dark, as well as to the different organisms populating each, and to do so would compromise its ability to perform well in either. ... Pick one, either day or night, and optimize your structure, function and behavior for that environment, then get away from the one you did not choose, to avoid attempting to optimize to both... In the adaptive theory, we hide from the danger of darkness; in this new theory we hide from the danger of adapting to the darkness on evolutionary timescales." from https://pmc.ncbi.nlm.nih.gov/articles/PMC7120898/
the identified genetics of "short sleep" humans may not be accurate: https://forum.effectivealtruism.org/posts/nSwaDrHunt3ohh9Et/cause-area-short-sleeper-genes?commentId=GCQf5qjG4LyEdEJov
The transcriptional repressor DEC2 regulates sleep length in mammals (hDEC2-P385R)
Several other genetic mutations related to short sleep are identified on the human germline genetic modifications page including DEC2 BHLHE41, GRM1, NPSR1, ADRB1, hSIK3, and WWOX.
A familial natural short sleep mutation in dec2 extends healthspan and lifespan in Drosophila (2025) -- "We used a Drosophila model to study the effects of the DEC2 dec2P384R mutation on animal health. Expression of a human Dec2 dec2P384R mutation in sleep-controlling neurons reduces sleep, and, remarkably, the short sleeping flies live significantly longer with improved health. The improved physiological effects were enabled, in part, by enhanced mitochondrial fitness and upregulation of multiple stress response pathways. Additionally, we demonstrate that dec2P384R boosts mitochondrial respiratory capacity in both flies and mammalian cells, suggesting a conserved mechanism by which this mutation promotes healthy aging. ... Expression of the human dec2P384R mutation in Drosophila sleep-regulating dorsal fan-shaped body (dFB) neurons was sufficient to reduce the total sleep per day. Remarkably, despite reduced sleep, these flies exhibited significantly extended lifespans, enhanced stress resistance, improved memory, and improved late-age mobility. ... Using AlphaFold3,54 we generated predicted structures of WT DEC2 and DEC2P384R proteins and compared their overall structures..."
drosophila sleep neurons:
- Drosophila sleep is regulated by distinct neuronal populations, including wake-promoting pigment-dispersing factor (PDF)-expressing neurons in the ventral lateral neurons (sLNv and lLNv), sleep-promoting neurons such as narrow-field R18G05+ cells in the dorsal fan-shaped body (dFB), and modulatory dopaminergic and GABAergic neurons in regions like the mushroom bodies and ellipsoid body.
- Dorsal fan-shaped body (dFB) neurons in the Drosophila central brain are glutamatergic sleep-promoting cells that integrate circadian inputs from pacemaker neurons to drive sleep homeostasis and rebound after deprivation.
Systemic and nasal delivery of orexin-a (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates -- "Hypocretin-1 (orexin-A) was administered to sleep-deprived (30–36 h) rhesus monkeys immediately preceding testing on a multi-image delayed match-to-sample (DMS) short-term memory task. The DMS task used multiple delays and stimulus images and effectively measures cognitive defects produced by sleep deprivation (Porrino et al., 2005). Two methods of administration of orexin-A were tested, intravenous injections (2.5–10.0 μg/kg, i.v.) and a novel method developed for nasal delivery via an atomizer spray mist to the nostrils (dose estimated 1.0 μg/kg). Results showed that orexin-A delivered via the intravenous and nasal routes significantly improved performance in sleep-deprived monkeys; however, the nasal delivery method was significantly more effective than the highest dose (10 μg/kg) of intravenous orexin-A tested. The improvement in performance by orexin-A was specific to trials classified as high versus low cognitive load as determined by performance difficulty under normal testing conditions. Except for the maximum intravenous dose (10 μg/kg), neither delivery method affected task performance in alert non-sleep-deprived animals. The improved performance in sleep-deprived animals was accompanied by orexin-A related alterations in local cerebral glucose metabolism (CMRglc) in specific brain regions shown previously to be engaged by the task and impaired by sleep deprivation (Porrino et al., 2005). Consistent with the differential effects on performance, nasal delivered orexin-A produced a more pronounced reversal of sleep deprivation induced changes in brain metabolic activity (CMRglc) than intravenous orexin-A. These findings provide strong evidence for the effectiveness of intranasal orexin-A in alleviating cognitive deficits produced by loss of sleep."
orexin receptor agonists are currently the subject of several clinical trials as a treatment for narcolepsy. Here are some self-reports from the orexin receptor agonist clinical trial participants.
intracerebroventricular (ICV) infusion of orexin-A increases wakefulness in narcoleptic mice. There are various orexin receptor agonists such as takeda's oveporextin, suntinorexton, firazorexton, alixorexton, etc. "What about automatic orexin peptide administration in sync with your personal circadian rhythm (think of insulin pumps)?"
There have also been cell therapy studies using orexin cell transplants into mouse or rat brain, showing increased wakefulness after cell treatment.
from Wikipedia: "Sleep (especially deep SWS and REM) is tricky behavior because it steeply increases predation risk. This means that, for sleep to have evolved, the functions of sleep should have provided a substantial advantage over the risk it entails. ... According to Tsoukalas (2012), REM sleep is an evolutionary transformation of a well-known defensive mechanism, the tonic immobility reflex. This reflex, also known as animal hypnosis or death feigning, functions as the last line of defense against an attacking predator and consists of the total immobilization of the animal: the animal appears dead (cf. "playing possum"). The neurophysiology and phenomenology of this reaction show striking similarities to REM sleep, a fact which betrays a deep evolutionary kinship. For example, both reactions exhibit brainstem control, paralysis, sympathetic activation, and thermoregulatory changes."
selectively breed mice for anti-sleep mice: longer wakefulness, shorter sleep, less sleep deprivation. We can also selectively breed brain colonizing microbes that reduce the total amount of necessary sleep, and recover from postmortem brains to retrieve the microbes that cause a greater sleepless effect and undergo selection that way.
selectively breed drosophila for wakefulness, longer wakefulness, shorter sleep, etc.
modafinil
brain stimulation -- which specific areas?
optogenetics to modulate sleep vs wakefulness?
https://lukepiette.posthaven.com/reducing-sleep-1
https://helenarosengarten.com/how-to-sleepless/sleeplessness
https://guzey.com/theses-on-sleep/
sci-fi book "Beggars in Spain" (Nancy Kress)
Sleep deprivation does not itself cause death, multiple days of sleeplessness have not been fatal in humans.
Modulating duration of wakefulness vs duration of sleep (short sleep). Can sleep deprivation be made to be less painful?
See also brain, genetic-modifications for more genetic interventions for sleep or anti-sleep.