User:Kinkreet/sandbox3

Physical homeostasis
Chronic sleep loss > increase in inflammatory mediators > alter sleep behavior.

cytokines in and how that affects the brain and sleep regulation
 * Normal
 * Infection

IL-1β >>[via serontin]>> neurons + neurotransmitters

sleep loss > cognitive impairment

sleep loss during time of vaccination reduces the vaccine's effectiveness.

sleep loss has also been linked to obesity, although studies show only correlation and not causation. It suggests that disrupted sleep decreases the leptin levels, but increases the ghrelin levels, which increases appetite and hunger. A recent review raises the issue of a lack of experimental data, however, this might be difficult as obesity is a result of numerous factors and can emerge slowly. While an observational study does not provide evidence of causation, an experimental approach would be both impractical and unethical. Sleep loss has been associated with diabetes and cardiovascular diseases, where people that sleep less, are more likely to be diabetic and/or suffer fatal heart attacks. However, these links must be treated with caution, as one not necessarily causes the other, but rather, both might be effects from a common cause (e.g. disrupted lifestyle).

cytokines are immunomodulators; unsurprisingly, during infection, the profile of cytokines will be different compared to when the individual was healthy.

IL-1β and TNFα are two cytokines which have been demonstrated to regulate sleep. When sleep deprived, the circulating levels of IL-1β and TNFα are increased; and the administration of these factors leads to symptoms associated with sleep loss, such as fatigue, poor cognition and increased sensitivity to pain. Most infections occur outside the brain, and thus most cytokines are produced in the peripheral immune system. To regulate something that is regulated inside the brain, the cytokines must be actively transported into the central nervous sysmtem (CNS) through the circumventricular organs (CVOs), which are structures of the brain that is highly vascularized. However, cytokines may also be synthesized in the brain from both neurons and glial cells.

IL-1 and/or TNF administration leads to increase in NREM sleep and a suppression of REM sleep. Antagonizing them (using inactivators, antibodies, or soluble receptors) reduced NREM sleep, even the increase in NREM sleep that is normally observed after sleep deprivation, excessive food intake, or acute elevation in temperature. IL-1 causes the NREM sleep to be fragmented.

IL-1 plasma levels are highest at the onset of sleep for humans, and IL-1 and TNF and their mRNA levels are highest at the NREM stage.

Mimicking bacterial infection by administering bacterial cell wall components such as lipid A, lipopolysaccharide and muramyl peptide, leads to an antigenic response that results in the increased production and release of pro-inflammatory cytokines, including IL-1 and TNF. At the same time, NREM sleep is increased and REM sleep is suppressed. Furthermore, when IL-1 or TNF are antagonized, the alteration in sleep is not observed.

IL-1 and TNF are known to interact with the serotonin system. Serotonin is a wake-promoting neurotransmitter. It is thought that serotonin carry out its action by inhibiting sleep-promoting neurons in the anterior hypothalamus, preoptic area and basal forebrain. It is also thought that the neurons that releases serotonin also produce sleep-inducing factors such as IL-1, and these factors will accumulate and overwhelm the wake-promoting role of serotonergic cell bodies, and induces sleep. In turn, IL-1 is thought to carry out its sleep-promoting effect through synthesis/release of growth hormone-releasing hormone, prostaglandin D2, adenosine and nitric oxide, as inhibiting any one of these systems prevented increase in NREM sleep as expected.

Serotonin levels are highest when awake, and decreases during NREM sleep, and is demolished in REM sleep.

Noradrenergic neurons of the locus coeruleus and serotonergic neurons in the raphe nuclei firing is diminished, and the neurotransmitters they releases are thought to gate the entry into REM sleep by inhibiting neurons that promote REM sleep. Indeed, inhibiting serotonin allows REM sleep whereas administering it inhibited REM sleep.

Infection
During the immune response elicited by infection, proinflammatory cytokines, including IL-1 and TNF are upregulated, and these move from the peripheral immune system into the brain, where it interacts with neurological systems, including the serotinergic sysmte, and increases the amount of NREM sleep while suppressing REM sleep.

Be interesting to see how the levels of immune modulators change during diurnal sleep (napping) to distinguish effects of circadian rhythm as opposed to sleep per se.

Muramyl peptide (initially called 'Factor S') is the first sleep-inducing substances to be identified. Muramyl peptide is a component of the bacterial cell wall and was found to increase in the cerebral spinal fluid during sleep deprivation.

Indeed, injection of TNF into the body cavity of mice induces 90 minutes more sleep within 9 hours of injection. Injection of either IL-1β or TNFα into the brain areas that regulate sleep (e.g. hypothalamus) increased NREM sleep. Antagonizing IL-1β and TNFα using antibodies, soluble receptors, or siRNA-knockdown animals, or removing their receptors, decreased the duration of sleep in mice.

IL-1β and TNFα themselves induces their own production. This is done through activating nuclear factor κ β (NFκβ), a transcription factor that regulates IL-1β, TNFα and the adenosine A1 receptor (A1AR).

General metabolism
When neurons fire, a bit of ATP is released to the extracellular environment, and these can build up and binds to purine type 2 receptors, such as the P2X7 receptor, and this increases the level of IL-1β and TNFα release from glial cells. When ventricular extracellular ATP is antagonized, the amount of sleep decreases; conversely, when ATP is agonized, sleep is increased. The levels of P2X7R mRNA changes during the day

Indeed, the TNF mRNA in the cortex and hypothalamus of rats increases by two-fold across the day, and increases with sleep propensity, and is reflected in a ten-fold increase in TNF protein level. In humans, increased levels of IL-1 mRNA is seen after sleep deprivation.

IL-1β and TNFα then induces downstream effectors such as adenosine, nitric oxide, prostaglandins.

Growth hormone releasing hormone (GHRH) - NREM Prolactin, nitric oxide (NO) - REM

Note
It is found that molecules which regulate sleep always have another function associated with it, furthering the fact that sleep is not regulated independently, but requires signals from other systems.