Sleep

Sleep is a ubiquitous and mysterious quiescent behavior of organisms ranging from far ends of the animal kingdom.

## Description

Sleep is characterized by a more subdued behavioral state of the organism, during which the organism loses awareness. It is also described by characteristic population electrical activity in mammals.

### Sleep Stages

* NREM
	+ Sharp wave-ripples
	+ Sleep spindles
* REM
	+ more prominent theta rhythm
	+ increased Acetylcholine levels

### Regulators of Sleep

For a thorough discussion of this topic, see 'Control of Sleep and Wakefulness' by Brown et al. (2012).

* Methods to increase wake time
	+ Dopamine, specifically the Ventral Tegmental Area is a positive regulator of wake.
	+ Norepinephrine, through the Locus coeruleus, promotes wake.
	+ Histamine promotes wake and shares reciprocal signaling with NE.
	+ Serotonin seems to have a more complex role but is higher during wake. It seems to promote a quiet waking state with lower relative cortical activation.
	+ Acetylcholine, originating from the Basal Forebrain and Pontine Tegmentum, promotes both wakefulness and REM sleep.
	+ Orexin increases duration of long waking bouts, suppress REM, and increase wakefulness when an animal is being starved.
	+ Neuropeptide S, which activates a GPCR that activates Phospholipase C. It is in glutamatergic neurons just rostral to LC.

* Methods to increase sleep time
	+ Fewer enhancers of sleep have been found
	+ Nitric Oxide containing cells appear to be more active during sleep.
	+ Optogenetic stimulation of melanin concentrating hormone containing neurons in Hypothalamus increases sleep time by around 50%.
	+ Ventrolateral preoptic nucleus (VLPO) activity is associated with sleep. Inhibits the ascending reticular arousal system.
	+ Median preoptic nucleus (MnPO) inhibits ascending arousal system and the lateral hypothalamus, Raphe nucleus, and LC.
* Other Regulators
	+ SNARE-mediated release of gliotransmitters (specifically adenosine) from astrocytes is necessary for sleep homeostasis.
	+ Sik3 is a protein kinase that was found to regulate sleep amount/need in mice in a forward genetic screen.

### Expression during sleep versus wake

Studies have carried out transcriptomic and proteomic work comparing sleep and wake in various neural tissues. At this point, I've not actually found a study that looks at sleep vs. wake and limits the collection of data from neural tissue (as opposed to glial and neural tissue). The data described below comes from these studies.

#### Elevated in sleep

* albumin D-site binding protein (DBP) up 176%. Governs circadian transcription of a number of enzymes in liver.
* sterol-CoA desaturase 2 up 90%. This protein is the main delta9 desaturate expressed in the CNS. Lower levels in the CNS, especially the hypothalamus, are associated with weight gain and higher energy expenditure.
* ADP-ribosylation-like 2 (arl2) is up 82%. It is a GTPase that seems to regulate membrane fusion. In particular it regulates mitochondrial fusion with inter membrane space.
* CaMKII inhibitor alpha is up 59%. CaMKII inhibitor is upregulated during consolidation of fear memory in Hippocampus.
* N-ethylmaleimide sensitive factor transcript is up 77% (protein up 33%?). This is a hexametric ATPase essential for most membrane tracking events and fusion in the cell.
* calcineurin B (CaN) up 50 to 65%. CaN is the only calcium activated protein phosphatase in the brain and a major regulator of key proteins involved in synaptic transmission and neuronal excitability. CaN is known to constrain LTP.
* Calmodulin-dependent protein kinase 4 is up 25%. CaMKIV is hypothesized to signal homeostatic plasticity in neurons.

Elevated in Wake

* c-fos is up 1230%.
	+ Another paper found c-fos up in sleep deprived.
* activity and neurotransmitter-induced early gene 1 (ania-1), 3' UTR up 602%.
* homer1c up 332%. homer1c is required for in metabotropic glutamate receptor-dependent LTP in hippocampus.
* activity regulated growth factor (Arc) up 309%.
	+ Another paper found up ~4-5x in sleep deprived.
* immediate early gene transcription factor NGFI-B up 250%.
* brain derived neurotrophic factor (BDNF) is up 71%.

## Function

See Sleep/Wake Potentiation for an article solely about potentiation versus weakening of neural connections/excitability over the course of sleep/wake.

### Sleep's modulation of factors

* Synaptic Homer1a levels are much higher after sleep dense episode (conflated with circadian time!).
	+ Homer1a PSD targeting appears to be controlled by Norepinephrine vs Adenosine signaling.
	+ Proposed that Sleep/Wake pressure regulation of Homer1a is what gates Homer1a's regulation of synaptic downscaling during sleep.

### Sleep Facilitation of Learning

* There is strong evidence that sleep contributes to consolidation of memories.
* General Thoughts:
	+ It seems reasonable that a lot of learning takes recurrent activity, replay of the firing patterns, and further that if widespread replay of this type took place during waking consciousness, it could interfere with behavior. Given that people dream i.e. hallucinate often when coming out of stages of sleep, it's plausible that this would happen during wake. One might posit that this suppression of memory patterns is a related and dysregulated phenomenon in patients with schizophrenia.
	+ Given that sleep is so ubiquitous, sleep's improvement of memory might be incidental to a more basic cellular process of homeostasis/regulation that maintains basic cellular health.
	+ Sleep supports consolidation of memory in all major memory systems but with preference for explicit and behaviorally relevant memories.

* Visual procedural memory consolidation promoted by sleep can be blocked using glutamatergic antagonists (against AMPA and NMDARs).
* In cats, ocular dominance plasticity was found to be greater when cats were allowed to sleep for 6 hours. This appears to be blocked by NMDAR antagonist APV and PKA inhibitor RP-8-Cl-cAMPS.
* REM sleep might increase pruning of new synapses/spines in the short term (0-16h) while maintaining and increasing the size of a fraction of synapses especially associated with motor learning in L5 Motor Cortex.

### Active System Consolidation

Hypothesis proposing that sleep has active, specific processes to support memory consolidation, such as patterned replay of memories.

#### Memory Transfer to Cortex

The field has often conceived of the conceptual model whereby memory patterns are transferred from different brain structures to the cortex during sleep. One prominent example of this is the Hippocampal-Neocortical Interaction.

* Thalamo-cortical (TC) transfer also appears to be a possibility. TC spindle-associated firing can trigger LTP. In addition, synchronous spindle activity occurs preferentially at synapses that were strengthened during encoding. More broadly, studies have found an increase in spindle density during NREM after learning various tasks, and some find a correlation between the spindles and memory improvement. Multiple studies have found that spindle activity and ripples increase during the up-state of a slow oscillation.
* Q: If a 'memory trace' or engram is in some sense transferred from the hippocampus or thalamus to the cortex, would it be possible to actually track the transfer? If you evoke the memory before when the proposed transfer occurs and then after, is the characteristic activity transferred?
* Enhancing (using electrode stimulation) of sharp wave-ripples in vivo during NREM sleep led to increased discrimination task performance.

### Synaptic Homeostasis Hypothesis (SHY)

One leading theory of sleep function is the SHY model pioneered by Tononi and Cirelli of UW. They propose that sleep leads do a general synaptic downscaling to compensate for the potentiation during wake. Evidence in support includes gene expression data showing that some genes that contribute to canonical LTP are expressed at lower levels during sleep. A counterpoint to this is that total cortical CaMKII levels do not change between wake-sleep.

* The fact that many neuromodulators associated with plasticity are at higher levels during wake might support this hypothesis (with the exception of Acetylcholine, which is at higher levels during REM).
* Proposes consolidation during sleep is in part a by product of downscaling.
* Difference in levels of AMPARs have been reported across sleep/wake
	+ Staining intensity of GluA1 is statistically lower after more sleep dense episode. However effect size is tiny (<8%) and appears to conflate circadian time.
	+ PSD-specific western blot data showed lower levels of GluA1, AKAP5, PKA.
	+ KO of Homer1a blocked these decreases in AMPARs.
* Ultrastructural evidence that synapses increase in size over course of awake periods and decrease over course of sleep. They found that the largest 20% of synapses did not show this behavior.
	+ There are questions about sleep paradigm used in this paper.

### Dual Process Hypothesis

This hypothesis that REM and NREM have contrasting roles in memory consolidation. It proposes that SWS promotes declarative, hippocampus-dependent memory and that REM supported non-declarative, hippocampus-independent memory. This is at least in part based on Human sleep data looking at the relative amount of time spent in NREM vs. REM. However, research has shown that the respective sleep stages can promote the opposite forms of memory. This has lead to an alteration to the hypothesis that argues it is the sequence of both SWS and REM that best promotes memory.

### Plasticity Summary Tables

Numbers refer to paper taken from's citations: 'Sleep, clocks, and synaptic plasticity'

## Sleep Deprivation

There are multiple ways of depriving an animal (normally a rodent) of sleep including water deprivation and gentle handing.

* A recent study did synapto-proteomics on rat parietal and thalamic regions deprived of sleep for 8 hours or 16 hours. The parietal cortex had ~3x more differentially expressed proteins. The largest functional groups represented were in protein synthesis/folding, CHO and energy metabolism, lipid metabolism and synaptic transmission.

## REM-NREM Switch Model

There's a popular model describing an antagonistic switching between REM and NREM sleep.

Broadly, cholinergic systems tend to promote REM sleep, and aminergic wake-promoting systems promote NREM sleep.  However, there is evidence that glutamatergic systems might also play a role in this model. The glutamatergic medial Pontine Tegmentum (PT) cells labeled by Atoh1 enhancer suppress REM and promote NREM. When restricting activation to the lateral cells in the PT, there is a wake-promoting, REM suppressing effect.  Sleep also promotes translation of mRNAs known to be related to plasticity.

Sleep deprivation causes death in rodents after ~2-3 weeks. While the actual direct cause of death is unclear, a large disruption in thermoregulation is likely key.

## References

1. ↑ http://www.nature.com/neuro/journal/v19/n10/full/nn.4377.html
2. ↑ 2.0 2.1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812689/
3. ↑ https://www.ncbi.nlm.nih.gov/pubmed/10622375
4. ↑ 4.0 4.1 4.2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621793/
5. ↑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026477/
6. ↑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899842/
7. ↑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685832/
8. ↑ 8.0 8.1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621793/
9. ↑ Schmitt, L. I., Sims, R. E., Dale, N., and Haydon, P. G. (2012). Wakefulness affects synaptic and network activity by increasing extracellular astrocyte-derived adenosine. *J. Neurosci.*
10. ↑ http://www.nature.com/nature/journal/v539/n7629/full/nature20142.html
11. ↑ http://www.sciencedirect.com.resources.library.brandeis.edu/science/article/pii/S0896627303008146?via%3Dihub
12. ↑ Hypothalamic stearoyl-CoA desaturase-2 (SCD2) controls whole-body energy expenditure.
13. ↑ The ARL2 GTPase regulates mitochondrial fusion from the intermembrane space.
14. ↑ An endogenous inhibitor of calcium/calmodulin-dependent kinase II is up-regulated during consolidation of fear memory
15. ↑ N-ethylmaleimide sensitive factor (NSF) structure and function.
16. ↑ Neural functions of calcineurin in synaptic plasticity and memory
17. ↑ 17.0 17.1 Gene expression in the rat brain during sleep deprivation and recovery sleep: an Affymetrix GeneChip® study
18. ↑ http://onlinelibrary.wiley.com/doi/10.1002/hipo.22222/abstract
19. ↑ 19.0 19.1 19.2 19.3 http://science.sciencemag.org/content/355/6324/511.full
20. ↑ http://www.nature.com.resources.library.brandeis.edu/nature/journal/v437/n7063/full/nature04286.html
21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 http://www.nature.com/nrn/journal/v11/n2/full/nrn2762.html
22. ↑ Visual-procedural memory consolidation during sleep blocked by glutamatergic receptor antagonists

J. Neurosci., 28 (2008), pp. 5513–5518
23. ↑ http://www.sciencedirect.com.resources.library.brandeis.edu/science/article/pii/S0896627301002793
24. ↑ http://www.sciencedirect.com.resources.library.brandeis.edu/science/article/pii/S0896627309000403
25. ↑ http://www.nature.com.resources.library.brandeis.edu/neuro/journal/v20/n3/full/nn.4479.html
26. ↑ https://www.ncbi.nlm.nih.gov/pubmed/16221848?dopt=Abstract&holding=npg
27. ↑ https://www.ncbi.nlm.nih.gov/pubmed/15749334?dopt=Abstract&holding=npg
28. ↑ http://www.nature.com.resources.library.brandeis.edu/neuro/journal/v19/n7/full/nn.4304.html
29. ↑ Extensive and divergent effects of sleep and wakefulness on brain gene expression

Neuron, 41 (2004), pp. 35–43
30. ↑ Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep

Nat. Neurosci., 11 (2008), pp. 200–208
31. ↑ Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats

J. Physiol., 575 (2006), pp. 807–819
32. ↑ http://science.sciencemag.org.resources.library.brandeis.edu/content/355/6324/507
33. ↑ http://www.sciencedirect.com/science/article/pii/S1044743117300052
34. ↑ http://link.springer.com.resources.library.brandeis.edu/article/10.1007/s00424-011-1054-y/fulltext.html
35. ↑ http://science.sciencemag.org.resources.library.brandeis.edu/content/350/6263/957.full
36. ↑ Protein synthesis during sleep consolidates cortical plasticity in vivo

Curr. Biol., 22 (2012), pp. 676–682