The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.

http://www2.neuroscience.umn.edu/eanwebsite/PDF%20GJClub/Science%20342%20373%202013.pdf

Sleep Drives Metabolite Clearance From the Adult Brain

Over more than a century of research has established the fact that sleep benefits the retention of memory. In this review we aim to comprehensively cover the field of "sleep and memory" research by providing a historical perspective on concepts and a discussion of more recent key findings. Whereas initial theories posed a passive role for sleep enhancing memories by protecting them from interfering stimuli, current theories highlight an active role for sleep in which memories undergo a process of system consolidation during sleep. Whereas older research concentrated on the role of rapid-eye-movement (REM) sleep, recent work has revealed the importance of slow-wave sleep (SWS) for memory consolidation and also enlightened some of the underlying electrophysiological, neurochemical, and genetic mechanisms, as well as developmental aspects in these processes. Specifically, newer findings characterize sleep as a brain state optimizing memory consolidation, in opposition to the waking brain being optimized for encoding of memories. Consolidation originates from reactivation of recently encoded neuronal memory representations, which occur during SWS and transform respective representations for integration into long-term memory. Ensuing REM sleep may stabilize transformed memories. While elaborated with respect to hippocampus-dependent memories, the concept of an active redistribution of memory representations from networks serving as temporary store into long-term stores might hold also for non-hippocampus-dependent memory, and even for nonneuronal, i.e., immunological memories, giving rise to the idea that the offline consolidation of memory during sleep represents a principle of long-term memory formation established in quite different physiological systems.

https://www.zora.uzh.ch/id/eprint/77770/1/physiol_rev_93.pdf

About sleep's role in memory

Sleep and the Price of Plasticity: From Synaptic and Cellular Homeostasis to Memory Consolidation and Integration

OBJECTIVE - To assess the relationship between habitual sleep disturbances and the incidence of type 2 diabetes and to obtain an estimate of the risk.
 
RESEARCH DESIGN AND METHODS - We conducted a systematic search of publications using MEDLINE (1955-April 2009), EMBASE, and the Cochrane Library and manual searches Without language restrictions. We included studies if they were prospective with follow-up >3 years and had an assessment of sleep disturbances at baseline and incidence of type 2 diabetes. We recorded several characteristics for each study. We extracted quantity and quality of sleep, how they were assessed, and incident cases defined with different validated methods. We extracted relative risks (RRs) and 95% Cl and pooled them using random-effects models. We performed sensitivity analysis and assessed heterogeneity and publication bias.
 
RESULTS - we included 10 Studies (13 independent cohort Samples; 107,756 male and female participants, follow-up range 4.2-32 years, and 3,586 incident cases Of type 2 diabetes). In pooled analyses, quantity and quality of sleep predicted the risk of development Of type 2 diabetes. For short duration of sleep (: 8-9 h/night), the RR was 1.48 (1.13-1.96, P = 0.005); for difficulty in initiating sleep, the RR was 1.57 (1.25-1.97, P < 0.0001); and for difficulty in maintaining sleep, the RR was 1.84 (1.39-2.43, P < 0.0001).
 
CONCLUSIONS - Quantity and quality of sleep consistently and significantly predict the risk Of the development Of type 2 diabetes. The mechanisms Underlying this relation may differ between short and long sleepers.

/pdf/quantity-and-quality-of-sleep-and-incidence-of-type-2-3arwq3xnbk.pdf

Quantity and Quality of Sleep and Incidence of Type 2 Diabetes A systematic review and meta-analysis

Amyloid-beta (Abeta) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease.

/pdf/amyloid-b-dynamics-are-regulated-by-orexin-and-the-sleep-2480ntt4gp.pdf

Amyloid-β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle

Drosophila exhibits a circadian rest-activity cycle, but it is not known whether fly rest constitutes sleep or is mere inactivity. It is shown here that, like mammalian sleep, rest in Drosophila is characterized by an increased arousal threshold and is homeostatically regulated independently of the circadian clock. As in mammals, rest is abundant in young flies, is reduced in older flies, and is modulated by stimulants and hypnotics. Several molecular markers modulated by sleep and waking in mammals are modulated by rest and activity in Drosophila, including cytochrome oxidase C, the endoplasmic reticulum chaperone protein BiP, and enzymes implicated in the catabolism of monoamines. Flies lacking one such enzyme, arylalkylamine N-acetyltransferase, show increased rest after rest deprivation. These results implicate the catabolism of monoamines in the regulation of sleep and waking in the fly and suggest that Drosophila may serve as a model system for the genetic dissection of sleep.

https://science.sciencemag.org/content/sci/287/5459/1834.full.pdf

Correlates of Sleep and Waking in Drosophila melanogaster

Sleep is controlled by two processes: a homeostatic drive that increases during waking and dissipates during sleep, and a circadian pacemaker that controls its timing1. Although these two systems can operate independently2,3, recent studies indicate a more intimate relationship4,5. To study the interaction between homeostatic and circadian processes in Drosophila, we examined homeostasis in the canonical loss-of-function clock mutants period (per01), timeless (tim01), clock (Clkjrk) and cycle (cyc01)6,7,8,9. cyc01 mutants showed a disproportionately large sleep rebound and died after 10 hours of sleep deprivation, although they were more resistant than other clock mutants to various stressors. Unlike other clock mutants, cyc01 flies showed a reduced expression of heat-shock genes after sleep loss. However, activating heat-shock genes before sleep deprivation rescued cyc01 flies from its lethal effects. Consistent with the protective effect of heat-shock genes, was the observation that flies carrying a mutation for the heat-shock protein Hsp83 (Hsp8308445)10 showed exaggerated homeostatic response and died after sleep deprivation. These data represent the first step in identifying the molecular mechanisms that constitute the sleep homeostat.

Stress response genes protect against lethal effects of sleep deprivation in Drosophila.

Sleep is believed to play an important role in memory consolidation. We induced sleep on demand by expressing the temperature-gated nonspecific cation channel Transient receptor potential cation channel (UAS-TrpA1) in neurons, including those with projections to the dorsal fan-shaped body (FB). When the temperature was raised to 31°C, flies entered a quiescent state that meets the criteria for identifying sleep. When sleep was induced for 4 hours after a massed-training protocol for courtship conditioning that is not capable of inducing long-term memory (LTM) by itself, flies develop an LTM. Activating the dorsal FB in the absence of sleep did not result in the formation of LTM after massed training.

https://science.sciencemag.org/content/sci/332/6037/1571.full.pdf

Inducing sleep by remote control facilitates memory consolidation in Drosophila.

Sleep is a vital, evolutionarily conserved phenomenon, whose function is unclear. Although mounting evidence supports a role for sleep in the consolidation of memories, until now, a molecular connection between sleep, plasticity, and memory formation has been difficult to demonstrate. We establish Drosophila as a model to investigate this relation and demonstrate that the intensity and/or complexity of prior social experience stably modifies sleep need and architecture. Furthermore, this experience-dependent plasticity in sleep need is subserved by the dopaminergic and adenosine 3',5'-monophosphate signaling pathways and a particular subset of 17 long-term memory genes.

https://science.sciencemag.org/content/sci/313/5794/1775.full.pdf

Waking Experience Affects Sleep Need in Drosophila

To ascertain the outcome of childhood vesico-ureteric reflux (VUR), 226 adults (37 males), mean age 27 years, were studied after 10–35 years, extended to 41 years by postal questionnaire in 161. At presentation (mean age 5 years) all had VUR (grade III–V in 68) and urinary tract infection (UTI); there was renal scarring in 85 (acquired before referral in 11 and during follow-up in 1), hypertension in 6 and impaired renal function in 5. They were managed and followed prospectively by one paediatrician; 63% of these children remained free from UTI; VUR persisted in 63 and had resolved in 69% of 193 children managed medically. At follow-up, 61% of adults had remained free from infection; 17 adults had hypertension and/or raised plasma creatinine, 16 with scarred kidneys. Their deterioration was predictable because of scar type, blood pressure or plasma creatinine levels in childhood. No new scars developed after puberty. Renal growth rates were unaffected by initial severity or persistence of VUR. On the later questionnaire, 9 further adults, mean age 38 years, had moderate hypertension. The adults with complications were those with extensive renal scarring and/or at least borderline hypertension in childhood. Those with VUR, but no scarring, and managed carefully in childhood, did not suffer serious consequences as adults. There is a need for early recognition and treatment of children with VUR and UTI to limit scar development.

Paul J. Shaw

Papers

Correlates of Sleep and Waking in Drosophila melanogaster

Stress response genes protect against lethal effects of sleep deprivation in Drosophila.

Inducing sleep by remote control facilitates memory consolidation in Drosophila.

Waking Experience Affects Sleep Need in Drosophila

Childhood reflux and urinary infection: a follow-up of 10-41 years in 226 adults.