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High cognitive functioning could be a protective factor for school difficulties, behavioral and mood impairments in children with narcolepsy. To investigate this factor, we studied the intellectual abilities of 74 children with narcolepsy (43 boys, 11.7 years old at diagnosis, 91% of cataplexies, 64% obese, 100% HLA positive for DR-DQB1*06:02). All children underwent a one-night polysomnography followed by Multiple Sleep Latency Tests, an evaluation of intelligence quotient (IQ), and filled standardized questionnaires. Thirty-eight percent had high potentialities (HP defined by IQ &gt, 130) and 48% had school difficulties. Using non-parametric tests, we found that HP children reported less difficulties at school and tended to have less impulsivity, conduct, and learning disorders than those without HP. They also tended to be less obese and had less desaturation. Using a multivariate regression analysis, we found an association between the REM sleep percentage and the IQ. REM sleep could be involved in the dynamic changes contributing to the equilibrium of intellectual functioning. This study highlights that despite their frequent school difficulties, narcolepsy per se is unlikely to be a cause of intellectual disability in children. Prompt diagnosis and management of comorbidities such as obesity and obstructive sleep apnea (OSA) could improve cognitive and school performances in these children.

Background and Study Objectives: Flies mutant for the canonical clock protein cycle (cyc01) exhibit a sleep rebound that is ∼10 times larger than wild-type flies and die after only 10 h of sleep deprivation. Surprisingly, when starved, cyc01 mutants can remain awake for 28 h without demonstrating negative outcomes. Thus, we hypothesized that identifying transcripts that are differentially regulated between waking induced by sleep deprivation and waking induced by starvation would identify genes that underlie the deleterious effects of sleep deprivation and/or protect flies from the negative consequences of waking. Design: We used partial complementary DNA microarrays to identify transcripts that are differentially expressed between cyc01 mutants that had been sleep deprived or starved for 7 h. We then used genetics to determine whether disrupting genes involved in lipid metabolism would exhibit alterations in their response to sleep deprivation. Setting: Laboratory. Patients or Participants: Drosophila melanogaster. Interventions: Sleep deprivation and starvation. Measurements and Results: We identified 84 genes with transcript levels that were differentially modulated by 7 h of sleep deprivation and starvation in cyc 01 mutants and were confirmed in independent samples using quantitative polymerase chain reaction. Several of these genes were predicted to be lipid metabolism genes, including bubblegum, cueball, and CG4500, which based on our data we have renamed heimdall (hll ). Using lipidomics we confirmed that knockdown of hll using RNA interference significantly decreased lipid stores. Importantly, genetically modifying bubblegum, cueball, or hll resulted in sleep rebound alterations following sleep deprivation compared to genetic background controls. Conclusions: We have identified a set of genes that may confer resilience/vulnerability to sleep deprivation and demonstrate that genes involved in lipid metabolism modulate sleep homeostasis.

Although patients with primary insomnia experience sleep disruption, they are able to maintain normal performance on a variety of cognitive tasks. This observation suggests that insomnia may be a condition where predisposing factors simultaneously increase the risk for insomnia and also mitigate against the deleterious consequences of waking. To gain insight into processes that might regulate sleep and buffer neuronal circuits during sleep loss, we manipulated three genes, fat facet (faf), highwire (hiw) and the GABA receptor Resistance to dieldrin (Rdl), that were differentially modulated in a Drosophila model of insomnia. Our results indicate that increasing faf and decreasing hiw or Rdl within wake-promoting large ventral lateral clock neurons (lLNvs) induces sleep loss. As expected, sleep loss induced by decreasing hiw in the lLNvs results in deficits in short-term memory and increases of synaptic growth. However, sleep loss induced by knocking down Rdl in the lLNvs protects flies from sleep-loss induced deficits in short-term memory and increases in synaptic markers. Surprisingly, decreasing hiw and Rdl within the Mushroom Bodies (MBs) protects against the negative effects of sleep deprivation (SD) as indicated by the absence of a subsequent homeostatic response, or deficits in short-term memory. Together these results indicate that specific genes are able to disrupt sleep and protect against the negative consequences of waking in a circuit dependent manner.

Amyloid precursor protein (App) plays a crucial role in Alzheimer's disease via the production and deposition of toxic β-amyloid peptides. App is heavily expressed in neurons, the focus of the vast majority of studies investigating its function. Meanwhile, almost nothing is known about App's function in glia, where it is also expressed, and can potentially participate in the regulation of neuronal physiology. In this report, we investigated whetherAppl, theDrosophilahomolog ofApp, could influence sleep–wake regulation when its function is manipulated in glial cells.Applinhibition in astrocyte-like and cortex glia resulted in higher sleep amounts and longer sleep bout duration during the night, while overexpression had the opposite effect. These sleep phenotypes were not the result of developmental defects, and were correlated with changes in expression in glutamine synthetase (GS) in astrocyte-like glia and in changes in the gap-junction component innexin2 in cortex glia. Downregulating both GS and innexin2, but not either one individually, resulted in higher sleep amounts, similarly toApplinhibition. Consistent with these results, the expression of GS and innexin2 are increased following sleep deprivation, indicating that GS and innexin2 genes are dynamically linked to vigilance states. Interestingly, the reduction of GS expression and the sleep phenotype observed uponApplinhibition could be rescued by increasing the expression of the glutamate transporter dEaat1. In contrast, reducing dEaat1 expression severely disrupted sleep. These results associate glutamate recycling, sleep, and a glial function for the App family proteins.SIGNIFICANCE STATEMENTThe amyloid precursor protein (App) has been intensively studied for its implication in Alzheimer's disease (AD). The attributed functions of App are linked to the physiology and cellular biology of neurons where the protein is predominantly expressed. Consequences on glia in AD are generally thought to be secondary effects of the pathology in neurons. Researchers still do not know whether App plays a role in glia in nonpathological conditions. We report here that glial App plays a role in physiology and in the regulation of sleep/wake, which has been shown recently to be involved in AD pathology. These results also associate glutamate recycling and sleep regulation, adding further complexity to the physiological role of App and to its implication in AD.

Although it is widely accepted that sleep must serve an essential biological function, little is known about molecules that underlie sleep regulation. Given that insomnia is a common sleep disorder that disrupts the ability to initiate and maintain restorative sleep, a better understanding of its molecular underpinning may provide crucial insights into sleep regulatory processes. Thus, we created a line of flies using laboratory selection that share traits with human insomnia. After 60 generations,insomnia-like(ins-l) flies sleep 60 min a day, exhibit difficulty initiating sleep, difficulty maintaining sleep, and show evidence of daytime cognitive impairment.ins-lflies are also hyperactive and hyperresponsive to environmental perturbations. In addition, they have difficulty maintaining their balance, have elevated levels of dopamine, are short-lived, and show increased levels of triglycerides, cholesterol, and free fatty acids. Although their core molecular clock remains intact,ins-lflies lose their ability to sleep when placed into constant darkness. Whole-genome profiling identified genes that are modified inins-lflies. Among those differentially expressed transcripts, genes involved in metabolism, neuronal activity, and sensory perception constituted over-represented categories. We demonstrate that two of these genes are upregulated in human subjects after acute sleep deprivation. Together, these data indicate that theins-lflies are a useful tool that can be used to identify molecules important for sleep regulation and may provide insights into both the causes and long-term consequences of insomnia.

Study Objectives: Several lines of evidence indicate that sleep plays a critical role in learning and memory. The aim of this study was to evaluate anesthesia resistant memory following sleep deprivation in Drosophila. Design: Four to 16 h after aversive olfactory training, flies were sleep deprived for 4 h. Memory was assessed 24 h after training. Training, sleep deprivation, and memory tests were performed at different times during the day to evaluate the importance of the time of day for memory formation. The role of circadian rhythms was further evaluated using circadian clock mutants. Results: Memory was disrupted when flies were exposed to 4 h of sleep deprivation during the consolidation phase. Interestingly, normal memory was observed following sleep deprivation when the memory test was performed during the 2 h preceding lights-off, a period characterized by maximum wake in flies. We also show that anesthesia resistant memory was less sensitive to sleep deprivation in flies with disrupted circadian rhythms. Conclusions: Our results indicate that anesthesia resistant memory, a consolidated memory less costly than long-term memory, is sensitive to sleep deprivation. In addition, we provide evidence that circadian factors influence memory vulnerability to sleep deprivation and memory retrieval. Taken together, the data show that memories weakened by sleep deprivation can be retrieved if the animals are tested at the optimal circadian time.

PARKINSON DISEASE (PD) RESULTS IN THE PROGRESSIVE LOSS OF DOPAMINERGIC NEURONS AND IS ASSOCIATED WITH MOTOR DEFICITS INCLUDING bradykinesia, rigidity, and loss of postural reflexes. In addition, many PD patients develop cognitive deficits eventually leading to dementia, thus significantly increasing the personal and socioeconomic burden of the disease.1 Cognitive impairments occur both at the early and late stages of the disease, independently of depression and dementia.2 These impairments are well documented and predominantly affect prefrontal cortex and dopamine dependent executive functions including working memory, response inhibition, and behavioral flexibility.3,4 Poorer cognitive performance correlates with increased severity of the motor deficits, indicating that they may share a similar etiology.5 In addition to motor and cognitive deficits, sleep abnormalities are highly prevalent in PD (> 74% of patients).6–9 Sleep disturbances are both a primary feature of the disease and a secondary consequence of medications, tremor, rigidity, and bradykinesia. Primary sleep disturbances include excessive daytime sleepiness and REM sleep behavior disorder (RBD). RBD may predate the motor symptoms by many years,10 can predict cognitive impairment,11 and is associated with dementia.12 In addition, PD patients present narcolepsy-like symptoms that appear to be associated with a substantial loss of hypocretin neurons.13 Secondary sleep disturbances include insomnia, sleep fragmentation, restless legs syndrome, and sleep apnea.14 Multiple lines of evidence in both mammals and flies indicate important interactions between sleep and dopaminergic systems.15–22 For example, in healthy adult wild-type flies, sleep deprivation results in an increase in dopamine levels, a reduction in dopamine D1-receptor (dDA1) mRNA and learning impairments that are recovered following a brief 2-h nap.21 A similar process affecting the D2/D3 receptor has been reported in sleep deprived humans.22 Importantly, dopaminergic transmission plays a critical role in regulating sleep following environmental manipulations associated with brain plasticity.23 Although increased dopamine may facilitate plastic processes in the healthy adult, an acute change in dopamine signaling during critical windows of plasticity in dopaminergic circuits may result in long-lasting decrements in learning and other adaptive behaviors that persist when normal dopamine levels are restored.24 Together, these observations raise the possibility that sleep deprivation, by affecting the function of dopaminergic systems,21 may be particularly deleterious during degenerative processes that alter dopamine signaling such as PD. Drosophila, with the availability of models recapitulating many features of PD, and the ease of manipulating and monitoring sleep, appears well suited to address this question.. Using the GAL4-UAS system25 human α-synuclein can be expressed throughout the nervous system of the adult fly. Flies expressing α-synuclein (αS flies) reproduce key symptoms of human PD: age dependent and progressive disruption of selective dopaminergic neuronal groups, motor dysfunction responsive to dopaminergic treatment, and formation of Lewy body-like protein inclusions.26,27 To evaluate the consequences of sleep deprivation in αS flies, a functional readout of dopaminergic systems that is relevant to the deficits observed in PD is required. Since cognitive impairments appearing early in PD affect executive functioning,3 we chose to evaluate short-term memory and response inhibition in αS flies, using aversive phototaxis suppression (APS).28 Here we show that at an intermediate stage of the pathology, a single sleep deprivation challenge results in persistent short-term memory defects in αS flies. To explore possible mechanisms underlying these impairments, we evaluated dopaminergic neuron numbers using whole brain immunohistochemistry and mRNA levels of genes involved in dopamine signaling. We found that learning impairments are prevented when αS flies are administered a D1 antagonist during sleep deprivation suggesting that the deficits are due to an extended activation of D1-like receptors. Finally, we report that flies fed curcumin, a compound known to protect against the neurotoxic effects of 6-hydroxydopamine in rats29 and inhibit the formation of α-synuclein aggregates,30 prevents sleep deprivation induced impairments in short-term memory in αS flies.

Individuals frequently find themselves confronted with a variety of challenges that threaten their wellbeing. While some individuals face these challenges efficiently and thrive (resilient) others are unable to cope and may suffer persistent consequences (vulnerable). Resilience/vulnerability to sleep disruption may contribute to the vulnerability of individuals exposed to challenging conditions. With that in mind we exploited individual differences in a fly's ability to form short-term memory (STM) following 3 different types of sleep disruption to identify the underlying genes. Our analysis showed that in each category of flies examined, there are individuals that form STM in the face of sleep loss (resilient) while other individuals show dramatic declines in cognitive behavior (vulnerable). Molecular genetic studies revealed that Antimicrobial Peptides, factors important for innate immunity, were candidates for conferring resilience/vulnerability to sleep deprivation. Specifically, Metchnikowin (Mtk), drosocin (dro) and Attacin (Att) transcript levels seemed to be differentially increased by sleep deprivation in glia (Mtk), neurons (dro) or primarily in the head fat body (Att). Follow-up genetic studies confirmed that expressing Mtk in glia but not neurons, and expressing dro in neurons but not glia, disrupted memory while modulating sleep in opposite directions. These data indicate that various factors within glia or neurons can contribute to individual differences in resilience/vulnerability to sleep deprivation.

Hypocretins (Hcrts) are two secreted neuropeptides, hypocretin-1 and hypocretin-2 that are cleaved from a prepropetide precursor. The locus coeruleus (LC) is adjacent to the fourth ventricle in the brainstem and contains neurons that synthetize the monoamine norepinephrine. Interestingly, physical lesions of the LC do not elicit consistent changes in cortical EEG or behavioral indices of arousal. Optogenetics is a technology in which a genetically encoded neuromodulatory actuator(s) is expressed in a targeted cell type of interest and activated by a specific wavelength of light. Optogenetics has allowed us to make major advances in our understanding of the Hcrt and LC systems, and this technology is applied to dissect other arousal systems as well. The ability to target and selectively manipulate Hcrt and LC neurons allows us the opportunity to study these nuclei in different contexts including rodent models of food intake, addiction, stress, attention, and male sexual arousal.

Study objectives Novel, safe, and efficient hypnotic compounds capable of enhancing physiological sleep are still in great demand in the therapy of insomnia. This study compares the sleep-wake effects of a new α1 GABA(A) receptor subunit ligand, GF-015535-00, with those of zolpidem, the widely utilized hypnotic compound. Methods Nine C57Bl6/J male mice were chronically implanted with electrodes for EEG and sleep-wake monitoring. Each mouse received 3 doses of GF-015535-00 and zolpidem. Time spent in sleep-wake states and cortical EEG power spectra were analyzed. Results Both zolpidem and GF-015535-00 prominently enhanced slow wave sleep and paradoxical sleep in the mouse. However, as compared with zolpidem, GF-015535-00 showed several important differences: (1) a comparable sleep-enhancing effect was obtained with a 10 fold smaller dose; (2) the induced sleep was less fragmented; (3) the risk of subsequent wake rebound was less prominent; and (4) the cortical EEG power ratio between slow wave sleep and wake was similar to that of natural sleep and thus compatible with physiological sleep. Conclusion The characteristics of the sleep-wake effects of GF-015535-00 in mice could be potentially beneficial for its use as a therapeutic compound in the treatment of insomnia. Further investigations are required to assess whether the same characteristics are conserved in other animal models and humans.

Study Objectives: Multiple lines of evidence indicate that sleep is important for the developing brain, although little is known about which cellular and molecular pathways are affected. Thus, the aim of this study was to determine whether the early adult life of Drosophila, which is associated with high amounts of sleep and critical periods of brain plasticity, could be used as a model to identify developmental processes that require sleep. Subjects: Wild type Canton-S Drosophila melanogaster. Design; Intervention: Flies were sleep deprived on their first full day of adult life and allowed to recover undisturbed for at least 3 days. The animals were then tested for short-term memory and response-inhibition using aversive phototaxis suppression (APS). Components of dopamine signaling were further evaluated using mRNA profiling, immunohistochemistry, and pharmacological treatments. Measurements and Results: Flies exposed to acute sleep deprivation on their first day of life showed impairments in short-term memory and response inhibition that persisted for at least 6 days. These impairments in adult performance were reversed by dopamine agonists, suggesting that the deficits were a consequence of reduced dopamine signaling. However, sleep deprivation did not impact dopaminergic neurons as measured by their number or by the levels of dopamine, pale (tyrosine hydroxylase), dopadecarboxylase, and the Dopamine transporter. However, dopamine pathways were impacted as measured by increased transcript levels of the dopamine receptors D2R and dDA1. Importantly, blocking signaling through the dDA1 receptor in animals that were sleep deprived during their critical developmental window prevented subsequent adult learning impairments. Conclusions: These data indicate that sleep plays an important and phylogenetically conserved role in the developing brain.

Starvation, which is common in the wild, appears to initiate a genetic program that allows fruitflies to remain awake without the sleepiness and cognitive impairments that typically follow sleep deprivation., Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. Recently, two genes, brummer (bmm) and Lipid storage droplet 2 (Lsd2), have been shown to modulate the response to starvation. bmm mutants have excess fat and are resistant to starvation, whereas Lsd2 mutants are lean and sensitive to starvation. Thus, we hypothesized that bmm and Lsd2 may play a role in sleep regulation. Indeed, bmm mutant flies display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking., Author Summary It is well established in humans that sleep deficits lead to adverse outcomes, including cognitive impairments and an increased risk for obesity. Given the relationship between sleep and lipid stores, we hypothesized that metabolic pathways play a role in sleep regulation and contribute to deficits induced by sleep loss. Since starvation has a large impact on metabolic pathways and is an environmental condition that is encountered by animals living in the wild, we examined its effects on sleep in the fruit fly Drosophila melanogaster. Interestingly, when flies are starved they display an immediate increase in waking. However, in contrast to sleep deprivation, waking induced by starvation does not result in increased sleepiness or impairments in short-term memory. To identify the mechanisms underlying these processes, we evaluated mutants for genes that have been shown to alter an animal's response to starvation. Interestingly, brummer mutants, which are fat, show an exaggerated response to sleep loss. In contrast, mutants for Lipid storage droplet 2 are lean and are able to stay awake without becoming sleepy or showing signs of cognitive impairment. These results indicate that while sleep loss can alter lipids, lipid enzymes may, in turn, play a role in regulating sleep and influence the response to sleep deprivation.

Background: Extended wakefulness disrupts acquisition of short-term memories in mammals. However, the underlying molecular mechanisms triggered by extended waking and restored by sleep are unknown. Moreover, the neuronal circuits that depend on sleep for optimal learning remain unidentified. Results: Learning was evaluated with aversive phototaxic suppression. In this task, flies learn to avoid light that is paired with an aversive stimulus (quinine-humidity). We demonstrate extensive homology in sleep-deprivation-induced learning impairment between flies and humans. Both 6 hr and 12 hr of sleep deprivation are sufficient to impair learning in Canton-S (Cs) flies. Moreover, learning is impaired at the end of the normal waking day in direct correlation with time spent awake. Mechanistic studies indicate that this task requires intact mushroom bodies (MBs) and requires the dopamine D1-like receptor (dDA1). Importantly, sleep-deprivation-induced learning impairments could be rescued by targeted gene expression of the dDA1 receptor to the MBs. Conclusions: These data provide direct evidence that extended wakefulness disrupts learning in Drosophila. These results demonstrate that it is possible to prevent the effects of sleep deprivation by targeting a single neuronal structure and identify cellular and molecular targets adversely affected by extended waking in a genetically tractable model organism.

Summary The role of the transmembrane receptor Notch in the adult brain is poorly understood. Here, we provide evidence that bunched , a negative regulator of Notch , is involved in sleep homeostasis. Genetic evidence indicates that interfering with bun c hed activity in the mushroom bodies (MBs) abolishes sleep homeostasis. Combining bunched and Delta loss-of-function mutations rescues normal homeostasis, suggesting that Notch signaling may be involved in regulating sensitivity to sleep loss. Preventing the downregulation of Delta by overexpressing a wild-type transgene in MBs reduces sleep homeostasis and, importantly, prevents learning impairments induced by sleep deprivation. Similar resistance to sleep loss is observed with Notch spl-1 gain-of-function mutants. Immunohistochemistry reveals that the Notch receptor is expressed in glia, whereas Delta is localized in neurons. Importantly, the expression in glia of the intracellular domain of Notch , a dominant activated form of the receptor, is sufficient to prevent learning deficits after sleep deprivation. Together, these results identify a novel neuron-glia signaling pathway dependent on Notch and regulated by bunched . These data highlight the emerging role of neuron-glia interactions in regulating both sleep and learning impairments associated with sleep loss.