Don't sleep now, sleep later. Fly study related to insomnia.

Belfer SJ, Bashaw AG, Perlis ML, Kayser MS. A Drosophila model of sleep restriction therapy for insomnia. Mol Psychiatry. 2019 Mar 1. PMID: 30824866.

From the abstract: "Insomnia is the most common sleep disorder among adults ... Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia; a key component of this intervention is restriction of sleep opportunity, which optimizes matching of sleep ability and opportunity, leading to enhanced sleep drive. Despite the well-documented efficacy of CBT-I, little is known regarding how CBT-I works at a cellular and molecular level to improve sleep ... Here, guided by human behavioral sleep therapies, we developed a Drosophila model for sleep restriction therapy (SRT) of insomnia. We demonstrate that restriction of sleep opportunity through manipulation of environmental cues improves sleep efficiency in multiple short-sleeping Drosophila mutants. The response to sleep opportunity restriction requires ongoing environmental inputs, but is independent of the molecular circadian clock. We apply this sleep opportunity restriction paradigm to aging and Alzheimer's disease fly models, and find that sleep impairments in these models are reversible with sleep restriction, with associated improvement in reproductive fitness and extended lifespan. This work establishes a model to investigate the neurobiological basis of CBT-I, and provides a platform that can be exploited toward novel treatment targets for insomnia."

Exploration of sleep in a fly model related to schizophrenia

Nagy S, Maurer GW, Hentze JL, Rose M, Werge TM, Rewitz K. AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance. PLoS Genet. 2018 Dec 19;14(12):e1007623. PMID: 30566533; PMCID: PMC6317821.

Abstract: "The human 1q21.1 deletion of ten genes is associated with increased risk of schizophrenia. This deletion involves the β-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell. Although neurons have a high demand for energy and low capacity to store nutrients, the role of AMPK in neuronal physiology is poorly defined. Here we show that AMPK is important in the nervous system for maintaining neuronal integrity and for stress survival and longevity in Drosophila. To understand the impact of this signaling system on behavior and its potential contribution to the 1q21.1 deletion syndrome, we focused on sleep, an important role of which is proposed to be the reestablishment of neuronal energy levels that are diminished during energy-demanding wakefulness. Sleep disturbances are one of the most common problems affecting individuals with psychiatric disorders. We show that AMPK is required for maintenance of proper sleep architecture and for sleep recovery following sleep deprivation. Neuronal AMPKβ loss specifically leads to sleep fragmentation and causes dysregulation of genes believed to play a role in sleep homeostasis. Our data also suggest that AMPKβ loss may contribute to the increased risk of developing mental disorders and sleep disturbances associated with the human 1q21.1 deletion."

Circadian rhythms, Parkinson's disease, and fruit fly research

De Lazzari F, Bisaglia M, Zordan MA, Sandrelli F. Circadian Rhythm Abnormalities in Parkinson's Disease from Humans to Flies and Back. Int J Mol Sci. 2018 Dec 6;19(12). pii: E3911. PMID: 30563246.

From the abstract: "Clinical and research studies have suggested a link between Parkinson's disease (PD) and alterations in the circadian clock. Drosophila melanogaster may represent a useful model to study the relationship between the circadian clock and PD. ... Here, we describe the fly circadian and dopaminergic systems and report recent studies which indicate the presence of circadian abnormalities in some fly PD genetic models. We discuss the use of Drosophila to investigate whether, in adults, the disruption of the circadian system might be causative of brain neurodegeneration. We also consider approaches using Drosophila, which might provide new information ... As a corollary, ... we suggest that genetic models of PD could be used to perform lifelong screens for drug-modulators of general and/or circadian-related PD traits."

Preprint: "A Drosophila Model for Behavioral Sleep Modification"

BioRxiv Preprint: "A Drosophila Model for Behavioral Sleep Modification"
Samuel J Belfer, Alexander G Bashaw, Michael L Perlis, Matthew S Kayser

doi: https://doi.org/10.1101/391375

URL: https://www.biorxiv.org/content/early/2018/08/13/391375

From the abstract: "Insomnia is the most common sleep disorder among adults, especially affecting individuals of advanced age or with neurodegenerative disease. ... Cognitive Behavioral Therapy for Insomnia (CBT-I) is the first-line treatment for insomnia ... Despite the well-documented efficacy of CBT-I, little is known regarding how CBT-I works at a cellular and molecular level ... Here, guided by human behavioral sleep therapies, we developed a Drosophila model for behavioral modification of sleep. ... We apply this sleep opportunity restriction paradigm to aging and Alzheimer's disease fly models, and find that sleep impairments in these models are reversible with sleep restriction ... This work establishes a model to investigate the neurobiological basis of CBT-I, and provides a platform that can be exploited towards novel treatment targets for insomnia."

Review on how fly and worm studies are helping to elucidate mechanisms that how sleep is induced by sickness

Davis KC, Raizen DM. A mechanism for sickness sleep: lessons from invertebrates. J Physiol. 2017 Aug 15;595(16):5415-5424. PMID: 28028818; PubMed Central PMCID: PMC5556163.

From the abstract: "During health, animal sleep is regulated by an internal clock and by the duration of prior wakefulness. During sickness, sleep is regulated by cytokines released from either peripheral cells or from cells within the nervous system. These cytokines regulate central nervous system neurons to induce sleep. Recent research in the invertebrates Caenorhabditis elegans and Drosophila melanogaster has led to new insights into the mechanism of sleep during sickness. ... We will here review key findings that have elucidated the central neuroendocrine mechanism of sleep during sickness. ... We speculate that these mechanisms may play a maladaptive role in human pathological conditions such as in the fatigue and anorexia associated with autoimmune diseases, with major depression, and with unexplained chronic fatigue."

Nobel Prize to Drosophila researchers

The Nobel Prize for physiology or medicine 2017 has been awarded to three Drosophila researchers, J.C. Hall, M. Rosbash, and M.W. Young, for their work uncovering molecular mechanisms of circadian rhythms. Read more at the the Nobel Prize website.

Review -- Relevance of circadian rhythm gene Timeless to human health and disease

Mazzoccoli G, Laukkanen MO, Vinciguerra M, Colangelo T, Colantuoni V. A Timeless Link Between Circadian Patterns and Disease. Trends Mol Med. 2016 Jan;22(1):68-81. PMID: 26691298.

From the abstract: "The Timeless (Tim) gene, originally identified in Drosophila melanogaster and subsequently in mammals, is involved in the molecular clockwork that drives 24h periodicity in physiology and behavior. The Tim protein is ... a multifaceted factor implicated in the maintenance of many cellular processes, tissue functions, and ultimately homeostasis of various organisms, from insects to humans. This review highlights the current knowledge of Tim functions, especially the most recent achievements, and illustrates the possible roles that this factor plays in the physiological preservation of health, as well as in the pathogenic mechanisms of related diseases."

Flies and sleep and neuronal diseases -- review

Zordan MA, Sandrelli F. Circadian Clock Dysfunction and Psychiatric Disease: Could Fruit Flies have a Say? Front Neurol. 2015 Apr 20;6:80. PMID: 25941512; PMCID: PMC4403521.

From the abstract: "There is evidence of a link between the circadian system and psychiatric diseases. ... Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here, we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. ... We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease."

Review of Drosophila a model for neuropsychopharmacology-related research

Narayanan AS, Rothenfluh A. I Believe I Can Fly!: Use of Drosophila as a Model Organism in Neuropsychopharmacology Research. Neuropsychopharmacology. 2015 Oct 30. PMID: 26576740.

From the abstract:  "... Here, we outline why we study an invertebrate organism in the context of neuropsychiatric disorders, and we discuss how we can gain insight from studies in Drosophila. ... Highlighting some translational examples, we underline the fact that their brains works more like ours than one would have anticipated."

Their Fig. 1 provides a nice graphical summary of translational approaches.

Sleep-deprived and feeling it: new use of fly as a model of sleep deprivation-related seizures

Lucey BP, Leahy A, Rosas R, Shaw PJ. A new model to study sleep deprivation-induced seizure. Free online at Sleep. 2015 May 1;38(5):777-85. PMID: 25515102.

NPR Morning Edition segment on fruit fly research and sleep

Review--Drosophila as a model for study of sleep disorders

Donelson NC, Sanyal S. Use of Drosophila in the investigation of Sleep Disorders. Exp Neurol. 2015 Jul 6. pii: S0014-4886(15)30034-0. PMID: 26160555.

From the abstract: "Genetic underpinnings for sleep disorders in humans remain poorly identified, investigated and understood. ... On the other hand, there have been steady and remarkable developments in the investigation of sleep using model organisms such as Drosophila. ... Here, we discuss the opportunities and limitations of studying sleep disorders in Drosophila and propose that a greater convergence of basic sleep research in model organisms and human genetics should catalyze better understanding of sleep disorders and generate viable therapeutic options."

Review discusses possibility of fly as a model for study of relationships between sleep and psychiatric disease

Zordan MA, Sandrelli F. Circadian Clock Dysfunction and Psychiatric Disease: Could Fruit Flies have a Say? Front Neurol. 2015 Apr 20;6:80. PMID: 25941512.

From the abstract: "… We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors. We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease."

Fly model of sleep-related seizures

Lucey BP, Leahy A, Rosas R, Shaw PJ. A New Model to Study Sleep Deprivation-Induced Seizure. Sleep. 2014 Nov 9. pii: sp-00337-14. PMID: 25515102.

From the abstract: "... Sleep deprivation increased seizure susceptibility in adult sesB^9ed4/+ and sei^ts1 mutants. Sleep deprivation also increased seizure susceptibility when sesB was disrupted using RNAi. The effect of sleep deprivation on seizure activity was reduced when sesB^9ed4/+ flies were given the anti-seizure drug, valproic acid. ... These findings show that Drosophila is a model organism for investigating the relationship between sleep and seizure activity."

Fly assay helps confirm relevance of ANK3 disruptions to neurodevelopmental disorders. Recent report.

Iqbal Z, Vandeweyer G, van der Voet M, Waryah AM, Zahoor MY, Besseling JA, Roca LT, Vulto-van Silfhout AT, Nijhof B, Kramer JM, Van der Aa N, Ansar M, Peeters H, Helsmoortel C, Gilissen C, Vissers LE, Veltman JA, de Brouwer AP, Frank Kooy R, Riazuddin S, Schenck A, van Bokhoven H, Rooms L. Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Hum Mol Genet. 2013 May 15;22(10):1960-70. PMID: 23390136.

From the abstract:  "... The causality of ANK3 mutations in the two families and the role of the gene in cognitive function were supported by memory defects in a Drosophila knockdown model. ...

Fly models of sleep disorders. Recent review.

Freeman AA, Syed S, Sanyal S. Modeling the genetic basis for human sleep disorders in Drosophila. Commun Integr Biol. 2013 Jan 1;6(1):e22733. PMID: 23802043.

From the abstract: "Sleep research in Drosophila is ... making impressive strides towards helping us understand the biological basis for and the purpose of sleep ..."