The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in Drosophila

Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal Hmgcr expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode duration. We localized the pars intercerebralis (PI), equivalent to the mammalian hypothalamus, as the region within the fly brain requiring Hmgcr activity for proper sleep maintenance. Lack of Hmgcr expression in the PI insulin-producing cells recapitulates the sleep effects of pan-neuronal Hmgcr knockdown. Conversely, loss of Hmgcr in a different PI subpopulation, the corticotropin releasing factor (CRF) homologue-expressing neurons (DH44 neurons), increases sleep latency and decreases sleep duration. The requirement for Hmgcr activity in different neurons signifies its importance in sleep regulation. Interestingly, loss of Hmgcr in the PI does not affect circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock. Taken together, these findings suggest that Hmgcr activity in the PI is essential for proper sleep homeostasis in flies.

Stimulants and Depressor Drugs in the Sleep-Wake Cycle Modulation: The case of alcohol and cannabinoids

A complex neurobiological network drives the sleep-wake cycle. In addition, external stimuli, including stimulants or depressor drugs, also influence the control of sleep. Here we review the recent advances that contribute to the comprehensive understanding of the actions of stimulants and depressor compounds, such as alcohol and cannabis, in sleep regulation. The objective of this review is to highlight the neurobiological mechanism engaged by alcohol and cannabis in sleep control.

Insomnia: Therapy and Role of neurotransmitters

Insomnia is one of the most common sleep disorders which affects 30-40 percent of the adult population. The present article provides a combined review on prevalence, categories of insomnia, pathophysiology, role of neurotransmitter on sleep and different types of therapies for insomnia. From this review it was estimated that hormones like melatonin, cortisol, and others produced by the hypothalamic-pituitary-adrenal axis regulate the sleep-wake cycle. Disturbance of this cycle leads to insomnia. Furthermore, Neurotransmitter like GABA-Lglutamic acid, Acetylcholine, Norepinephrine, Dopamine, Serotonin, Steroids, Orexin, and Adenosine plays a major role in sleep regulation. Any alteration or disturbance in the neurotransmitter level affects sleep. It was concluded that Mechanism of action of almost all natural and synthetic derived drugs in regulation of neurotransmitters.

The Regulation of Sleep

The words “regulation” and “control” have different meanings. A rich literature exists on the control mechanisms of sleep—the genomic, molecular, cellular, and circuit processes responsible for arousal state changes and characteristics. The regulation of sleep refers to functions and homeostatic maintenance of those functions. Much less is known about sleep regulation than sleep control, largely because functions of sleep are still unknown. Regulation requires information about the regulated variable that can be used as feedback information to achieve optimal levels. The circadian timing of sleep is regulated, and the feedback information is entraining stimuli such as the light–dark cycle. Sleep itself is homeostatically regulated, as evidenced by sleep deprivation experiments. Eletroenceophalography (EEG) slow-wave activity (SWA) is regulated, and it appears that adenosine is the major source of feedback information, and that fact indicates an energetic function for sleep. The last aspect of sleep regulation discussed in this short article is the non-rapid eye movement (NREM) and rapid eye movement (REM) sleep cycling. Evidence is discussed that supports the argument that NREM sleep is in a homeostatic relationship with wake, and REM sleep is in a homeostatic relationship with NREM sleep.

Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep

Sleep is nearly ubiquitous throughout the animal kingdom, with deficiencies in sleep having been linked to a wide range of human disorders and diseases. While genome wide association studies (GWAS) in humans have been identified loci robustly associated with several heritable diseases or traits, little is known about the functional roles of the underlying causal variants in regulating sleep duration or quality. We applied an ATAC-seq/promoter focused Capture C methodology in iPSC-derived neural progenitors to carry out a variant-to-gene mapping campaign that identified 88 candidate sleep effector genes connected to relevant GWAS signals. To functionally validate the role of the implicated effector genes in sleep regulation, we performed a neuron-specific RNAi screen in the fruit fly, Drosophila melanogaster. This approach identified a number of genes that regulated sleep, including phosphatidylinositol N-acetylglucosaminyltransferase subunit Q (PIG-Q). This gene encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)-anchor biosynthesis. We show that flies deficient for PIG-Q have longer sleep during both the day and night due to an increase in the total number of sleep bouts. Subsequent systematic investigation of other PIG-family genes identified increased sleep in flies for multiple different genes within the PIG pathway. We then mutated the PIG-Q locus in zebrafish and identified similar increases in sleep to those observed in Drosophila, confirming deep homology of PIG-Q mediated sleep regulation. These results provide the first physical variant-to-gene mapping of human sleep genes, and reveals a novel and conserved role for GPI-anchor biosynthesis in sleep regulation.

Dopamine and GPCR-mediated modulation of DN1 clock neurons gates the circadian timing of sleep

The metronome-like circadian regulation of sleep timing must still adapt to an uncertain environment. Recent studies in Drosophila indicate that neuromodulation not only plays a key role in clock neuron synchronization but also affects interactions between the clock network and brain sleep centers. We show here that the targets of neuromodulators, G-Protein Coupled Receptors (GPCRs), are highly enriched in the fly brain circadian clock network. Single cell sequencing indicates that they are not only differentially expressed but also define clock neuron identity. We generated a comprehensive guide library to mutagenize individual GPCRs in specific neurons and verified the strategy with a targeted sequencing approach. Combined with a behavioral screen, the mutagenesis strategy revealed a novel role of dopamine in sleep regulation by identifying two dopamine receptors and a clock neuron subpopulation that gate the timing of sleep.

insomniac links the development and function of a sleep regulatory circuit

Although many genes are known to influence sleep, when and how they impact sleep-regulatory circuits remain ill-defined. Here we show that Insomniac (Inc), a conserved adaptor for the autism-associated Cul3 ubiquitin ligase, acts in a restricted period of neuronal development to impact sleep in adult Drosophila. The loss of inc causes structural and functional alterations within the mushroom body, a center for sensory integration, associative learning, and sleep regulation. In inc mutants, mushroom body neurons are produced in excess, develop anatomical defects that impede circuit assembly, and are unable to promote sleep when activated in adulthood. Our findings link neurogenesis and postmitotic development of sleep-regulatory neurons to their adult function and suggest that developmental perturbations of circuits that couple sensory inputs and sleep may underlie sleep dysfunction in neurodevelopmental disorders.

LKB1 Is Physiologically Required for Sleep from Drosophila to the Mouse

LKB1 is known as a master kinase for 14 kinases related to the adenosine monophosphate (AMP)-activated protein kinase (AMPK). Two of them (SIK3 and AMPKa;) have previously been implicated in sleep regulation. We generated loss-of-function (LOF) mutants for Lkb1 in both Drosophila and mice. Sleep was reduced in Lkb1-mutant flies and in flies with neuronal deletion of Lkb1. Sleep was reduced in mice after virally mediated reduction of Lkb1 in the brain. Electroencephalography (EEG) analysis showed that non-rapid eye movement (NREM) sleep and sleep need were both reduced in Lkb1-mutant mice. These results indicate that LKB1 plays a physiological role in sleep regulation conserved from flies to mice.