An inherited life-threatening arrhythmia model established by screening randomly mutagenized mice.

Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite progress in the development of devices to prevent SCDs, the precise molecular mechanisms that induce detrimental arrhythmias remain to be fully investigated, and more effective therapies are desirable. In the present study, we screened a large-scale randomly mutagenized mouse library by electrocardiography to establish a disease model of IASs and consequently found one pedigree that exhibited spontaneous ventricular arrhythmias (VAs) followed by SCD within 1 y after birth. Genetic analysis successfully revealed a missense mutation (p.I4093V) of the ryanodine receptor 2 gene to be a cause of the arrhythmia. We found an age-related increase in arrhythmia frequency accompanied by cardiomegaly and decreased ventricular contractility in the Ryr2I4093V/+ mice. Ca2+ signaling analysis and a ryanodine binding assay indicated that the mutant ryanodine receptor 2 had a gain-of-function phenotype and enhanced Ca2+ sensitivity. Using this model, we detected the significant suppression of VA following flecainide or dantrolene treatment. Collectively, we established an inherited life-threatening arrhythmia mouse model from an electrocardiogram-based screen of randomly mutagenized mice. The present IAS model may prove feasible for use in investigating the mechanisms of SCD and assessing therapies.

Neuronal subtype-specific transcriptomic changes in the cerebral neocortex associated with sleep pressure.

Sleep is homeostatically regulated by sleep pressure, which increases during wakefulness and dissipates during sleep. Recent studies have suggested that the cerebral neocortex, a six-layered structure composed of various layer- and projection-specific neuronal subtypes, is involved in the representation of sleep pressure governed by transcriptional regulation. Here, we examined the transcriptomic changes in neuronal subtypes in the neocortex upon increased sleep pressure using single-nucleus RNA sequencing datasets and predicted the putative intracellular and intercellular molecules involved in transcriptome alterations. We revealed that sleep deprivation (SD) had the greatest effect on the transcriptome of layer 2 and 3 intratelencephalic (L2/3 IT) neurons among the neocortical glutamatergic neuronal subtypes. The expression of mutant SIK3 (SLP), which is known to increase sleep pressure, also induced profound changes in the transcriptome of L2/3 IT neurons. We identified Junb as a candidate transcription factor involved in the alteration of the L2/3 IT neuronal transcriptome by SD and SIK3 (SLP) expression. Finally, we inferred putative intercellular ligands, including BDNF, LSAMP, and PRNP, which may be involved in SD-induced alteration of the transcriptome of L2/3 IT neurons. We suggest that the transcriptome of L2/3 IT neurons is most impacted by increased sleep pressure among neocortical glutamatergic neuronal subtypes and identify putative molecules involved in such transcriptional alterations.

A novel GABAergic population in the medial vestibular nucleus maintains wakefulness and gates rapid eye movement sleep.

Body rocking can either induce sleep or arousal. That is, the vestibular sense influences sleep-wake states. Neuronal interactions between sleep-wake systems and vestibular systems, however, remain unclear. In this study, we found that GABAergic neurons in the lateral part of the medial vestibular nucleus (LMVN), a primary vestibular afferent projection site, control sleep-wake states. Specific inhibition of LMVN GABAergic neurons revealed that the firing of LMVN GABAergic neurons underlies stable wakefulness and smooth transitions from non-rapid-eye-movement (NREM) sleep to rapid eye movement (REM) sleep and that LMVN GABAergic neurons do not affect body balance control in freely moving conditions. Selective axonal tracing of LMVN GABAergic neurons indicated that LMVN GABAergic neurons send axons not only to areas involved in vestibular and oculomotor functions but also to areas regulating sleep-wake states. Our findings suggest that LMVN GABAergic neurons stabilize wakefulness and gate the entry into REM sleep through the use of vestibular information.

Crucial role of TFAP2B in the nervous system for regulating NREM sleep.

The AP-2 transcription factors are crucial for regulating sleep in both vertebrate and invertebrate animals. In mice, loss of function of the transcription factor AP-2ß (TFAP2B) reduces non-rapid eye movement (NREM) sleep. When and where TFAP2B functions, however, is unclear. Here, we used the Cre-loxP system to generate mice in which Tfap2b was specifically deleted in the nervous system during development and mice in which neuronal Tfap2b was specifically deleted postnatally. Both types of mice exhibited reduced NREM sleep, but the nervous system-specific deletion of Tfap2b resulted in more severe sleep phenotypes accompanied by defective light entrainment of the circadian clock and stereotypic jumping behavior. These findings indicate that TFAP2B in postnatal neurons functions at least partly in sleep regulation and imply that TFAP2B also functions either at earlier stages or in additional cell types within the nervous system.

Validation of sleep-staging accuracy for an in-home sleep electroencephalography device compared with simultaneous polysomnography in patients with obstructive sleep apnea.

Efforts to simplify standard polysomnography (PSG) in laboratories, especially for obstructive sleep apnea (OSA), and assess its agreement with portable electroencephalogram (EEG) devices are limited. We aimed to evaluate the agreement between a portable EEG device and type I PSG in patients with OSA and examine the EEG-based arousal index's ability to estimate apnea severity. We enrolled 77 Japanese patients with OSA who underwent simultaneous type I PSG and portable EEG monitoring. Combining pulse rate, oxygen saturation (SpO2), and EEG improved sleep staging accuracy. Bland-Altman plots, paired t-tests, and receiver operating characteristics curves were used to assess agreement and screening accuracy. Significant small biases were observed for total sleep time, sleep latency, awakening after falling asleep, sleep efficiency, N1, N2, and N3 rates, arousal index, and apnea indexes. All variables showed > 95% agreement in the Bland-Altman analysis, with interclass correlation coefficients of 0.761-0.982, indicating high inter-instrument validity. The EEG-based arousal index demonstrated sufficient power for screening AHI ≥ 15 and ≥ 30 and yielded promising results in predicting apnea severity. Portable EEG device showed strong agreement with type I PSG in patients with OSA. These suggest that patients with OSA may assess their condition at home.

Association between idiopathic hypersomnia and a genetic variant in the PER3 gene.

We aim to identify genetic markers associated with idiopathic hypersomnia, a disabling orphan central nervous system disorder of hypersomnolence that is still poorly understood. In our study, DNA was extracted from 79 unrelated patients diagnosed with idiopathic hypersomnia with long sleep time at the National Reference Center for Narcolepsy-France according to very stringent diagnostic criteria. Whole exome sequencing on the first 30 patients with idiopathic hypersomnia (25 females and 5 males) allowed the single nucleotide variants to be compared with a control population of 574 healthy subjects from the French Exome project database. We focused on the identification of genetic variants among 182 genes related to the regulation of sleep and circadian rhythm. Candidate variants obtained by exome sequencing analysis were then validated in a second sample of 49 patients with idiopathic hypersomnia (37 females and 12 males). Our study characterised seven variants from six genes significantly associated with idiopathic hypersomnia compared with controls. A targeted sequencing analysis of these seven variants on 49 other patients with idiopathic hypersomnia confirmed the relative over-representation of the A➔C variant of rs2859390, located in a potential splicing-site of PER3 gene. Our findings support a genetic predisposition and identify pathways involved in the pathogeny of idiopathic hypersomnia. A variant of the PER3 gene may predispose to idiopathic hypersomnia with long sleep time.

Association between electroencephalogram-based sleep characteristics and physical health in the general adult population.

We examined the associations between electroencephalogram (EEG)-based sleep characteristics and physical health parameters in general adults via a cross-sectional study recruiting 100 volunteers aged 30-59 years. Sleep characteristics were measured at home using a portable multichannel electroencephalography recorder. Using the k-means + + clustering method, according to 10 EEG-based parameters, participants were grouped into better (n = 39), middle (n = 46), and worse (n = 15) sleep groups. Comparing 50 physical health parameters among the groups, we identified four signals of difference (P < 0.05), including systolic (sBP) and diastolic blood pressure (dBP), γ-glutamyl transpeptidase (γ-GTP), and serum creatinine, where sBP reached a Bonferroni-corrected threshold (P < 0.001). The sBP was higher by 7.9 (95% confidence interval 1.9-13.9) and 15.7 (7.3-24.0) mmHg before adjustment and 5.4 (- 0.1-10.9) and 8.7 (1.1-16.3) mmHg after adjustment for age, sex, body mass index, smoking, drinking habits, and 3% oxygen desaturation index in the middle and worse sleep groups, respectively, than in the better group. As another approach, among 500 combinations of EEG-based and physical health parameters, there were 45 signals of correlation, of which 4 (N1% and sBP, dBP, γ-GTP, and triglycerides) reached a Bonferroni-corrected threshold (P < 0.0001). Thus, EEG-based sleep characteristics are associated with several physical health parameters, particularly sBP.

Microglia modulate sleep/wakefulness under baseline conditions and under acute social defeat stress in adult mice.

Although sleep is tightly regulated by multiple neuronal circuits in the brain, nonneuronal cells such as glial cells have been increasingly recognized as crucial sleep regulators. Recent studies have shown that microglia may act to maintain wakefulness. Here, we investigated the possible involvement of microglia in the regulation of sleep quantity and quality under baseline and stress conditions through electroencephalography (EEG)/electromyography (EMG) recordings, and by employing pharmacological methods to eliminate microglial cells in the adult mouse brain. We found that severe microglial depletion induced by the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 (PLX) reversibly decreased the total wake time and the wake episode duration and increased the EEG slow-wave power during wakefulness under baseline conditions. To examine the role of microglia in sleep/wake regulation under mental stress, we used the acute social defeat stress (ASDS) paradigm, an ethological model for psychosocial stress. Sleep analysis under ASDS revealed that microglial depletion exacerbated the stress-induced decrease in the total wake time and increase in anxiety-like behaviors in the open field test. These results demonstrate that microglia actively modulate sleep quantity and architecture under both baseline and stress conditions. Our findings suggest that microglia may potentially provide resilience against acute psychosocial stress by regulating restorative sleep.

A phosphorylation-deficient mutant of Sik3, a homolog of Sleepy, alters circadian sleep regulation by PDF neurons in Drosophila.

Sleep behavior has been observed from non-vertebrates to humans. Sleepy mutation in mice resulted in a notable increase in sleep and was identified as an exon-skipping mutation of the salt-inducible kinase 3 (Sik3) gene, conserved among animals. The skipped exon includes a serine residue that is phosphorylated by protein kinase A. Overexpression of a mutant gene with the conversion of this serine into alanine (Sik3-SA) increased sleep in both mice and the fruit fly Drosophila melanogaster. However, the mechanism by which Sik3-SA increases sleep remains unclear. Here, we found that Sik3-SA overexpression in all neurons increased sleep under both light-dark (LD) conditions and constant dark (DD) conditions in Drosophila. Additionally, overexpression of Sik3-SA only in PDF neurons, which are a cluster of clock neurons regulating the circadian rhythm, increased sleep during subjective daytime while decreasing the amplitude of circadian rhythm. Furthermore, suppressing Sik3-SA overexpression specifically in PDF neurons in flies overexpressing Sik3-SA in all neurons reversed the sleep increase during subjective daytime. These results indicate that Sik3-SA alters the circadian function of PDF neurons and leads to an increase in sleep during subjective daytime under constant dark conditions.

Forward genetic screen of Caenorhabditis elegans mutants with impaired sleep reveals a crucial role of neuronal diacylglycerol kinase DGK-1 in regulating sleep.

The sleep state is widely observed in animals. The molecular mechanisms underlying sleep regulation, however, remain largely unclear. In the nematode Caenorhabditis elegans, developmentally timed sleep (DTS) and stress-induced sleep (SIS) are 2 types of quiescent behaviors that fulfill the definition of sleep and share conserved sleep-regulating molecules with mammals. To identify novel sleep-regulating molecules, we conducted an unbiased forward genetic screen based on DTS phenotypes. We isolated 2 mutants, rem8 and rem10, that exhibited significantly disrupted DTS and SIS. The causal gene of the abnormal sleep phenotypes in both mutants was mapped to dgk-1, which encodes diacylglycerol kinase. Perhaps due to the diminished SIS, dgk-1 mutant worms exhibited decreased survival following exposure to a noxious stimulus. Pan-neuronal and/or cholinergic expression of dgk-1 partly rescued the dgk-1 mutant defects in DTS, SIS, and post-stress survival. Moreover, we revealed that pkc-1/nPKC participates in sleep regulation and counteracts the effect of dgk-1; the reduced DTS, SIS, and post-stress survival rate were partly suppressed in the pkc-1; dgk-1 double mutant compared with the dgk-1 single mutant. Excessive sleep observed in the pkc-1 mutant was also suppressed in the pkc-1; dgk-1 double mutant, implying that dgk-1 has a complicated mode of action. Our findings indicate that neuronal DGK-1 is essential for normal sleep and that the counterbalance between DGK-1 and PKC-1 is crucial for regulating sleep and mitigating post-stress damage.

Severe hypocalcemia after denosumab treatment leading to refractory ventricular tachycardia and veno-arterial extracorporeal membrane oxygenation support: a case report.

BACKGROUND: Severe hypocalcemia may lead to life-threatening arrhythmias. Denosumab is an effective treatment for osteoporosis that allows long intervals between doses. However, there is a risk of hypocalcemia in some patients. Due to the long half-life of denosumab, emergency physicians caring for patients presenting with symptoms of hypocalcemia may not be aware of the medication, and adverse effects may last longer. CASE PRESENTATION: A 55-year-old woman with a history of systemic lupus erythematosus (SLE) and anxiety disorder called for an ambulance for symptoms of hyperventilation and muscle cramps. After evaluation at the local hospital, she developed pulseless ventricular tachycardia and was resuscitated by defibrillation by the hospital staff. After conversion to sinus rhythm, she was transported to a tertiary center. Upon arrival, pulseless ventricular tachycardia occurred again, and veno-arterial extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pumping (IABP) were implemented. Laboratory results showed severe hypocalcemia (corrected calcium level of 5.3 mg/dL) whereupon intravenous calcium supplementation was started. She had received the first dose of denosumab (60 mg) by subcutaneous injection 24 days prior to hospitalization. She was eventually weaned from ECMO and IABP support. CONCLUSION: Cardiac arrest due to hypocalcemia is relatively rare but can be fatal. In the present case, hyperventilation may have acutely exacerbated pre-existing hypocalcemia, leading to ventricular tachycardia. The patient had a slightly decreased serum calcium level prior to denosumab. Close monitoring may be preferable after the primary dose of denosumab in selected patients. Emergency physicians caring for patients who may be suffering from symptoms/signs of hypocalcemia must be mindful of medications that have long half-lives and affect electrolyte balance when treating fatal arrhythmia due to hypocalcemia.

Face validation and pharmacologic analysis of Sik3Sleepy mutant mouse as a possible model of idiopathic hypersomnia.

Idiopathic hypersomnia (IH) is a chronic neurologic disorder with unknown mechanisms that result in long night-time sleep, daytime sleepiness, long non-refreshing naps, and difficult awakening presenting as sleep drunkenness. IH patients are typically diagnosed by shorter sleep latency on multiple sleep latency test (MSLT) along with long sleep time. Only symptomatic drug treatments are currently available for IH and no animal model to study it. Sleepy mice carry a splicing mutation in the Sik3 gene, leading to increased sleep time and sleep need. Here we used a mouse version of MSLT and a decay analysis of wake EEG delta power to validate the Sleepy mutant mouse as an animal model for IH. Sleepy mice had shorter sleep latency in the dark (active) phase than wild-type mice. They also showed lower decay of EEG delta density during wakefulness, possibly reflecting increased sleep inertia. These data indicate that the Sleepy mouse may have partial face validity as a mouse model for idiopathic hypersomnia. We then investigated the effect of orexin-A and the orexin receptor 2-selective agonist YNT-185 on the sleepiness symptoms of the Sleepy mouse. Intracerebroventricular orexin-A promoted wakefulness for 3 h and decreased wake EEG delta density after injection in Sleepy mice and wild-type mice. Moreover, Sleepy mice but not wild-type mice showed a sleep rebound after the orexin-A-induced wakefulness. Intraperitoneal YNT-185 promoted wakefulness for 3 h after injection in Sleepy mice, indicating the potential of using orexin agonists to treat not only orexin deficiency but hypersomnolence of various etiologies.

Positive allosteric adenosine A2A receptor modulation suppresses insomnia associated with mania- and schizophrenia-like behaviors in mice.

Background: Insomnia is associated with psychiatric illnesses such as bipolar disorder or schizophrenia. Treating insomnia improves psychotic symptoms severity, quality of life, and functional outcomes. Patients with psychiatric disorders are often dissatisfied with the available therapeutic options for their insomnia. In contrast, positive allosteric modulation of adenosine A2A receptors (A2ARs) leads to slow-wave sleep without cardiovascular side effects in contrast to A2AR agonists. Methods: We investigated the hypnotic effects of A2AR positive allosteric modulators (PAMs) in mice with mania-like behavior produced by ablating GABAergic neurons in the ventral medial midbrain/pons area and in a mouse model of schizophrenia by knocking out of microtubule-associated protein 6. We also compared the properties of sleep induced by A2AR PAMs in mice with mania-like behavior with those induced by DORA-22, a dual orexin receptor antagonist that improves sleep in pre-clinical models, and the benzodiazepine diazepam. Results: A2AR PAMs suppress insomnia associated with mania- or schizophrenia-like behaviors in mice. A2AR PAM-mediated suppression of insomnia in mice with mania-like behavior was similar to that mediated by DORA-22, and, unlike diazepam, did not result in abnormal sleep. Conclusion: A2AR allosteric modulation may represent a new therapeutic avenue for sleep disruption associated with bipolar disorder or psychosis.

Design and Synthesis of Orexin 1 Receptor-Selective Agonists.

Orexins are a family of neuropeptides that regulate various physiological events, such as sleep/wakefulness as well as emotional and feeding behavior, and that act on two G-protein-coupled receptors, i.e., orexin 1 (OX1R) and orexin 2 receptors (OX2R). Since the discovery that dysfunction of the orexin/OX2R system causes the sleep disorder narcolepsy, several OX2R-selective and OX1/2R dual agonists have been disclosed. However, an OX1R-selective agonist has not yet been reported, despite the importance of the biological function of OX1R. Herein, we report the discovery of a potent OX1R-selective agonist, (R,E)-3-(4-methoxy-3-(N-(8-(2-(3-methoxyphenyl)-N-methylacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)phenyl)-N-(pyridin-4-yl)acrylamide [(R)-YNT-3708; EC50 = 7.48 nM for OX1R; OX2R/OX1R EC50 ratio = 22.5]. The OX1R-selective agonist (R)-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OX1R in mice.

ER proteostasis regulators cell-non-autonomously control sleep.

Sleep is regulated by peripheral tissues under fatigue. The molecular pathways in peripheral cells that trigger systemic sleep-related signals, however, are unclear. Here, a forward genetic screen in C. elegans identifies 3 genes that strongly affect sleep amount: sel-1, sel-11, and mars-1. sel-1 and sel-11 encode endoplasmic reticulum (ER)-associated degradation components, whereas mars-1 encodes methionyl-tRNA synthetase. We find that these machineries function in non-neuronal tissues and that the ER unfolded protein response components inositol-requiring enzyme 1 (IRE1)/XBP1 and protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor-2α (eIF2α)/activating transcription factor-4 (ATF4) participate in non-neuronal sleep regulation, partly by reducing global translation. Neuronal epidermal growth factor receptor (EGFR) signaling is also required. Mouse studies suggest that this mechanism is conserved in mammals. Considering that prolonged wakefulness increases ER proteostasis stress in peripheral tissues, our results suggest that peripheral ER proteostasis factors control sleep homeostasis. Moreover, based on our results, peripheral tissues likely cope with ER stress not only by the well-established cell-autonomous mechanisms but also by promoting the individual's sleep.

SIK3-HDAC4 in the suprachiasmatic nucleus regulates the timing of arousal at the dark onset and circadian period in mice.

Mammals exhibit circadian cycles of sleep and wakefulness under the control of the suprachiasmatic nucleus (SCN), such as the strong arousal phase-locked to the beginning of the dark phase in laboratory mice. Here, we demonstrate that salt-inducible kinase 3 (SIK3) deficiency in gamma-aminobutyric acid (GABA)-ergic neurons or neuromedin S (NMS)-producing neurons delayed the arousal peak phase and lengthened the behavioral circadian cycle under both 12-h light:12-h dark condition (LD) and constant dark condition (DD) without changing daily sleep amounts. In contrast, the induction of a gain-of-function mutant allele of Sik3 in GABAergic neurons exhibited advanced activity onset and a shorter circadian period. Loss of SIK3 in arginine vasopressin (AVP)-producing neurons lengthened the circadian cycle, but the arousal peak phase was similar to that in control mice. Heterozygous deficiency of histone deacetylase (HDAC) 4, a SIK3 substrate, shortened the circadian cycle, whereas mice with HDAC4 S245A, which is resistant to phosphorylation by SIK3, delayed the arousal peak phase. Phase-delayed core clock gene expressions were detected in the liver of mice lacking SIK3 in GABAergic neurons. These results suggest that the SIK3-HDAC4 pathway regulates the circadian period length and the timing of arousal through NMS-positive neurons in the SCN.

Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5­trioxazatriquinane skeleton.

A novel series of 1,3,5­trioxazatriquinane with multiple effective residues (TriMER) derivatives with amino-methylene side chains was designed and synthesized based on the docking-simulation results between orexin receptors (OXRs) and TriMER-type OXR antagonists. In vitro screening against orexin receptors identified six TriMER derivatives with a cis side-chain configuration, and, among these, 20d and 28d showed full agonist activity against OX2R at a concentration of 10 µM. To determine the absolute stereochemistry of these hit compounds, we also conducted the first asymmetric synthesis of a 1,3,5­trioxazatriquinane skeleton using a Katsuki-Sharpless asymmetric epoxidation as the key reaction and obtained a set of the individual stereoisomers. After evaluating their activity, (+)-20d (EC50 = 3.87 µM for OX2R) and (+)-28d (EC50 = 1.62 µM for OX2R) were determined as eutomers for OX2R agonist activity. Our results provide a new class of skeleton consisting of an (R)-1,3,5­trioxazatriquinane core with flexible methylene linkers and hydrophobic substituents at the terminals of the side chains via carbamates/sulfonamides as OX2R agonists.

Progenitor-derived endothelin controls dermal sheath contraction for hair follicle regression.

Substantial follicle remodelling during the regression phase of the hair growth cycle is coordinated by the contraction of the dermal sheath smooth muscle, but how dermal-sheath-generated forces are regulated is unclear. Here, we identify spatiotemporally controlled endothelin signalling-a potent vasoconstriction-regulating pathway-as the key activating mechanism of dermal sheath contraction. Pharmacological blocking or genetic ablation of both endothelin receptors, ETA and ETB, impedes dermal sheath contraction and halts follicle regression. Epithelial progenitors at the club hair-epithelial strand bottleneck produce the endothelin ligand ET-1, which is required for follicle regression. ET signalling in dermal sheath cells and downstream contraction is dynamically regulated by cytoplasmic Ca2+ levels through cell membrane and sarcoplasmic reticulum calcium channels. Together, these findings illuminate an epithelial-mesenchymal interaction paradigm in which progenitors-destined to undergo programmed cell death-control the contraction of the surrounding sheath smooth muscle to orchestrate homeostatic tissue regression and reorganization for the next stem cell activation and regeneration cycle.

Mechanisms of Sleep/Wake Regulation under Hypodopaminergic State: Insights from MitoPark Mouse Model of Parkinson's Disease.

Sleep/wake alterations are predominant in neurological and neuropsychiatric disorders involving dopamine dysfunction. Unfortunately, specific, mechanisms-based therapies for these debilitating sleep problems are currently lacking. The pathophysiological mechanisms of sleep/wake alterations within a hypodopaminergic MitoPark mouse model of Parkinson's disease (PD) are investigated. MitoPark mice replicate most PD-related sleep alterations, including sleep fragmentation, hypersomnia, and daytime sleepiness. Surprisingly, these alterations are not accounted for by a dysfunction in the circadian or homeostatic regulatory processes of sleep, nor by acute masking effects of light or darkness. Rather, the sleep phenotype is linked with the impairment of instrumental arousal and sleep modulation by behavioral valence. These alterations correlate with changes in high-theta (8-11.5 Hz) electroencephalogram power density during motivationally-charged wakefulness. These results demonstrate that sleep/wake alterations induced by dopamine dysfunction are mediated by impaired modulation of sleep by motivational valence and provide translational insights into sleep problems associated with disorders linked to dopamine dysfunction.