Disturbing sleep in female adolescent mice does not increase vulnerability to depression triggers later in life.

Poor sleep quality is a major issue for many adolescents and is associated with fatigue, poor academic performance, and depression. Adolescence is a crucial neurodevelopmental stage where multiple neuropsychiatric illnesses often emerge, suggesting increased central nervous system vulnerability, specifically at this age, which could be exacerbated by poor sleep. Studies on adolescent mice show that sleep deprivation or sleep disturbance (SD) induces structural and functional brain changes, indicating that SD affects the adolescent brain.

CaMKIIα hub ligands are unable to reverse known phenotypes in Angelman syndrome mice.

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of ubiquitin-protein ligase E3A (UBE3A), resulting in marked changes in synaptic plasticity. In AS mice, a dysregulation of Ca/calmodulin-dependent protein kinase II alpha (CaMKIIα) was previously described. This has been convincingly validated through genetic rescue of prominent phenotypes in mouse cross-breeding experiments.

and Evaluation of Pellotine: A Hypnotic Alkaloid.

Quality of life is often reduced in patients with sleep-wake disorders. Insomnia is commonly treated with benzodiazepines, despite their well-known side effects. Pellotine (), a alkaloid, has been reported to have short-acting sleep-inducing properties in humans.

Experimental sickness reduces hypocretin receptor 1 expression in the lateral hypothalamus and ventral tegmental area of female mice.

Recent studies have focused on how sickness behaviours, including lethargy, are coordinated in the brain in response to peripheral infections. Decreased hypocretin (orexin) signalling is associated with lethargy and previous research suggests that hypocretin signalling is downregulated during sickness. However, there are studies that find increases or no change in hypocretin signalling during sickness.

Molecular consequences of peripheral Influenza A infection on cell populations in the murine hypothalamus.

Infection with Influenza A virus (IAV) causes the well-known symptoms of the flu, including fever, loss of appetite, and excessive sleepiness. These responses, mediated by the brain, will normally disappear once the virus is cleared from the system, but a severe respiratory virus infection may cause long-lasting neurological disturbances. These include encephalitis lethargica and narcolepsy.

Repeated polysomnography and multiple sleep latency test in narcolepsy type 1 and other hypersomnolence disorders.

Background: The diagnosis of narcolepsy is based on clinical information, combined with polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). PSG and the MSLT are moderately reliable at diagnosing narcolepsy type 1 (NT1) but unreliable for diagnosing narcolepsy type 2 (NT2). This is a problem, especially given the increased risk of a false-positive MSLT in the context of circadian misalignment or sleep deprivation, both of which commonly occur in the general population.

The immunopathogenesis of narcolepsy type 1.

Narcolepsy type 1 (NT1) is a chronic sleep disorder resulting from the loss of a small population of hypothalamic neurons that produce wake-promoting hypocretin (HCRT; also known as orexin) peptides. An immune-mediated pathology for NT1 has long been suspected given its exceptionally tight association with the MHC class II allele HLA-DQB1*06:02, as well as recent genetic evidence showing associations with polymorphisms of T cell receptor genes and other immune-relevant loci and the increased incidence of NT1 that has been observed after vaccination with the influenza vaccine Pandemrix. The search for both self-antigens and foreign antigens recognized by the pathogenic T cell response in NT1 is ongoing.

Non-invasive detection of narcolepsy type I phenotypical features and disease progression by continuous home-cage monitoring of activity in two mouse models: the HCRT-KO and DTA model.

Narcolepsy type 1 (NT1) is a neurological disorder caused by disruption of hypocretin (HCRT; or orexin) neurotransmission leading to fragmented sleep/wake states, excessive daytime sleepiness, and cataplexy (abrupt muscle atonia during wakefulness). Electroencephalography and electromyography (EEG/EMG) monitoring is the gold standard to assess NT1 phenotypical features in both humans and mice. Here, we evaluated the digital ventilated home-cage (DVC®) activity system as an alternative to detect NT1 features in two NT1 mouse models: the genetic HCRT-knockout (-KO) model, and the inducible HCRT neuron-ablation hcrt-tTA;TetO-DTA (DTA) model, including both sexes.

Increased muscle activity during sleep and more RBD symptoms in H1N1-(Pandemrix)-vaccinated narcolepsy type 1 patients compared with their non-narcoleptic siblings.

Study Objectives: Narcolepsy type 1 (NT1) is characterized by unstable sleep-wake and muscle tonus regulation during sleep. We characterized dream enactment and muscle activity during sleep in a cohort of post-H1N1 NT1 patients and their siblings, and analyzed whether clinical phenotypic characteristics and major risk factors are associated with increased muscle activity.

Methods: RBD symptoms and polysomnography m.

Repeated measures of hypocretin-1 in Danish and Italian patients with narcolepsy and in controls.

Study Objectives: The assay currently used worldwide to measure cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) for diagnosing narcolepsy uses a competitive radioimmunoassay with polyclonal anti-hcrt-1 antibodies. This assay detects multiple hypocretin-1 immunoreactive species in the CSF that are all derived from full-length hcrt-1. We aimed to revalidate CSF-hcrt-1 cut-offs for narcolepsy type 1 (NT1) diagnosis and to evaluate temporal changes in CSF-hcrt-1 levels in patients suspected of having central hypersomnia.

How hypocretin agonists may improve the quality of wake in narcolepsy.

Excessive daytime sleepiness (EDS) is a complex symptom characterized by a strong urge to sleep during daytime accompanied by problems such as attention deficits, anxiety, and lower cognitive performance. The efficacy of treatments for EDS is determined by their ability to decrease sleepiness, and less attention has been given to the effects these compounds have on the quality of the wake itself. Hypocretin (HCRT; orexin) signalling is implicated in narcolepsy, and hypocretin receptor 2 (HCRTR2) agonists are in clinical trials for treating EDS in narcolepsy.

Production of human entorhinal stellate cell-like cells by forward programming shows an important role of Foxp1 in reprogramming.

Stellate cells are principal neurons in the entorhinal cortex that contribute to spatial processing. They also play a role in the context of Alzheimer's disease as they accumulate Amyloid beta early in the disease. Producing human stellate cells from pluripotent stem cells would allow researchers to study early mechanisms of Alzheimer's disease, however, no protocols currently exist for producing such cells.

The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio.

Hypocretin (Hcrt), also known as orexin, neuropeptide signaling stabilizes sleep and wakefulness in all vertebrates. A lack of Hcrt causes the sleep disorder narcolepsy, and increased Hcrt signaling has been speculated to cause insomnia, but while the signaling pathways of Hcrt are relatively well-described, the intracellular mechanisms that regulate its expression remain unclear. Here, we tested the role of microRNAs (miRNAs) in regulating Hcrt expression.

Sex-related differences within sleep-wake dynamics, cataplexy, and EEG fast-delta power in a narcolepsy mouse model.

Narcolepsy type 1 (NT1) is a sleep-wake disorder caused by selective loss of hypocretin (HCRT, also called orexin) neurons. Although the prevalence of NT1 is equal in men and women, sex differences in NT1 symptomatology have been reported in humans and other species. Yet, most preclinical studies fail to include females, resulting in gender bias within translational drug development.

Emerging therapeutic targets for narcolepsy.

Introduction: Narcolepsy type 1 (NT1) and type 2 (NT2) are chronic sleep disorders primarily characterized by excessive daytime sleepiness (EDS), disturbed sleep-wake regulation, and reduced quality of life. The precise disease mechanism is unclear, but it is certain that in NT1 the hypocretin/orexin (Hcrt) system is affected. Current treatment options are symptomatic - they improve EDS and/or reduce cataplexy.

Narcolepsy type 1 patients have lower levels of effector memory CD4 T cells compared to their siblings when controlling for H1N1-(Pandemrix™)-vaccination and HLA DQB1∗06:02 status.

Study Objectives: Evidence suggests a cell-mediated autoimmune pathogenesis for narcolepsy type 1 (NT1), but it is not clear whether the disease is associated with overall changes in T cell subsets. The increase in NT1 incidence after H1N1 vaccination campaign with the Pandemrix™ vaccine suggests that disease-relevant changes in the immune system following this vaccination were important. In this study, we aimed to investigate differentiated T cell subsets and levels of CD25 and CD69 activation markers in a cohort of mainly Pandemrix™-vaccinated NT1 patients compared with their vaccinated and unvaccinated siblings.

GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain.

Ca/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers, yet pharmacological modulation of the hub domain has never been demonstrated. Here, using a combination of photoaffinity labeling and chemical proteomics, we show that compounds related to the natural substance γ-hydroxybutyrate (GHB) bind selectively to CaMKIIα.

Diagnostic value of actigraphy in hypersomnolence disorders.

Objective: Differentiating between the central hypersomnias presents a challenge to the diagnosis of patients with hypersomnolence. Actitigraphy may support efforts to distinguish them. We aimed to evaluate: 1) the ability of actigraphy to quantify sleep continuity measures in comparison with polysomnography in patients with hypersomnolence; 2) whether actigraphy can distinguish patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid from patients with narcolepsy type 1 and from sleep-healthy controls; and 3) the distinct activity profiles and circadian rhythms of patients with narcolepsy type 1, patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid, and sleep-healthy controls.

Narcolepsy Type I as an autoimmune disorder.

Narcolepsy Type 1 (NT1) is hypothesized to be an autoimmune disease targeting the hypocretin/orexin neurons in the lateral hypothalamus. Ample genetic and epidemiologic evidence point in the direction of a pathogenesis involving the immune system. Many autoantibodies have been detected in blood samples from NT1 patients, but none in a consistent manner.

Pre-treatment of blood samples reveal normal blood hypocretin/orexin signal in narcolepsy type 1.

The hypocretin/orexin system regulates arousal through central nervous system mechanisms and plays an important role in sleep, wakefulness and energy homeostasis. It is unclear whether hypocretin peptides are also present in blood due to difficulties in measuring reliable and reproducible levels of the peptides in blood samples. Lack of hypocretin signalling causes the sleep disorder narcolepsy type 1, and low concentration of cerebrospinal fluid hypocretin-1/orexin-A peptide is a hallmark of the disease.

GABA receptor β -subunit knock-out mice show increased delta power in NREM sleep and decreased theta power in REM sleep.

γ-Aminobutyric acid (GABA) acting through heteropentameric GABA receptors plays a pivotal role in the sleep-promoting circuitry. Whereas the role of the different GABA receptor α-subunits in sleep regulation and in mediating the effect of benzodiazepines for treatment of insomnia is well-described, the β-subunits are less studied. Here we report the first study characterizing sleep in mice lacking the GABA receptor β -subunit (β mice).

High nocturnal sleep fragmentation is associated with low T lymphocyte P2Y11 protein levels in narcolepsy type 1.

Study Objectives: Narcolepsy type 1 (NT1) is associated with hypocretin neuron loss. However, there are still unexplained phenotypic NT1 features. We investigated the associations between clinical and sleep phenotypic characteristics, the NT1-associated P2RY11 polymorphism rs2305795, and P2Y11 protein levels in T lymphocytes in patients with NT1, their first-degree relatives and unrelated controls.

Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission.

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lep mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points.