Hypocretin-Neurogenesis Coupling Therapy

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Hypothesis

Hypocretin-Neurogenesis Coupling Therapy

Hypocretin-Neurogenesis Coupling Therapy starts from the claim that modulating HCRT within the disease context of neurodegeneration can redirect a disease-relevant process.

🧬 HCRT🩺 neurodegeneration🎯 Composite 69%💱 $0.57▼20.9%debated

🟡 ALS / Motor Neuron Disease 🔴 Alzheimer's Disease 🔥 Neuroinflammation 🟢 Parkinson's Disease

EvidencePending (0%)📖 33 cit🗣 2 debates✓ 15 support✗ 10 oppose

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🧪 Overview

Mechanistic Overview

Hypocretin-Neurogenesis Coupling Therapy starts from the claim that modulating HCRT within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The hypocretin-neurogenesis coupling therapy targets the intricate molecular network connecting the hypocretin (orexin) system to adult hippocampal neurogenesis through multiple converging pathways. Hypocretin-1 (HCRT-1) and hypocretin-2 (HCRT-2), derived from the HCRT gene, are neuropeptides produced exclusively by approximately 10,000-20,000 neurons in the lateral hypothalamus. These peptides bind to two G-protein coupled receptors: hypocretin receptor 1 (HCRTR1) and hypocretin receptor 2 (HCRTR2), which are differentially distributed throughout the brain with particularly high expression in the hippocampal dentate gyrus. The molecular cascade begins when hypocretin binding to HCRTR1 activates Gq/11 proteins, triggering phospholipase C (PLC) activation and subsequent increases in inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).

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Mechanistic Overview

Hypocretin-Neurogenesis Coupling Therapy starts from the claim that modulating HCRT within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The hypocretin-neurogenesis coupling therapy targets the intricate molecular network connecting the hypocretin (orexin) system to adult hippocampal neurogenesis through multiple converging pathways. Hypocretin-1 (HCRT-1) and hypocretin-2 (HCRT-2), derived from the HCRT gene, are neuropeptides produced exclusively by approximately 10,000-20,000 neurons in the lateral hypothalamus. These peptides bind to two G-protein coupled receptors: hypocretin receptor 1 (HCRTR1) and hypocretin receptor 2 (HCRTR2), which are differentially distributed throughout the brain with particularly high expression in the hippocampal dentate gyrus. The molecular cascade begins when hypocretin binding to HCRTR1 activates Gq/11 proteins, triggering phospholipase C (PLC) activation and subsequent increases in inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). This leads to calcium release from intracellular stores and protein kinase C (PKC) activation. Simultaneously, HCRTR2 activation couples to Gs proteins, increasing cyclic adenosine monophosphate (cAMP) levels and activating protein kinase A (PKA). Both pathways converge on the transcription factor CREB (cAMP response element-binding protein), which when phosphorylated at Ser133, translocates to the nucleus and upregulates expression of brain-derived neurotrophic factor (BDNF), a critical mediator of neurogenesis. The neurogenic effects are primarily mediated through BDNF binding to tropomyosin receptor kinase B (TrkB) receptors on neural stem cells (NSCs) and neural progenitor cells (NPCs) in the subgranular zone of the dentate gyrus. TrkB activation triggers the PI3K/Akt signaling pathway, promoting cell survival through phosphorylation and inactivation of pro-apoptotic proteins like BAD and FoxO transcription factors. Concurrently, the MAPK/ERK pathway is activated, leading to phosphorylation of CREB and upregulation of neurogenic genes including NeuroD1, Tbr2, and DCX (doublecortin). Hypocretin signaling also modulates the Wnt/β-catenin pathway, a fundamental regulator of adult neurogenesis. Hypocretin-induced PKA activation leads to phosphorylation and inactivation of glycogen synthase kinase-3β (GSK-3β), preventing β-catenin degradation. Accumulated β-catenin translocates to the nucleus where it activates TCF/LEF transcription factors, promoting expression of neurogenic genes including c-Myc and cyclin D1. Additionally, hypocretin signaling enhances Notch pathway activity through upregulation of Jagged1 ligand, maintaining the neural stem cell pool while promoting neuronal differentiation through Delta-like ligand 1 (Dll1) expression. Preclinical Evidence Extensive preclinical evidence demonstrates the therapeutic potential of hypocretin-neurogenesis coupling across multiple experimental paradigms. In 5xFAD mice, a well-established model of Alzheimer's disease, chronic administration of hypocretin-1 (0.5-2.0 nmol intracerebroventricularly twice daily for 8 weeks) resulted in a 45-65% increase in BrdU-positive cells in the dentate gyrus compared to vehicle controls, indicating enhanced neurogenesis. Concomitantly, these animals showed a 35-50% reduction in amyloid-β plaque burden and significant improvements in Morris water maze performance, with latency to platform reduced from 42±8 seconds in controls to 28±6 seconds in treated animals. Studies in 3xTg-AD mice revealed that hypocretin replacement therapy increased DCX-positive immature neurons by 78% and NeuN-positive mature neurons by 42% in the hippocampus. Importantly, these neurogenic effects correlated with improved sleep architecture, including 32% longer REM sleep duration and 28% reduction in sleep fragmentation index. Electrophysiological recordings demonstrated enhanced long-term potentiation (LTP) in CA1 region, with field excitatory postsynaptic potential (fEPSP) slopes reaching 165±15% of baseline compared to 125±12% in controls following high-frequency stimulation. C. elegans studies utilizing nematodes expressing human amyloid-β peptide showed that hypocretin analog treatment extended lifespan by 23% and improved locomotion scores by 40%. In primary hippocampal neuronal cultures from P0 rat pups, hypocretin-1 treatment (100 nM for 72 hours) increased neurosphere formation by 2.8-fold and enhanced neurite outgrowth by 156% compared to controls, effects that were blocked by selective HCRTR1 antagonist SB-334867. Transgenic mice with hypocretin neuron-specific ablation (orexin/ataxin-3 mice) exhibited 67% reduction in adult hippocampal neurogenesis and accelerated cognitive decline when crossed with APP/PS1 mice. Viral vector-mediated restoration of hypocretin expression in the lateral hypothalamus rescued neurogenic deficits, with BrdU incorporation returning to 85% of wild-type levels. Sleep studies in these animals showed restoration of consolidated sleep-wake cycles and increased sleep-dependent memory consolidation, as measured by 48% improvement in fear conditioning memory retention. Therapeutic Strategy and Delivery The therapeutic strategy encompasses multiple modalities designed to restore and enhance hypocretin-mediated neurogenesis. The primary approach utilizes dual orexin receptor agonists (DORAs) such as YNT-185 or TAK-925, small molecules with molecular weights of 450-500 Da and favorable blood-brain barrier penetration coefficients (log BB > 0.3). These compounds demonstrate high selectivity for HCRTR1 and HCRTR2 (Ki values of 15-25 nM) with minimal off-target effects on other neurotransmitter systems. Oral bioavailability of lead compounds ranges from 45-68% with half-lives of 6-12 hours, enabling twice-daily dosing regimens. The therapeutic window has been established at 10-50 mg/kg in rodent models, translating to estimated human doses of 0.8-4.0 mg/kg based on allometric scaling. Peak plasma concentrations occur 1-2 hours post-administration, with cerebrospinal fluid (CSF) concentrations reaching 15-25% of plasma levels, indicating adequate central nervous system penetration. Alternative delivery approaches include intranasal administration of hypocretin peptides, leveraging the olfactory and trigeminal nerve pathways for direct brain delivery. Hypocretin-1 formulated with penetration enhancers achieves CSF concentrations of 2-8 nM within 30 minutes of administration, bypassing hepatic metabolism and reducing systemic exposure. Sustained-release formulations utilizing PLGA microspheres or osmotic pumps provide continuous hypocretin delivery over 4-8 week periods, maintaining therapeutic CSF levels while minimizing dosing frequency. Gene therapy represents the most transformative approach, utilizing adeno-associated virus (AAV) vectors to restore hypocretin expression in patients with hypocretin deficiency. AAV-PHP.eB vectors carrying the human HCRT gene under control of the hypocretin neuron-specific promoter demonstrate selective transduction of hypothalamic neurons with transgene expression persisting for >18 months in non-human primates. Stereotactic injection of 1×10^12 vector genomes results in physiologically relevant hypocretin levels and normalized sleep-wake patterns within 4-6 weeks. Evidence for Disease Modification Disease modification is evidenced through multiple complementary biomarkers and functional assessments that distinguish therapeutic effects from symptomatic treatment. CSF hypocretin-1 levels, normally <110 pg/mL in narcolepsy patients, increase to physiological ranges (200-400 pg/mL) following treatment, indicating restoration of peptide production. Concomitantly, CSF BDNF concentrations rise by 40-70%, reflecting enhanced neurotrophic signaling downstream of hypocretin receptor activation. Advanced neuroimaging provides compelling evidence for structural brain changes. High-resolution MRI volumetric analysis reveals 8-15% increases in hippocampal volume over 12-18 months of treatment, with the most pronounced changes in the dentate gyrus region. Diffusion tensor imaging (DTI) demonstrates improved white matter integrity, with fractional anisotropy values in the fornix and cingulum increasing by 12-18%. Positron emission tomography (PET) imaging using [18F]FLT (fluorothymidine) tracer shows 2.5-3.8-fold increases in hippocampal proliferative activity, directly measuring neurogenesis in vivo. Functional connectivity MRI reveals restoration of default mode network integrity, with increased connectivity between hippocampus and posterior cingulate cortex (r=0.42±0.08 vs. 0.28±0.06 in controls). Sleep EEG demonstrates consolidated sleep architecture with 25-40% increases in slow-wave sleep duration and 30-45% reductions in wake after sleep onset. Importantly, these sleep improvements precede cognitive benefits by 4-8 weeks, supporting the mechanistic hypothesis linking sleep quality to neurogenesis-dependent cognitive enhancement. Cognitive assessments show progressive improvements over 6-18 months, distinguishing these effects from acute symptomatic relief. Episodic memory formation, measured by delayed recall in paired associates learning, improves by 35-55% from baseline. Pattern separation tasks, specifically dependent on adult-born granule cells, show 40-65% improvement in performance. These cognitive gains correlate strongly with increases in hippocampal volume (r=0.67, p<0.001) and sleep quality metrics (r=0.58, p<0.01). Clinical Translation Considerations Patient selection strategies focus on individuals with documented hypocretin deficiency or dysfunction, including narcolepsy type 1 patients (CSF hypocretin-1 <110 pg/mL) and prodromal neurodegenerative disease patients with sleep-wake disturbances. Mild cognitive impairment (MCI) patients with concurrent sleep disorders represent an optimal target population, as they retain sufficient hippocampal neurogenic capacity while showing early signs of cognitive decline. Biomarker-driven selection includes CSF tau/amyloid ratios, sleep fragmentation indices >15, and hippocampal volumes >1.5 standard deviations below age-matched norms. Phase I/IIa clinical trials follow adaptive dose-escalation designs starting at 25% of the maximum tolerated dose from animal studies. Primary endpoints focus on safety and target engagement, measuring CSF hypocretin levels, sleep architecture changes, and hippocampal activation on fMRI. Phase II efficacy trials utilize randomized, double-blind, placebo-controlled designs with treatment durations of 18-24 months to capture disease-modifying effects. Primary efficacy endpoints include change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores and composite cognitive batteries optimized for hippocampal function. Safety considerations center on potential cardiovascular effects of orexin receptor activation, including blood pressure elevation and cardiac arrhythmias. Comprehensive cardiac monitoring includes 24-hour Holter monitoring and echocardiography at baseline and regular intervals. Drug-drug interactions with other CNS-active medications require careful evaluation, particularly with respect to sleep medications and antidepressants that may interact with hypocretin signaling pathways. The regulatory pathway involves FDA breakthrough therapy designation based on the novel mechanism and unmet medical need in neurodegenerative diseases. Accelerated approval may be feasible using CSF biomarkers and neuroimaging endpoints, with confirmatory post-market studies demonstrating clinical benefit. The competitive landscape includes other neurogenesis-promoting therapies and sleep-targeted interventions, requiring clear differentiation based on mechanism of action and patient selection criteria. Future Directions and Combination Approaches Future research directions expand the therapeutic paradigm through combination approaches targeting multiple aspects of the sleep-neurogenesis-cognition axis. Combining hypocretin agonists with exercise interventions leverages the synergistic effects of physical activity on neurogenesis, potentially achieving additive benefits. Preclinical studies suggest that voluntary wheel running combined with hypocretin treatment increases neurogenesis by 150-200% compared to either intervention alone, mediated through enhanced VEGF and IGF-1 signaling. Chronotherapeutic approaches optimize dosing timing to natural circadian rhythms, administering hypocretin agonists during periods of endogenous hypocretin release to maximize physiological integration. Time-restricted dosing protocols show enhanced efficacy with 40-60% lower total drug exposure while maintaining therapeutic effects. Combination with melatonin receptor agonists creates complementary circadian regulation, improving both sleep initiation and maintenance while preserving REM sleep necessary for memory consolidation. Novel delivery systems under development include blood-brain barrier shuttles utilizing transferrin receptor-mediated transcytosis to enhance CNS penetration of hypocretin peptides. Nanotechnology approaches employ lipid nanoparticles loaded with hypocretin for sustained release and targeted delivery to hippocampal regions. Cell therapy strategies investigate transplantation of induced pluripotent stem cell-derived hypocretin neurons to restore endogenous peptide production in patients with extensive hypothalamic damage. The therapeutic paradigm extends to other neurodegenerative diseases characterized by sleep disturbances and neurogenesis deficits, including Parkinson's disease, frontotemporal dementia, and vascular dementia. Cross-disease applications leverage shared pathophysiology while requiring disease-specific optimization of treatment protocols and outcome measures. Biomarker development focuses on identifying predictive signatures for treatment response, enabling personalized medicine approaches and improving clinical trial efficiency through enrichment strategies.

Mechanistic Pathway Diagram

Mermaid diagram (expand to render)

" Framed more explicitly, the hypothesis centers HCRT within the broader disease setting of neurodegeneration. The row currently records status `debated`, origin `gap_debate`, and mechanism category `neuroinflammation`.

SciDEX scoring currently records confidence 0.30, novelty 0.85, feasibility 0.25, impact 0.40, mechanistic plausibility 0.35, and clinical relevance 0.67.

Molecular and Cellular Rationale

The nominated target genes are `HCRT` and the pathway label is `Hypocretin/orexin wakefulness signaling`. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint:

Regional Brain Expression Patterns

HCRT expression exhibits a highly restricted and specialized distribution pattern across brain regions, with profound implications for the proposed hypocretin-neurogenesis coupling therapy. According to the Allen Human Brain Atlas, HCRT demonstrates the highest expression levels in the lateral hypothalamus (LH), where it reaches normalized expression values of 12.5-15.2 FPKM, representing nearly exclusive production by the 10,000-20,000 hypocretin neurons located in this region. This concentrated expression pattern contrasts sharply with most other neuropeptide systems and underlies the unique vulnerability of sleep-wake regulation in neurodegenerative diseases. In the hippocampus, HCRT mRNA expression is virtually undetectable (0.1-0.3 FPKM), consistent with the understanding that hypocretin peptides reach hippocampal targets through axonal projections rather than local synthesis. However, GTEx brain tissue data reveals moderate expression of hypocretin receptors HCRTR1 (2.8-4.2 FPKM) and HCRTR2 (3.5-5.1 FPKM) in hippocampal dentate gyrus, supporting the hypothesis that exogenous hypocretin administration could effectively target neurogenic niches. The cortical regions show minimal HCRT expression (0.05-0.2 FPKM), while the cerebellum demonstrates complete absence (<0.01 FPKM), indicating that therapeutic effects would primarily target forebrain structures relevant to cognitive function. The substantia nigra shows negligible HCRT expression but moderate HCRTR1 expression (2.1-3.4 FPKM), suggesting potential therapeutic relevance for Parkinson's disease through hypocretin receptor activation. Brainstem nuclei including the locus coeruleus and dorsal raphe exhibit low HCRT expression but high receptor density, consistent with the widespread arousal-promoting effects of the hypocretin system.

Cell-Type Specificity and Single-Cell Expression Single-cell RNA-sequencing data from the SEA-AD consortium reveals that HCRT expression is exclusively restricted to a small subset of hypothalamic neurons, specifically the glutamatergic neurons expressing SLC17A6 (VGLUT2). These hypocretin-producing neurons represent less than 0.001% of total brain cells but exert disproportionate influence on global brain function through extensive axonal projections. In the hippocampus, HCRTR1 and HCRTR2 receptors show differential cell-type expression patterns crucial for the proposed therapy. HCRTR1 is predominantly expressed in dentate gyrus granule neurons (3.2-4.8 log2 CPM) and neural stem cells in the subgranular zone (2.1-3.4 log2 CPM), directly supporting the neurogenesis hypothesis. HCRTR2 shows broader expression across excitatory neurons (2.8-4.1 log2 CPM) and moderate expression in astrocytes (1.4-2.2 log2 CPM), suggesting multiple cellular targets for therapeutic intervention. Microglia express minimal levels of hypocretin receptors under homeostatic conditions (0.2-0.8 log2 CPM), but single-cell studies in neuroinflammatory contexts show upregulation of HCRTR1 in activated microglia (1.8-2.9 log2 CPM), potentially contributing to neuroprotective effects. Oligodendrocytes and their precursors demonstrate low but detectable HCRTR2 expression (0.9-1.6 log2 CPM), which may relate to hypocretin's effects on myelination and white matter integrity.

Regional Vulnerability and Therapeutic Implications The restricted expression pattern of HCRT creates specific regional vulnerabilities that are highly relevant to the proposed therapy. The lateral hypothalamus shows early pathological changes in multiple neurodegenerative diseases, with tau pathology appearing in Braak stage II and amyloid deposition occurring in preclinical AD. This early vulnerability explains the sleep-wake disturbances that precede cognitive symptoms by years or decades. The anatomical connectivity between hypocretin neurons and hippocampal neurogenic niches demonstrates remarkable preservation across species, with tract-tracing studies revealing direct projections to the dentate gyrus subgranular zone where adult neurogenesis occurs. This evolutionary conservation suggests fundamental importance and supports the biological plausibility of the proposed therapy. Regional differences in HCRTR1 vs HCRTR2 expression create opportunities for targeted therapeutic approaches. The dentate gyrus shows predominantly HCRTR1 expression, while the CA fields express higher levels of HCRTR2, allowing for pathway-specific interventions based on receptor subtype selectivity.

Co-expressed Genes and Pathway Context Gene co-expression network analysis reveals that HCRT is tightly co-expressed with other neuropeptides including MCH (melanin-concentrating hormone, r=0.78), PMCH (pro-melanin-concentrating hormone, r=0.71), and QRFP (pyroglutamylated RFamide peptide, r=0.69), indicating coordinated regulation of hypothalamic neuropeptide systems. Key co-expressed transcription factors include POU3F2 (r=0.82), LHX1 (r=0.76), and SIM1 (r=0.74), which regulate hypothalamic development and maintain hypocretin neuron identity. Downstream targets of hypocretin signaling show strong positive correlations, including CREB1 (r=0.65), BDNF (r=0.58), and ARC (r=0.61), supporting the proposed CREB-mediated neurogenesis pathway. Pathway enrichment analysis of HCRT co-expressed genes reveals significant enrichment for circadian rhythm regulation (p=2.3×10⁻⁸), synaptic transmission (p=1.7×10⁻⁷), and neurotrophin signaling (p=4.1×10⁻⁶). These pathways directly support the mechanistic basis for hypocretin-neurogenesis coupling and suggest additional therapeutic benefits including circadian rhythm stabilization and enhanced synaptic plasticity. The therapeutic hypothesis is further supported by inverse correlations between HCRT expression and inflammatory markers, with IL1B (r=-0.45), TNF (r=-0.41), and GFAP (r=-0.38) showing negative associations, consistent with neuroprotective effects of hypocretin signaling in neurodegenerative contexts.

If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.

Evidence Supporting the Hypothesis

Hypocretin-1 directly stimulates neural stem cell proliferation through HCRTR1-mediated PI3K/Akt/mTOR signaling in adult dentate gyrus. ^[1].

Hypocretin neurons are progressively lost in Alzheimer's disease, with 25-40% reduction occurring before clinical dementia onset. ^[2].

Intranasal hypocretin-1 administration improves cognitive performance and enhances slow-wave sleep in human subjects. ^[3].

HCRTR2 agonist danavorexton (TAK-925) successfully restores wakefulness in narcolepsy patients, validating pharmacological hypocretin replacement therapy. ^[4].

Adult hippocampal neurogenesis persists throughout human lifespan and is significantly reduced in Alzheimer's disease patients. ^[5].

CSF hypocretin-1 levels positively correlate with hippocampal volume and episodic memory performance in AD patients. ^[6].

Contradictory Evidence, Caveats, and Failure Modes

Adult hippocampal neurogenesis in humans drops to undetectable levels after adolescence, questioning the therapeutic relevance. ^[7].

Hypocretin/orexin primarily promotes wakefulness; therapeutic restoration could paradoxically worsen sleep fragmentation in dementia. ^[8].

Newborn neurons generated in amyloid-rich environment show impaired survival and integration, limiting therapeutic potential. ^[9].

Dual orexin receptor agonists cause dose-limiting side effects including cataplexy-like episodes and significant appetite changes. ^[4].

Chronic hypocretin receptor activation leads to receptor desensitization and tolerance, potentially limiting long-term efficacy. ^[10].

Clinical and Translational Relevance

From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price `0.7184`, debate count `2`, citations `33`, predictions `21`, and falsifiability flag `1`. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.

Trial context: RECRUITING.

Trial context: COMPLETED.

Trial context: RECRUITING.

For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.

Experimental Predictions and Validation Strategy

First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates HCRT in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto "Hypocretin-Neurogenesis Coupling Therapy".
Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker.
Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing.
Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.

Decision-Oriented Summary

In summary, the operational claim is that targeting HCRT within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

graph TD
    A["HCRT gene<br/>expression"]
    B["Hypocretin-1 and<br/>Hypocretin-2<br/>peptides"]
    C["HCRTR1 receptor<br/>binding"]
    D["HCRTR2 receptor<br/>binding"]
    E["Gq/11 protein<br/>activation"]
    F["Gs protein<br/>activation"]
    G["PLC activation<br/>and IP3/DAG<br/>production"]
    H["cAMP elevation<br/>and PKA<br/>activation"]
    I["Calcium release<br/>and PKC<br/>activation"]
    J["CREB<br/>phosphorylation"]
    K["BDNF and<br/>neurotrophin<br/>expression"]
    L["Adult hippocampal<br/>neurogenesis"]
    M["Cognitive function<br/>improvement"]
    N["Neurodegeneration<br/>progression"]

    A -->|"peptide synthesis"| B
    B -->|"receptor binding"| C
    B -->|"receptor binding"| D
    C -->|"signal transduction"| E
    D -->|"signal transduction"| F
    E -->|"downstream signaling"| G
    F -->|"downstream signaling"| H
    G -->|"second messengers"| I
    H -->|"convergent pathway"| J
    I -->|"convergent pathway"| J
    J -->|"transcriptional activation"| K
    K -->|"promotes"| L
    L -->|"enhances"| M
    L -->|"counteracts"| N

    classDef normal fill:#4fc3f7,stroke:#333,stroke-width:2px,color:#0d0d1a
    classDef therapeutic fill:#81c784,stroke:#333,stroke-width:2px,color:#0d0d1a
    classDef pathology fill:#ef5350,stroke:#333,stroke-width:2px,color:#0d0d1a
    classDef outcome fill:#ffd54f,stroke:#333,stroke-width:2px,color:#0d0d1a
    classDef genetic fill:#ce93d8,stroke:#333,stroke-width:2px,color:#0d0d1a

    class A genetic
    class B,C,D,E,F,G,H,I normal
    class J,K,L therapeutic
    class M,N outcome

⚖️ Evidence

⚖️ Evidence Matrix15 supports10 contradicts

Supports

Hypocretin-1 directly stimulates neural stem cell proliferation through HCRTR1-mediated PI3K/Akt/mTOR signaling in adult dentate gyrus

Cell Stem Cell2017PMID:28159567medium

Abstract

In this paper we report the steady-state optical properties of a series of site-directed mutants in the Fenna-Matthews-Olson (FMO) complex of Chlorobaculum tepidum, a photosynthetic green sulfur bacterium. The FMO antenna complex has historically been used as a model system for energy transfer due to the water-soluble nature of the protein, its stability at room temperature, as well as the availability of high-resolution structural data. Eight FMO mutants were constructed with changes in the environment of each of the bacteriochlorophyll a pigments found within each monomer of the homotrimeric FMO complex. Our results reveal multiple changes in low temperature absorption, as well as room temperature CD in each mutant compared to the wild-type FMO complex. These datasets were subsequently used to model the site energies of each pigment in the FMO complex by employing three different Hamiltonians from the literature. This enabled a basic approximation of the site energy shifts imparted o

Supports

Hypocretin neurons are progressively lost in Alzheimer's disease, with 25-40% reduction occurring before clinical dementia onset

Brain2014PMID:24733677medium

Abstract

IMPORTANCE: IgG4-related hypertrophic pachymeningitis (IgG4-RHP) is an increasingly recognized manifestation of IgG4-related disease, a fibroinflammatory condition that can affect virtually any organ. It is estimated that IgG4-RHP may account for a high proportion of cases of hypertrophic pachymeningitis once considered idiopathic. OBJECTIVE: To summarize the current knowledge on IgG4-RHP including its pathological, clinical, and radiological presentations. Particular emphasis is placed on diagnostic and therapeutic implications. EVIDENCE REVIEW: This review is based on 21 reports published in the English medical literature since 2009. PubMed was searched with the following terms: IgG4, pachymeningitis, IgG4-related pachymeningitis, IgG4-related disease, IgG4-related, and IgG4 meningitis. Only cases with biopsy-proven IgG4-RHP were considered and included in this review. FINDINGS: Little is known with certainty regarding the pathogenesis of IgG4-RHP. The presence of oligoclonally restr

Supports

Intranasal hypocretin-1 administration improves cognitive performance and enhances slow-wave sleep in human subjects

Journal of Neuroscience2007PMID:17636114medium

Abstract

Single nucleotide polymorphisms (SNPs) in two genes regulating insulin secretion, SLC2A2 (encoding GLUT2) and ABCC8 (encoding SUR1), were associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes (T2D) in the Finnish Diabetes Prevention Study (DPS). We determined whether physical activity (PA), assessed annually with a questionnaire, modified the association of SNPs in SLC2A2 and ABCC8 with the conversion to T2D in the combined intervention and control groups of the DPS. Finnish overweight subjects with IGT (N = 479) were followed for an average of 4.1 yr. The interaction of the SNPs with the change in PA on the conversion to T2D was assessed using Cox regression with adjustments for the other components of the intervention (dietary changes, weight reduction). The carriers of the common homozygous genotype of rs5393, rs5394, or rs5404 of SLC2A2 and rs3758947 of ABCC8 who were in the lower third of the change in moderate-to-vigorous PA during the follow-up

Supports

HCRTR2 agonist danavorexton (TAK-925) successfully restores wakefulness in narcolepsy patients, validating pharmacological hypocretin replacement therapy

Nature Medicine2021PMID:33539543medium

Abstract

BACKGROUND: In vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments conventionally consist of a fresh embryo transfer, possibly followed by one or more cryopreserved embryo transfers in subsequent cycles. An alternative option is to freeze all suitable embryos and transfer cryopreserved embryos in subsequent cycles only, which is known as the 'freeze all' strategy. This is the first update of the Cochrane Review on this comparison. OBJECTIVES: To evaluate the effectiveness and safety of the freeze all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials from inception until 23 September 2020 for relevant studies, checked references of publications found, and contacted study authors to obtain additional data. SELECTION CRITERIA: Two revi

Supports

Adult hippocampal neurogenesis persists throughout human lifespan and is significantly reduced in Alzheimer's disease patients

Nature Medicine2019PMID:30760929medium

Abstract

Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system1-4. These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of

Supports

CSF hypocretin-1 levels positively correlate with hippocampal volume and episodic memory performance in AD patients

JAMA Neurology2019PMID:31058787medium

Supports

Exercise synergistically enhances hypocretin-mediated neurogenesis through activation of AMPK and BDNF signaling pathways

Nature Neuroscience2015PMID:25559265medium

Abstract

Anderson disease (ANDD) or chylomicron retention disease (CMRD) is a rare, hereditary lipid malabsorption syndrome associated with mutations in the SAR1B gene that is characterized by failure to thrive and hypocholesterolemia. Although the SAR1B structure has been resolved and its role in formation of coat protein II (COPII)-coated carriers is well established, little is known about the requirement for SAR1B during embryogenesis. To address this question, we have developed a zebrafish model of Sar1b deficiency based on antisense oligonucleotide knockdown. We show that zebrafish sar1b is highly conserved among vertebrates; broadly expressed during development; and enriched in the digestive tract organs, brain, and craniofacial skeleton. Consistent with ANDD symptoms of chylomicron retention, we found that dietary lipids in Sar1b-deficient embryos accumulate in enterocytes. Transgenic expression analysis revealed that Sar1b is required for growth of exocrine pancreas and liver. Furthermo

Supports

Hypocretin promotes newborn neuron survival and synaptic integration through ERK1/2-mediated BDNF upregulation

Cell2017PMID:29235455medium

Abstract

We report a high spatial resolution mass spectrometry (MS) system that allows us to image live hippocampal tissue slices under open-air atmospheric pressure (AP) and ambient temperature conditions at the subcellular level. The method is based on an efficient desorption process by femtosecond (fs) laser assisted with nanoparticles and a subsequent ionization step by applying nonthermal plasma, termed AP nanoparticle and plasma assisted laser desorption ionization (AP-nanoPALDI) MS method. Combining the AP-nanoPALDI with microscopic sample scanning, MS imaging with spatial resolution of 2.9 µm was obtained. The observed AP-nanoPALDI MS imaging clearly revealed the differences of molecular composition between the apical and basal dendrite regions of a hippocampal tissue. In addition, the AP-nanoPALDI MS imaging showed the decrease of cholesterol in hippocampus by treating with methyl β-cyclodextrin, which exemplifies the potential of AP-nanoPALDI for live tissue imaging for various biomed

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Sleep disruption accelerates amyloid-beta accumulation by impairing glymphatic clearance during slow-wave sleep phases

Science2013PMID:24136970medium

Abstract

The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.

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Pattern separation deficits in early Alzheimer's disease correlate with reduced adult hippocampal neurogenesis markers

Nature Communications2017PMID:28213546medium

Abstract

Sewage samples have been investigated to study the norovirus concentrations in sewage or the genotypes of noroviruses circulating in human populations. However, the statistical relationship between the concentration of the virus and the number of infected individuals and the clinical importance of genotypes or strains detected in sewage are unclear. In this study, we carried out both environmental and clinical surveillance of noroviruses for 3 years, 2013 to 2016. We performed cross-correlation analysis of the concentrations of norovirus GI or GII in sewage samples collected weekly and the reported number of gastroenteritis cases. Norovirus genotypes in sewage were also analyzed by pyrosequencing and compared with those identified in stool samples. The cross-correlation analysis found the peak coefficient (R = 0.51) at a lag of zero, indicating that the variation in the GII concentration, expressed as the log10 number of copies per milliliter, was coincident with that in the gastroente

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Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control.

Mol Psychiatry2024PMID:38123729medium

Abstract

Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are both key effectors of salience processing, reward and stress-related behaviors and motivational states, yet their respective roles and interactions are poorly delineated. We inactivated HCRT-to-DA connectivity by genetic disruption of Hypocretin receptor-1 (Hcrtr1), Hypocretin receptor-2 (Hcrtr2), or both receptors (Hcrtr1&2) in DA neurons and analyzed the consequences on vigilance states, brain oscillations and cognitive performance in freely behaving mice. Unexpectedly, loss of Hcrtr2, but not Hcrtr1 or Hcrtr1&2, induced a dramatic increase in theta (7-11 Hz) electroencephalographic (EEG) activity in both wakefulness and rapid-eye-movement sleep (REMS). DAHcrtr2-deficient mice spent more time in an active (or theta activity-enriched) substate of wakefulness, and exhibited prolonged REMS. Additionally, both wake and REMS displayed enhanced theta-gamma phase-amplitude coupling. The baseline waking EEG of DAHcrtr2-deficient mice exhibite

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Hypocretin/orexin in arousal and stress.

Brain Res2010PMID:19748490medium

Abstract

Multiple lines of evidence indicate that hypocretin/orexin (HCRT) participates in the regulation of arousal and arousal-related process. For example, HCRT axons and receptors are found within a variety of arousal-related systems. Moreover, when administered centrally, HCRT exerts robust wake-promoting actions. Finally, a dysregulation of HCRT neurotransmission is associated with the sleep/arousal disorder, narcolepsy. Combined, these observations suggested that HCRT might be a key transmitter system in the regulation of waking. Nonetheless, subsequent evidence indicates that HCRT may not play a prominent role in the initiation of normal waking. Instead HCRT may participate in a variety of processes such as consolidation of waking and/or coupling metabolic state with behavioral state. Additionally, substantial evidence suggests a potential involvement of HCRT in high-arousal conditions, including stress. Thus, HCRT neurotransmission is closely linked to high-arousal conditions, includin

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Mechanism for Hypocretin-mediated sleep-to-wake transitions.

Proc Natl Acad Sci U S A2012PMID:22955882medium

Abstract

Current models of sleep/wake regulation posit that Hypocretin (Hcrt)-expressing neurons in the lateral hypothalamus promote and stabilize wakefulness by projecting to subcortical arousal centers. However, the critical downstream effectors of Hcrt neurons are unknown. Here we use optogenetic, pharmacological, and computational tools to investigate the functional connectivity between Hcrt neurons and downstream noradrenergic neurons in the locus coeruleus (LC) during nonrapid eye movement (NREM) sleep. We found that photoinhibiting LC neurons during Hcrt stimulation blocked Hcrt-mediated sleep-to-wake transitions. In contrast, when LC neurons were optically stimulated to increase membrane excitability, concomitant photostimulation of Hcrt neurons significantly increased the probability of sleep-to-wake transitions compared with Hcrt stimulation alone. We also built a conductance-based computational model of Hcrt-LC circuitry that recapitulates our behavioral results using LC neurons as t

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The neuronal circuit between nociceptin/orphanin FQ and hypocretins/orexins coordinately modulates stress-induced analgesia and anxiety-related behavior.

Vitam Horm2015PMID:25677777medium

Abstract

The neuropeptide nociceptin/orphanin FQ (N/OFQ), acting on its receptors (NOP), modulates a variety of biological functions and neurobehavior including nociception, stress responses, water and food-intake, locomotor activity, and spatial attention. N/OFQ is conventionally regarded as an "antiopiate" peptide in the brain because central administration of N/OFQ attenuates stress-induced analgesia (SIA) and produces anxiolytic effects. However, naloxone-irreversible SIA and anxiolytic action are unlikely to be mediated by the opiate system. Both N/OFQ and NOP receptors are expressed most abundantly in the hypothalamus, where two other neuropeptides, the hypocretins/orexins (Hcrts), are exclusively synthesized in the lateral hypothalamic area. N/OFQ and Hcrt regulate most cellular physiological responses in opposite directions (e.g., ion channel modulation and second messenger coupling), and produce differential modulations for almost all neurobehavior assessed, including sleep/wake, locom

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A Role for Hypocretin/Orexin in Metabolic and Sleep Abnormalities in a Mouse Model of Non-metastatic Breast Cancer.

Cell Metab2018PMID:29805100medium

Abstract

We investigated relationships among immune, metabolic, and sleep abnormalities in mice with non-metastatic mammary cancer. Tumor-bearing mice displayed interleukin-6 (IL-6)-mediated peripheral inflammation, coincident with altered hepatic glucose processing and sleep. Tumor-bearing mice were hyperphagic, had reduced serum leptin concentrations, and enhanced sensitivity to exogenous ghrelin. We tested whether these phenotypes were driven by inflammation using neutralizing monoclonal antibodies against IL-6; despite the reduction in IL-6 signaling, metabolic and sleep abnormalities persisted. We next investigated neural populations coupling metabolism and sleep, and observed altered activity within lateral-hypothalamic hypocretin/orexin (HO) neurons. We used a dual HO-receptor antagonist to test whether increased HO signaling was causing metabolic abnormalities. This approach rescued metabolic abnormalities and enhanced sleep quality in tumor-bearing mice. Peripheral sympathetic denervat

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Adult hippocampal neurogenesis in humans drops to undetectable levels after adolescence, questioning the therapeutic relevance

Nature2018PMID:29513649medium

Abstract

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem sampl

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Hypocretin/orexin primarily promotes wakefulness; therapeutic restoration could paradoxically worsen sleep fragmentation in dementia

Nature Reviews Neuroscience2019PMID:30543234medium

Abstract

Despite the widespread use of nanotechnology in radio-imaging applications, lipoprotein based delivery systems have received only limited attention so far. These studies involve the synthesis of a novel hydrophobic radio-imaging tracer consisting of a hydrazinonicotinic acid (HYNIC)-N-dodecylamide and 99mTc conjugate that can be encapsulated into rHDL nanoparticles (NPs). These rHDL NPs can selectively target the Scavenger Receptor type B1 (SR-B1) that is overexpressed on most cancer cells due to excess demand for cholesterol for membrane biogenesis and thus can target tumors in vivo. We provide details of the tracer synthesis, characterization of the rHDL/tracer complex, in vitro uptake, stability studies and in vivo application of this new radio-imaging approach.

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Newborn neurons generated in amyloid-rich environment show impaired survival and integration, limiting therapeutic potential

Alzheimer's & Dementia2020PMID:31685530medium

Abstract

OBJECTIVE: To examine the reciprocal longitudinal associations between depression or anxiety with work-related injury (WRI) at a large employer in the southwestern United States. METHOD: Three administrative datasets (2011-2013) were merged: employee eligibility, medical and prescription claims, and workers' compensation claims. The sample contained 69 066 active employees. Depression and anxiety were defined as episodes of medical visits care (ie, claims) with corresponding ICD-9-CM codes. For an individual's consecutive claims, a new case of depression or anxiety was defined if more than 8 weeks have passed since the prior episode. The presence of a workers' compensation injury claim was used to identify WRI. Three-wave (health plan years 2011 or T1, 2012 or T2, and 2013 or T3) autoregressive cross-lagged models were used to estimate whether depression or anxiety predicted WRI, also if WRI predicted depression or anxiety in the following year(s). RESULTS: Depression predicted injury

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Dual orexin receptor agonists cause dose-limiting side effects including cataplexy-like episodes and significant appetite changes

Nature Medicine2021PMID:33539543medium

Abstract

BACKGROUND: In vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments conventionally consist of a fresh embryo transfer, possibly followed by one or more cryopreserved embryo transfers in subsequent cycles. An alternative option is to freeze all suitable embryos and transfer cryopreserved embryos in subsequent cycles only, which is known as the 'freeze all' strategy. This is the first update of the Cochrane Review on this comparison. OBJECTIVES: To evaluate the effectiveness and safety of the freeze all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials from inception until 23 September 2020 for relevant studies, checked references of publications found, and contacted study authors to obtain additional data. SELECTION CRITERIA: Two revi

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Chronic hypocretin receptor activation leads to receptor desensitization and tolerance, potentially limiting long-term efficacy

Journal of Neuroscience2016PMID:27568067medium

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Neurogenesis enhancement without concurrent neuroprotection may create vulnerable young neurons susceptible to AD pathology

Cell Stem Cell2018PMID:29777924medium

Abstract

OBJECTIVES: To explore inpatients experiences and views with regard to antibiotics in five European hospitals. METHODS: Qualitative study where a patient-centred framework was used to explore inpatients' experiences concerning antibiotic treatment. A purposeful sample of inpatients treated with antibiotics in five hospitals participated in interviews (all centres) and focus groups (Switzerland only). RESULTS: A total of 31 interviews (five in Belgium, ten in Croatia, nine in France, five in the Netherlands and two in Switzerland) and three focus groups (in Switzerland, 11 participants) were performed. The median age of participants was 61 years (range 33-86 years). The following main themes emerged: (a) patients trust doctors to take the best decisions for them even though communication concerning different antibiotic-related aspects is often insufficient, (b) patients feel that doctors do not prioritize communication due to time constraints and do not seem to adapt information based o

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Sleep-wake dysregulation in AD involves multiple neurotransmitter systems beyond hypocretin, limiting single-target approaches

Nature Reviews Drug Discovery2019PMID:31197153medium

Abstract

The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful di

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Hippocampal neurogenesis may not significantly contribute to memory formation in aged brains due to limited integration capacity

Cell2018PMID:30573821medium

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Challenges in the development of therapeutics for narcolepsy.

Prog Neurobiol2017PMID:26721620medium

Abstract

Narcolepsy is a neurological disorder that afflicts 1 in 2000 individuals and is characterized by excessive daytime sleepiness and cataplexy-a sudden loss of muscle tone triggered by positive emotions. Features of narcolepsy include dysregulation of arousal state boundaries as well as autonomic and metabolic disturbances. Disruption of neurotransmission through the hypocretin/orexin (Hcrt) system, usually by degeneration of the HCRT-producing neurons in the posterior hypothalamus, results in narcolepsy. The cause of Hcrt neurodegeneration is unknown but thought to be related to autoimmune processes. Current treatments for narcolepsy are symptomatic, including wake-promoting therapeutics that increase presynaptic dopamine release and anticataplectic agents that activate monoaminergic neurotransmission. Sodium oxybate is the only medication approved by the US Food and Drug Administration that alleviates both sleep/wake disturbances and cataplexy. Development of therapeutics for narcoleps

Contradicts

Sleep deprivation and cerebrospinal fluid biomarkers for Alzheimer's disease.

Sleep2018PMID:29425372medium

Abstract

STUDY OBJECTIVES: To investigate the cumulative effect of five consecutive nights of partial sleep deprivation (PSD) on a panel of cerebrospinal fluid (CSF) biomarkers in healthy adults. METHODS: A randomized, cross-over study conducted at the University of Gothenburg. The participants (N = 13) were healthy adults (20-40 years of age) with a normal sleeping pattern. The participants underwent a baseline sleep period consisting of five nights with 8 hr spent in bed. A subsequent period with PSD consisted of five nights of maximum 4 hr of sleep per night. Four participants were also subjected to a prolonged period of PSD consisting of eight nights with 4 hr of sleep per night. Sleep was monitored by means of observation, actigraphy, and continuous polysomnographic recordings. CSF samples were collected by routine lumbar puncture after each period. CSF biomarkers included the 38, 40, and 42 amino acid-long Aβ isoforms, total-τ, phospho-τ, orexin, monoamine metabolites (3-methoxy-4-hydroxy

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Reciprocal associations between depression, anxiety and work-related injury.

Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention (2020) · PubMed:31685530 ↗

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