ArticleTranslational psychiatry2023
Melatonin alleviates depression-like behaviors and cognitive dysfunction in mice by regulating the circadian rhythm of AQP4 polarization.
Article in Translational psychiatry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers, 2 of them syntheses that pooled it.
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The trial behind it
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Who cites it
76 citing papers in PubMed, 2 syntheses or guidelines pooled it, 99 citations in OpenAlex.
- The Anti-Aging Benefits of Phytoestrogens: Insights and Evidence.Current medicinal chemistry · 2026Pooled it
- Sleep disorders in Parkinson's disease: evaluating pharmacological treatments through systematic review and meta-analysis.BMC neurology · 2025Pooled it
- Vortioxetine Improves Brain Glymphatic System Function, Functional Connectivity, and Cognitive Functions in Major Depressive Disorder.Depression and anxiety · 2025Trial
- The glymphatic-lymphatic axis: known pathways, open questions, and emerging roles in neurodegeneration.Translational neurodegeneration · 2026Review
- Glymphatic system dysfunction: a link between sleep disorders and neurodegeneration.Psychopharmacology · 2026Review
- Surgical and anesthetic rewiring of the glymphatic system in postoperative cognitive dysfunction.Neural regeneration research · 2026Article
- IL-15 receptor alpha deficiency triggers depressive-like behaviors via enhanced microglial synapse pruning.Molecular psychiatry · 2026Article
- Central nervous system lymphatic network: from the maintenance of brain homeostasis to emerging therapeutic perspectives in neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Continuous OFT-Based Behavioral Phenotyping Reveals Neural Stem Cell-Associated Shifts in Depression-like Mice.Brain sciences · 2026Article
- The role of glymphatic dysfunction in cerebral small vessel disease and vascular cognitive impairment, and therapeutic implications.International journal of stroke : official journal of the International Stroke Society · 2026Review
- Serial failure of the brain clearance continuum in Alzheimer's disease: mechanisms and therapeutic perspectives.Journal of neurology · 2026Review
- The Clearance-Centered Bottleneck in Alzheimer's Disease: From Coupled Glymphatic-Lymphatic Circuits to Therapeutic Opportunities.Molecular neurobiology · 2026Review
- Cholinergic basal forebrain modulation of glymphatic function: implications for depression.Translational psychiatry · 2026Article
- The mechanism of polycystic ovarian syndrome induced by circadian rhythm disturbance and the therapeutic effect of melatonin.Journal of clinical biochemistry and nutrition · 2026Article
- Melatonin reverses obesity-induced neurodegeneration through glymphatic restoration.Neural regeneration research · 2026Article
- Microglia depletion alleviates the disruptions in circadian rhythms and anxiety caused by bmal1 deficiency.Brain, behavior, & immunity - health · 2026Article
- Glymphatic system impairment in neurological disorders: potential mechanisms and therapeutic targets.Molecular biomedicine · 2026Review
- Analysis of gut microbiota and intestinal mucosal neurotransmitter changes and their correlation in adolescent depression mice.Annals of general psychiatry · 2026Article
- Sleep-circadian modulation of autophagy and glymphatic function: failure of coordinated brain clearance in Parkinson's disease.NPJ Parkinson's disease · 2026Review
- The biological clock in parkinson's disease: mechanisms and chronotherapy.NPJ Parkinson's disease · 2026Review
16 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Depression is a common chronic psychiatric illness, which is resistant to medical treatments. While melatonin may alleviate certain depression symptoms, evidence for its efficacy against core symptoms is lacking. Here, we tested a mechanism whereby melatonin rescues the behavioral outcomes of the chronic unpredictable mild stress (CUMS) mouse model of depression. CUMS mice showed depressive behaviors to tail suspension, open field behavior, and sucrose preference test, and cognitive dysfunction in the Morris water maze. Impairments in these measures were relieved by melatonin treatment. Moreover, CUMS mice had impaired glymphatic function across the sleep-wake cycle due to the astrocytic loss and disturbance of circadian regulation of the polarized expression of aquaporin-4 (AQP4) water channels in perivascular astrocytes. EEG results in CUMS mice showed a reduced total sleep time and non-rapid eye movement (NREM) sleep, due to sleep fragmentation in the light phase. CUMS mice lost the normal rhythmic expressions of circadian proteins Per2, Cry2, Bmal1, Clock, and Per1. However, the melatonin treatment restored glymphatic system function and the polarization of AQP4, while improving sleep structure, and rectifying the abnormal expression of Per2, Bmal1, Clock, and Per1 in CUMS mice. Interestingly, Per2 expression correlated negatively with the polarization of AQP4. Further studies demonstrated that Per2 directed the location of AQP4 expression via interactions with the α-dystrobrevin (Dtna) subunit of AQP4 in primary cultured astrocytes. In conclusion, we report a new mechanism whereby melatonin improves depression outcomes by regulating the expression of the circadian protein Per2, maintaining the circadian rhythm of astrocytic AQP4 polarization, and restoring glymphatic function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.