Anything but small: Microarousals stand at the crossroad between noradrenaline signaling and key sleep functions

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Continuous sleep restores the brain and body, whereas fragmented harms cognition health. Microarousals (MAs), brief (3- to 15-s-long) wake intrusions into sleep, are clinical markers for various disorders. Recent rodent studies show that MAs during healthy non-rapid eye movement (NREM) driven by infraslow fluctuations of noradrenaline (NA) in coordination with electrophysiological rhythms, vasomotor activity, cerebral blood volume, glymphatic flow. hence part dynamics, raising questions about their biological roles. We propose bolster NREM sleep's benefits associated NA fluctuations, according an inverted U-shaped curve. Weakened noradrenergic as may occur neurodegenerative diseases or aids, reduce MAs, exacerbated caused stress fragment collapse signaling. suggest crucial restorative plasticity-promoting functions advance our insight normal pathological arousal dynamics from sleep.

Language: Английский

---

SLEEP DISORDERS AND RISK OF ALZHEIMER'S DISEASE: A TWO-WAY ROAD

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: unknown, P. 102514 - 102514

Published: Sept. 1, 2024

Language: Английский

---

Deciphering the Functions of Raphe–Hippocampal Serotonergic and Glutamatergic Circuits and their Deficits in Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1234 - 1234

Published: Jan. 30, 2025

Subcortical innervation of the hippocampus by raphe nucleus is essential for emotional and cognitive control. The two major afferents from to originate serotonergic glutamatergic neurons, which control hippocampal inhibitory network, theta activity, synaptic plasticity have been extensively explored in growing body literature, whereas those circuits received little attention. Notably, both between are disrupted Alzheimer's disease (AD), may contribute initiation progression behavioral psychological symptoms dementia. Thus, deciphering mechanism underlying abnormal raphe-hippocampal AD crucial prevent dementia-associated symptoms. In this review, we summarize anatomical, neurochemical, electrophysiological diversity nuclei as well architecture circuitry. We then elucidate subcortical activity their role regulation emotion cognition. Additionally, present an overview pathogenesis analyze available therapies that can potentially be used clinically alleviate neuropsychiatric decline course.

Language: Английский

---

Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 5, 2025

Histamine H3 receptor (H3R) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although H3R is elevated in Alzheimer's disease (AD) patients, whether can rescue AD-associated neural impairments deficits remains unknown. Pitolisant a clinically approved antagonist/inverse agonist treats narcolepsy. Here, we find pitolisant reverses AD-like pathophysiology an AD mouse model. Behavioral assays vivo wide-field Ca2+ imaging revealed recognition memory, learning flexibility, slow-wave impairment were all improved following the 15-day treatment. Improved memory was tightly correlated with coherence, suggesting slow waves serve as biomarker for treatment response drug screening. Furthermore, reduced amyloid-β deposition dystrophic neurites surrounding plaques, enhanced lysosomal activity, inhibiting which blocked restoration. Our findings identify potential therapeutic agent treatments.

Language: Английский

---

Tauopathy after long‐term cervical lymphadenectomy

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(4)

Published: April 1, 2025

Abstract INTRODUCTION This study examined the effects of long‐term cervical lymphadenectomy (cLE) on cognitive and Alzheimer's disease (AD)–like tauopathy changes. METHODS Male C57BL/6 mice were used to assess cLE impacts sleep, brain pathways, pathologies. RNA sequencing proteomics analyzed gene/protein changes, with results verified by western blotting immunofluorescence. RESULTS CLE led sleep psychiatric disorders, linked mitogen‐activated protein kinase/extracellular signal‐regulated kinase (ERK) pathway activation. Activation ERK may interfere autophagy is associated phosphorylated tau accumulation. Peripheral blood analysis shows decreased waste in peripheral post‐cLE, implicating impaired lymphatic drainage build‐up. DISCUSSION These findings suggest a potential connection between AD‐like tauopathy, potentially influencing surgical decisions. Highlights Cervical cornerstone head neck cancers, affecting millions people each year. We provide first evidence mildly functioning significant anxiety–depressive disorders after cLE. Long‐term not only directly impairs wastes (amyloid beta, [p‐tau]) drainage, but also activates Erk1/2 signaling leading attenuation autophagy. found for time that accelerated deposition p‐tau young mice. Patients clinical lymph node dissection showed reduced consistent mouse models. suggests need further evaluation neurologic dissection, procedure affects

Language: Английский

---

Monoaminergic signaling during mammalian NREM sleep - Recent insights and next-level questions

Current Opinion in Neurobiology, Journal Year: 2025, Volume and Issue: 92, P. 103025 - 103025

Published: April 22, 2025

Language: Английский

---

Echoes in the night: How sleep quality influences auditory health

Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

---

Sleep as a window to understand and regulate Alzheimer’s disease: emerging roles of thalamic reticular nucleus

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(6), P. 1711 - 1712

Published: July 10, 2024

Introduction: Alzheimer's disease (AD) is a common neurodegenerative disorder and the primary cause of dementia. Considerable evidence supports "amyloid hypothesis," stating that pathogenesis AD primarily caused by deposition amyloid-β (Aβ), which drives tau phosphorylation, neuroinflammation, neurodegeneration in brain. The amyloid hypothesis strengthened significant moderate benefit lecanemab, humanized antibody through an anti-amyloid mechanism, showing slowed clinical decline (van Dyck et al., 2023). recent positive results trials have brought back focus on biochemical, genetic, pharmacological approaches (Zhang, As complex disease, neuropathology risk are heterogeneous regulated aging, genetics, sex, combination with other risk-modifying factors. Among factors AD, sleep disturbance important factor may occur early last throughout disease. Sleep tightly lifespan has plausible protective effects against various human disorders, besides AD. Insufficient or disrupted challenge to brain health major public issue - more than third American adults do not get enough regularly disorders associated disruption (e.g., apnea, insomnia) impact at least adult population. bidirectional relationship between disturbances well known. For example, deprivation humans leads Aβ42 abnormality cerebrospinal fluid; hand, Aβ overproduction sleep-regulating regions, both mice exhibit shorter fragmented sleep. Other mediators sleep-AD cycle include pathologic tau, microglia activation, impaired blood-brain barrier, glymphatic system, loss nighttime blood pressure dipping, hypoxia. Because represents threat neuroanatomical structures be become research. One candidate region involved pathophysiology thalamic reticular nucleus (TRN). TRN receives inputs from multiple regions arousal-sleep including ventrolateral preoptic area, laterodorsal tegmentum, reciprocal connections thalamus, cortex. Therefore, it integrates these signals regulate specifically inhibits thalamocortical relay neurons, reducing transmission sensory cortex promoting slow-wave Another function serve as pacemaker for spindles during non-rapid eye movement During sleep, GABAergic neurons fire bursting mode, leading post-inhibitory rebound spikes provide feedback TRN, creating spindles. roles studies only tried elucidate molecular mechanisms underlying but also attempted uncover TRN-related therapeutic potential Below we will our perspectives regarding use window better understand (Figure 1).Figure 1: Role being understanding regulating AD.Created BioRender.com. AD: disease; eCB: endocannabinoid; NADA: N-arachidonoyl dopamine; TRN: nucleus.Thalamic linked disturbance: How unclear been recently explored. properties were analyzed APPSwedish/Indiana-containing transgenic J20 contain (Jagirdar 2021). displayed reduced neuronal activity, itself site deposition. In tissue, there fewer FosB/∆FosB-expressing cells while gradient different stages. Based literature, support two hypotheses mechanism impairment pathology. First, activity dyshomeostasis hyperexcitability proposed firing homeostasis plasticity key ingredients pre-symptomatic (Styr Slutsky, 2018; 2024), accompanied inhibition epileptic inhibiting Second, genetic factors, such mutations ABCA7, contribute abnormalities ceramide signaling (Liu 2021; Hijazi role neurodegeneration, neuroinflammation elusive moment. (Weng 2020). mice, fragmentation was found before 4–5 months age, increased decreased time, followed memory deficits. spindles, impairs consolidation worsens dementia, completing vicious cycle. noradrenergic input locus coeruleus unstable unfavorable autonomic cardiovascular outcomes. This because imposes infraslow oscillation 0.02 Hz measured sigma band power 11–16 wave, synchronized cyclic alternating patterns pupil size, breathing, heart rate (Osorio-Forero treatment response when targeting disease: Restoring reduce There few methods reported restore functions, far translation. selective activation using DREADDs (designer receptor exclusively activated designer drugs) time deep importantly plaque load hippocampus 2021), suggests loss-of-function pathology reduction achieved restoring mediated improved quality. study (Ding 2023) showed dopamine (NADA), endocannabinoid, pain-related chronic mouse model. Along same line animal model, local NADA administration restored attenuated hyperalgesia, mice. Thus, endocannabinoid system implicated target, microglial protecting damage, cell survival, potentiating neurons. high density CB1 sensitive NADA. Reduced one possible ways connect At microstructures can used elements function. Spindle N2 natural choice due TRN's spindle generation. Sigma alternative density, amplitude does require fine-tuning detection parameters. addition, spindle-slow coupling reflects intactness circuits involving TRN. most accurate combining microstructure measurements. Taken together, target biomarker state potentially Future directions steps toward translation: direction shown Jagirdar al. (2021), phosphorylated yet contributes fragility fragmentation. More work needed clarify how fits into connection manifesting research within larger context inhibitory neuron (Carello-Collar 2: Going beyond unknown. receptors, hence modulated system. promising molecule validated disturbance-mediated pain Owing functions nervous disturbance-related disorders. 3: Several Food Drug Administration (FDA)-approved medications acetylcholinesterase inhibitors N-methyl-D-aspartate partial antagonists, palliative modest symptomatic relief slow progression. Recent FDA approval lecanemab new hopes patients, along antibodies donanemab (not approved April 2024). It warrants future investigations focusing changes under treatments. expected ergonomic measurement devices widely available near future, those home. mentioned above, marker However, categories spindles: fast (> 13 Hz) (< (Fernandez Luthi, They display spatial temporal distributions correlated cognition memory. clear if merely manifestations source not. need investigate determine indicator. sleep-related metrics proposed, K-complex, pattern, coupling, oscillation, depth. Combining specific artificial intelligence-based approaches. These should their association optimize decision-making. Conclusion: We review highlight interactions data provided proof concept supporting enhancing possibilities regulation mechanisms. A circuitry-level supported Massachusetts General Hospital Scientific Projects Accelerate Research Collaboration (SPARC) award Cure Fund (to CZ); National Institutes Health (NIH), R01NS102190, RF1NS120947, R01HL161253 MBW); RF1NS120947 RJT). Dr. Westover co-founder Beacon Biosignals, any part this article. Thomas patent ECG/PPG spectrogram licensed Beth Israel Deaconess Medical Center MyCardio, LLC. He consults GLG Councils Guidepoint Global. authors nothing disclose. C-Editors: Zhao M, Sun Y, Qiu Y; T-Editor: Jia Y

Language: Английский

---

The association between insomnia and cognitive decline: a scoping review

Sleep Medicine, Journal Year: 2024, Volume and Issue: 124, P. 540 - 550

Published: Oct. 17, 2024

Language: Английский

---

Memantine and the Kynurenine Pathway in the Brain: Selective Targeting of Kynurenic Acid in the Rat Cerebral Cortex

Cells, Journal Year: 2024, Volume and Issue: 13(17), P. 1424 - 1424

Published: Aug. 26, 2024

Cytoprotective and neurotoxic kynurenines formed along the kynurenine pathway (KP) were identified as possible therapeutic targets in various neuropsychiatric conditions. Memantine, an adamantane derivative modulating dopamine-, noradrenaline-, serotonin-, glutamate-mediated neurotransmission is currently considered for therapy dementia, psychiatric disorders, migraines, or ischemia. Previous studies have revealed that memantine potently stimulates synthesis of neuroprotective kynurenic acid (KYNA) vitro via a protein kinase A-dependent mechanism. Here, effects acute prolonged administration on brain functional changes cerebral KP assessed rats using chromatographic enzymatic methods. Five-day but not single treatment with selectively activated cortical towards KYNA. KYNA increases accompanied by moderate decrease tryptophan (TRP) L-kynurenine (L-KYN) concentrations without 3-hydroxykynurenine (3-HK) levels. Enzymatic activity biosynthetic enzymes ex vivo was stimulated after memantine. As does directly stimulate KATs' proteins, higher KATs most probably results from increased expression respective genes. Noteworthy, KYNA, 3-HK, TRP, L-KYN striatum, hippocampus, cerebellum affected. Selective increase seems to represent one mechanisms underlying clinical efficacy It tempting hypothesize combination drugs could strongly boost provide more effective option treating pathologies at early stages. Further should evaluate this issue experimental animal models under scenarios.

Language: Английский

---