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

Neuron, Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: Английский

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Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS

Frontiers in Neuroscience, Год журнала: 2021, Номер 15

Опубликована: Фев. 9, 2021

The classic concept of the absence lymphatic vessels in central nervous system (CNS), suggesting immune privilege brain spite its high metabolic rate, was predominant until recent times. On other hand, this idea left questioned how cerebral interstitial fluid is cleared waste products. It generally thought that clearance depends on cerebrospinal (CSF). Not long ago, an anatomically and functionally discrete paravascular space revised to provide a pathway for molecules drained within space. According model, CSF enters parenchyma along arterial spaces. Once mixed with solutes process mediated by aquaporin-4, exits through extracellular venous spaces, thus being removed from brain. This includes participation perivascular glial cells due sieving effect their end-feet. Such draining resembles peripheral system, therefore, term “glymphatic” (glial-lymphatic) has been coined. Specific studies focused potential role glymphatic healthy pathological conditions, including neurodegenerative diseases. mainly concerns Alzheimer’s disease (AD), as well hemorrhagic ischemic neurovascular disorders; acute degenerative processes, such normal pressure hydrocephalus or traumatic injury are involved well. Novel morphological functional investigations also suggested alternative models drain pathways, which enriched our insight homeostatic processes neural microenvironment. Under light these considerations, present article aims discuss findings concepts drainage blood–brain barrier (BBB) attempt understand conditions may be detrimental CNS, paving way neurodegeneration.

Язык: Английский

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A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

Brain, Год журнала: 2021, Номер 145(6), С. 1924 - 1938

Опубликована: Дек. 14, 2021

Abstract The locus coeruleus is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration dementia. Locus dysfunction contributes to pathobiology experimental models, which can be rescued increasing norepinephrine transmission. To test augmentation as a potential disease-modifying therapy, we performed biomarker-driven phase II trial atomoxetine, clinically-approved transporter inhibitor, subjects mild cognitive impairment due disease. design was single-centre, 12-month double-blind crossover trial. Thirty-nine participants and biomarker evidence were randomized atomoxetine or placebo treatment. Assessments collected at baseline, 6- (crossover) 12-months (completer). Target engagement assessed CSF plasma measures metabolites. Prespecified primary outcomes levels IL1α TECK. Secondary/exploratory included clinical measures, analyses amyloid-β42, Tau, pTau181, mass spectrometry proteomics immune-based targeted inflammation-related cytokines, well brain imaging MRI fluorodeoxyglucose-PET. Baseline demographic similar across arms. Dropout rates 5.1% for 2.7% placebo, no significant differences adverse events. Atomoxetine robustly increased levels. IL-1α TECK not measurable most samples. There treatment effects on cognition outcomes, expected given short duration. associated reduction pTau181 compared but change amyloid-β42. also significantly altered abundances protein panels linked pathophysiologies, including synaptic, metabolism glial immunity, CDCP1, CD244, TWEAK osteoprotegerin proteins. Treatment brain-derived neurotrophic factor reduced triglycerides plasma. Resting state functional showed inter-network connectivity between insula hippocampus. Fluorodeoxyglucose-PET atomoxetine-associated uptake hippocampus, parahippocampal gyrus, middle temporal pole, inferior gyrus fusiform carry-over 6 months after In summary, safe, tolerated achieved target prodromal pTau, normalized synaptic function, activity key lobe circuits. Further study warranted repurposing drug slow progression.

Язык: Английский

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When the Locus Coeruleus Speaks Up in Sleep: Recent Insights, Emerging Perspectives

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(9), С. 5028 - 5028

Опубликована: Апрель 30, 2022

For decades, numerous seminal studies have built our understanding of the locus coeruleus (LC), vertebrate brain’s principal noradrenergic system. Containing a numerically small but broadly efferent cell population, LC provides brain-wide modulation that optimizes network function in context attentive and flexible interaction with sensory environment. This review turns attention to LC’s roles during sleep. We show these go beyond down-scaled versions ones wakefulness. Novel dynamic assessments noradrenaline signaling activity uncover rich diversity patterns establish as an integral portion sleep regulation function. The could be involved beneficial functions for sleeping brain, even minute alterations its functionality may prove quintessential disorders.

Язык: Английский

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Cognition through the lens of a body–brain dynamic system

Trends in Neurosciences, Год журнала: 2022, Номер 45(9), С. 667 - 677

Опубликована: Июль 6, 2022

Язык: Английский

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Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

Alzheimer s & Dementia, Год журнала: 2023, Номер 19(5), С. 2182 - 2196

Опубликована: Янв. 15, 2023

Abstract The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau‐associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction cortical lesions. Accumulating evidence supports role behavioral neuropsychiatric manifestations featured AD. Experimental studies even suggest that AD‐associated drives brain neuroinflammatory status contributes to progression, including exacerbation Given important pathophysiologic etiologic roles involve AD stages, there is an urgent need expand our understanding mechanisms underlying vulnerability more precisely detail clinical progression changes Here, Professional Interest Area International Society Advance Research Treatment highlights knowledge gaps about within provides recommendations priorities specific research, biomarker development, modeling, intervention. Highlights Neuromodulatory degenerate pathological stages. pathophysiology exacerbated by degeneration. symptoms dementia. Biomarkers integrity would be value‐creating dementia care. present strategic prospects disease‐modifying therapies.

Язык: Английский

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Noradrenaline released from locus coeruleus axons contracts cerebral capillary pericytes via α₂ adrenergic receptors

Journal of Cerebral Blood Flow & Metabolism, Год журнала: 2023, Номер 43(7), С. 1142 - 1152

Опубликована: Янв. 23, 2023

Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and capillary pericytes. This allows neuronal activity to evoke vasodilation that increases local cerebral blood flow (CBF). Much of the resistance within brain is located capillaries have NA sites closer pericytes than arterioles. In acute slices, contracted but did not raise pericyte cytoplasmic Ca 2+ concentration, while α 1 agonist phenylephrine contraction. Blocking 2 adrenergic receptors (α Rs, which induce contraction by inhibiting cAMP production), greatly reduced NA-evoked contraction, whereas stimulating Rs using xylazine (a sedative) or clonidine (an anti-hypertensive drug) evoked Noradrenaline-evoked constriction are thus mediated via Rs. Consequently, may only modulate CBF health pathological conditions, also contribute changes R ligands administered research, veterinary clinical settings.

Язык: Английский

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Tonic and burst-like locus coeruleus stimulation distinctly shift network activity across the cortical hierarchy

Nature Neuroscience, Год журнала: 2024, Номер 27(11), С. 2167 - 2177

Опубликована: Сен. 16, 2024

Abstract Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across brain, modulating multiple behavioral states. NA is mediated by both tonic burst-like LC activity. However, it unknown whether functional target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology magnetic resonance imaging mice, we show that patterns elicit brain responses hinge their distinct dynamics. During moderate activation, engages regions associated with associative processing, while stimulation biases toward sensory processing. These activation locally couple increased astrocytic inhibitory change brain’s topological configuration line hierarchical organization of cerebral cortex. Together, findings reveal how LC–NA system achieves a nuanced regulation global circuit operations.

Язык: Английский

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Astrocyte–Endotheliocyte Axis in the Regulation of the Blood–Brain Barrier

Neurochemical Research, Год журнала: 2021, Номер 46(10), С. 2538 - 2550

Опубликована: Май 7, 2021

Язык: Английский

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Research Evidence of the Role of the Glymphatic System and Its Potential Pharmacological Modulation in Neurodegenerative Diseases

Journal of Clinical Medicine, Год журнала: 2022, Номер 11(23), С. 6964 - 6964

Опубликована: Ноя. 25, 2022

The glymphatic system is a unique pathway that utilises end-feet Aquaporin 4 (AQP4) channels within perivascular astrocytes, which believed to cause cerebrospinal fluid (CSF) inflow into space (PVS), providing nutrients and waste disposal of the brain parenchyma. It theorised bulk flow CSF PVS removes products, soluble proteins, products metabolic activity, such as amyloid-β (Aβ). In experimental model, selectively active during slow-wave sleep, its activity affected by both sleep dysfunction deprivation. Dysfunction has been proposed potential key driver neurodegeneration. This hypothesis indirectly supported close relationship between neurodegenerative diseases alterations, frequently occurring years before clinical diagnosis. Therefore, detailed characterisation function in human physiology disease would shed light on early stage pathophysiology. study also critical identifying means for pharmacological modulation, may have modification. review will critically outline primary evidence from literature about neurodegeneration discuss rationale current knowledge modulation animal model applications trials.

Язык: Английский

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