Connectome-based modelling of neurodegenerative diseases: towards precision medicine and mechanistic insight

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(10), P. 620 - 639

Published: Aug. 24, 2023

Language: Английский

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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

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Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105167 - 105167

Published: April 11, 2023

Noradrenergic and cholinergic systems are among the most vulnerable brain in neuropsychiatric diseases of ageing, including Alzheimer's disease, Parkinson's Lewy body dementia, progressive supranuclear palsy. As these fail, they contribute directly to many characteristic cognitive psychiatric symptoms. However, their contribution symptoms is not sufficiently understood, pharmacological interventions targeting noradrenergic have met with mixed success. Part challenge complex neurobiology systems, operating across multiple timescales, non-linear changes adult lifespan disease course. We address challenges a detailed review outlining roles cognition behaviour, how influence disease. By bridging levels analysis, we highlight opportunities for improving drug therapies pursuing personalised medicine strategies.

Language: Английский

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Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition

Nature Aging, Journal Year: 2024, Volume and Issue: 4(5), P. 625 - 637

Published: April 25, 2024

Abstract Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer’s disease. By combining vivo longitudinal magnetic resonance imaging measures of LC integrity, positron emission tomography and cognition with autopsy data transcriptomic information, we examined whether changes precede deposition specific genetic features underlie LC’s selective vulnerability to tau. We found integrity preceded medial temporal lobe accumulation, together these processes were associated lower cognitive performance. Common gene expression profiles between LC–medial lobe–limbic map biological functions protein transport regulation. These findings advance our understanding spatiotemporal patterns initial spreading from disease pathology. can be a promising indicator for identifying time window when individuals are at risk progression underscore importance interventions mitigating spread.

Language: Английский

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Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 168(5), P. 801 - 821

Published: June 30, 2023

Abstract Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which alarming given that obesity prevalence peaks at rates are accelerating worldwide. Midlife, but not late‐life risk, suggesting this interaction specific to preclinical AD. pathology begins age, with accumulation amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach young adult (6.5 months old) male female TgF344‐AD rats overexpress mutant human precursor protein presenilin‐1 wild‐type (WT) controls determine whether inducing high‐fat/high‐sugar “Western” diet during brain dysfunction dorsal hippocampus (dHC), region vulnerable effects early Analyses dHC gene expression data showed dysregulated mitochondrial neurotransmission pathways, up‐regulated genes involved cholesterol synthesis. Western amplified number were different between WT added pathways noradrenergic signaling, inhibition synthesis, decreased intracellular lipid transporters. Importantly, impaired dHC‐dependent spatial working memory rats, confirming dietary intervention accelerated decline. To examine later consequences transcriptional dysregulation, we measured monoamine levels older (13 both sexes after long‐term chow or consumption. Norepinephrine (NE) abundance was significantly NE turnover increased, attenuated AD‐induced turnover. Collectively, these findings indicate prodromal impairs memory, potentiates decline likely leading an overproduction cholesterol, interferes compensatory transmission. image

Language: Английский

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Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 10, 2024

Language: Английский

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Diurnal Modulation of Locus Coeruleus Noradrenergic Neurons in Anesthetized Adult Male Rats

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

The locus coeruleus (LC) is the primary source of noradrenaline (NA) in brain and its activity essential for learning, memory, stress, arousal, mood. LC-NA neuron varies over sleep-wake cycle, with higher during wakefulness, correlating increased CSF NA levels. Whether spontaneous burst firing neurons active inactive periods controlled by mechanisms independent wakefulness natural sleep, currently unknown. Here, using multichannel vivo electrophysiology under anesthesia, we assessed adult male Fisher 344 rats at two different times day- ZT4- period (light phase) ZT16-the (dark phase)- contributions from behavioral arousal sleep. In dark phase, exhibit average rate baseline compared to light phase. Using a relatively weak foot shock paradigm, observed distinct populations some increasing, others decreasing, their baseline. Additionally, while spike frequency evoked bursts consistent across dark-light units recorded phase have more frequent longer duration than those Our findings show that wake state, intrinsic diurnal activity, variability response stimulation demonstrates physiological heterogeneity just beginning be appreciated. Multichannel assesses large within an intact LC. Recording anesthesia eliminates influence behavior sleep on physiology. data heightened suggesting hardwired rhythm. variable highlighting heterogeneity, contemporary view LC physiology complex previously

Language: Английский

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Loss of excitatory inputs and decreased tonic and evoked activity of locus coeruleus neurons in aged P301S mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract Tau pathology in the locus coeruleus (LC) is associated with several neurodegenerative conditions including Alzheimer’s disease and frontotemporal dementia. Phosphorylated tau accumulates LC results inflammation, synaptic loss, eventually cell death as progresses. Loss of neurons noradrenergic innervation thought to contribute symptoms cognitive decline later disease. While loss degeneration has been well studied, less known about changes physiology at advanced stages that precedes neurodegeneration. In this study, we investigated ex vivo electrophysiological properties male female mice from P301S mouse model tauopathy 9 months age, a time-point when significant accumulation, death, impairments are observed. We found reduction excitatory inputs post-synaptic current kinetics P301S. There was also decrease spontaneous discharge an increase AP threshold both sexes. Finally, observed excitability rheobase mice. Despite activity slice, did not identify differences total tissue norepinephrine (NE) or NE metabolites prefrontal cortex hippocampus. Together these findings demonstrate reductions late accumulation. However, compensatory mechanisms may maintain normal levels projection regions vivo.

Language: Английский

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tDCS Cranial Nerve Co-Stimulation: Unveiling Brainstem Pathways Involved in Trigeminal Nerve Direct Current Stimulation in Rats

Brain stimulation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Fading Blue: Exploring the Causes of Locus Coeruleus Damage Across the Lifespan

Antioxidants, Journal Year: 2025, Volume and Issue: 14(3), P. 255 - 255

Published: Feb. 22, 2025

Locus Coeruleus (LC) is a brain nucleus that involved in variety of key functions (ranging from attention modulation to sleep-wake cycle regulation, memory encoding); its proper function necessary both during development and for integrity maintenance, at the microscale macroscale level. Due their specific intrinsic extrinsic features, LC cells are considered particularly susceptible damage concerning insults. This explains involvement degenerative diseases not only adults (in context neurodegenerative disease, mainly), but also children relation early hypoxic Down's Syndrome, among others). In this narrative review, we dissect potential mechanisms through which affected different diseases, with special emphasis on high rate activity it subjected oxidative stress associated it. Further research aimed deepening our understanding these needed enable strategies future could slow down degeneration subjects predisposed disorders.

Language: Английский

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