Biology subjects

Noain, D.

Publications and source records attributed to Noain, D..

11 recordsLinked to original sources

bioRxiv2026

Bidirectional restoration of sleep homeostasis in neurodegeneration via closed-loop auditory stimulation

Sleep-wake disturbances in Alzheimers (AD) and Parkinsons disease (PD) are linked to disrupted slow-wave activity (SWA) and SW-spindle coupling, critical for memory consolidation and protein clearance. While SWA enhancement shows promise in aging, disease-specific effects on SW synchronization (local, linked to sleep depth vs. global, linked to arousal), spindle dynamics and sleep homeostasis remain unexplored in neurodegeneration. Using mouse closed-loop auditory stimulation (mCLAS), we probed its acute effects on SW subtypes, spindle characteristics, SW-spindle coupling and sleep homeostasis in Tg2576 (AD) and M83 (PD) mice. mCLAS adaptively modulates SW subtypes and SW-spindle coupling depending on baseline impairments. In AD mice, it reduces global synchrony while potentiating local phenomena and network recruitment, restoring SW-spindle coupling strength and normalizing spindle power. In PD mice, mCLAS increases global synchrony, reorganizing 24-hour SW dynamics towards wild-type patterns, while reducing excessive SW-spindle coupling and enhancing spindle power. Critically, mCLAS bidirectionally regulates sleep homeostasis: boosting deficient slow-wave energy in AD and reducing excess in PD to restore physiological sleep. These findings suggest mCLAS acts via complementary mechanisms to rescue sleep homeostasis in neurodegeneration, by modulating cortical synchrony in AD and arousal in PD, offering a noninvasive path to potentially mitigate cognitive decline and pathological progression.

neuroscience↗

bioRxiv2025

Sound-Enhanced Sleep Depth Reduces Traumatic Brain Injury Damage and Sequelae and Supports Microglial Response

Traumatic brain injury significantly reduces the quality of life for millions of survivors worldwide, with no established treatments currently available. High slow-wave activity (SWA) sleep immediately after rodent TBI improves posttraumatic outcomes. However, pharmacological SWA-enhancing strategies are hindered by severe specificity and scalability issues that prevent it from effectively reaching clinical implementation. Alternatively, closed-loop auditory stimulation (CLAS) of sleep slow waves offers specific SWA enhancement with high translational potential. Our present results demonstrate that up-phase-targeted CLAS (upCLAS)-mediated SWA enhancement reduced diffuse axonal injury, decreased demyelination, and preserved cognitive ability in TBI rats. The alleviated posttraumatic phenotype was associated with increased microglia response, likely mediating CLAS neuroprotective effect in the acute injury phase. Auditory-enhanced SWA may thus constitute a novel noninvasive neuroprotective therapy preventing TBI sequelae via boosted cellular response to tissue damage.

neuroscience↗

bioRxiv2024

Pharmacological enhancement of slow-wave activity improves cognition and reduces amyloidosis at an early stage in a mouse model of Alzheimer's disease

Improving sleep in murine Alzheimers disease (AD) is associated with reduced brain amyloidosis. However, the window of opportunity for successful sleep-targeted interventions regarding reduction of pathological hallmarks and related cognitive performance remains poorly characterized. Here, we enhanced slow-wave activity (SWA) during sleep via sodium oxybate (SO) oral administration for 2 weeks at early (6 months old) or moderately late (11 months old) disease stages in Tg2576 mice, and evaluated resulting neuropathology and behavioral performance. We observed that cognitive performance of 6 months old Tg2576 mice significantly improved upon SO treatment, whereas no change was observed in 11 months old mice. Histochemical assessment of amyloid plaques demonstrated that SO-treated 11 months old Tg2576 mice had significantly less plaque burden than placebo-treated ones, whereas ELISA of insoluble protein fractions from 6 months old Tg2576 mice brains indicated lower A{beta}-42/A{beta}-40 ratio in SO-treated group vs. placebo-treated controls. Altogether, our results suggest that SWA-dependent reduction of brain amyloidosis leads to alleviated behavioral impairment in Tg2576 mice only if administered early in the disease course, potentially highlighting the key importance of early sleep-based interventions in clinical cohorts. Significance statementA staggering amount of people worldwide live with AD. Despite extensive efforts from academy and industry, no cure is available to date. Sleep may be a modifiable factor involved in onset, progression and potentially also treatment of AD. However, knowledge regarding important aspects of sleep-targeted treatments is missing, e.g. adequate window of opportunity for their efficacious application, their minimal duration or their effect onto both pathology and cognition. We found that pharmacologically enhanced sleep depth is associated with reduced amyloid neuropathology in AD mice brains at both early- and moderately advanced-stage disease. However, only early-stage disease mice significantly benefited from sleep-enhancing treatment. Our results strongly encourage further mechanistic research and the launch of larger scale preclinical investigations in early AD populations.

neuroscience↗

bioRxiv2024

mCLAS adaptively rescues disease-specific sleep and wake phenotypes in neurodegeneration

Sleep alterations are hallmarks of prodromal Alzheimers (AD) and Parkinsons disease (PD), with fundamental neuropathological processes of both diseases showing susceptibility of change upon deep sleep modulation. However, promising pharmacological deep sleep enhancement results are hindered by specificity and scalability issues, thus advocating for noninvasive slow-wave activity (SWA) boosting methods to investigate the links between deep sleep and neurodegeneration. Accordingly, we have recently introduced mouse closed-loop auditory stimulation (mCLAS), which is able to successfully boost SWA during deep sleep in neurodegeneration models. Here, we aim at further exploring mCLAS acute effect onto disease-specific sleep and wake alterations in AD (Tg2576) and PD (M83) mice. We found that mCLAS adaptively rescues pathological sleep and wake traits depending on the disease-specific impairments observed at baseline in each model. Notably, in AD mice mCLAS significantly increases NREM long/short bout ratio, decreases vigilance state distances by decreasing transition velocities and increases the percentage of cumulative time spent in NREM sleep in the last three hours of the dark period. Contrastingly, in PD mice mCLAS significantly decreases NREM sleep consolidation, by potentiating faster and more frequent transitions between vigilance states, decreases average EMG muscle tone during REM sleep and increases alpha power in WAKE and NREM sleep. Overall, our results indicate that mCLAS selectively prompts an acute alleviation of neurodegeneration-associated sleep and wake phenotypes, by either potentiating sleep consolidation and vigilance state stability in AD or by rescuing bradysomnia and decreasing cortical hyperexcitability in PD. Further experiments assessing the electrophysiological, neuropathological and behavioural long-term effects of mCLAS in neurodegeneration may majorly impact the clinical establishment of sleep-based therapies.

neuroscience↗

bioRxiv2024

Spinal cord perfusion impairments in the M83 mouse model of Parkinson's disease

Metabolism and bioenergetics in the central nervous system play important roles in the pathophysiology of Parkinsons disease (PD). Here, we employed a multimodal imaging approach to assess oxygenation changes in the spinal cord of a transgenic M83 murine model of PD in comparison to non-transgenic littermates at 9-12 months-of-age. A lower oxygen saturation (SO2)SVOT was detected in vivo with spiral volumetric optoacoustic tomography (SVOT) in the spinal cord of M83 mice compared to non-transgenic littermate mice. Ex-vivo high-field T1-weighted magnetic resonance imaging (MRI) and immunostaining for alpha-synuclein (phospho-S129) and vascular organisation (CD31 and GLUT1) were used to investigate the nature of the abnormalities detected via in vivo imaging. Ex-vivo analysis showed that the vascular network in the spinal cord was not impaired in the spinal cord of M83 mice. Ex-vivo MRI assisted with deep learning-based automatic segmentation showed no volumetric atrophy in the spinal cord of M83 mice compared to non-transgenic littermates, whereas nuclear alpha-synuclein phosphorylated at Ser129 site could be linked to early pathology and metabolic dysfunction. The proposed and validated non-invasive high-resolution imaging tool to study oxygen saturation in the spinal cord of PD mice holds promise for assessing early changes preceding motor deficits in PD mice.

neuroscience↗

bioRxiv2024

Novel murine closed-loop auditory stimulation paradigm elicits macrostructural sleep benefits in neurodegeneration

Boosting slow-wave activity (SWA) by modulating slow-waves through closed-loop auditory stimulation (CLAS) might provide a powerful nonpharmacological tool to investigate the link between sleep and neurodegeneration. Nevertheless, CLAS in this context was not yet explored. Here, we established mouse CLAS (mCLAS)-mediated SWA enhancement and explored its effects onto sleep deficits in neurodegeneration, by targeting the up-phase of slow-waves in mouse models of Alzheimers (AD, Tg2576) and Parkinsons disease (PD, M83). We found that tracking a 2Hz component of slow-waves leads to highest precision of NREM sleep detection in mice, and that its combination with a 30{degrees} up-phase-target produces a significant SWA 15-30% increase from baseline in WTAD and TGAD mice versus a MOCK group. Conversely, combining 2Hz with a 40{degrees} phase target yields a significant increase ranging 30-35% in WTPD and TGPD mice. Interestingly, these phase-target-triggered SWA increases are not genotype dependent but strain specific. Sleep alterations that may contribute to disease progression and burden were described in AD and PD lines. Notably, pathological sleep traits where rescued by mCLAS, which elicited a 14% decrease of pathologically heightened NREM sleep fragmentation in TGAD mice, accompanied by a steep decrease in microarousal events during both light and dark periods. Overall, our results indicate that model-tailored phase-targeting is key to modulate SWA through mCLAS, prompting the acute alleviation of key neurodegeneration-associated sleep phenotypes and potentiating sleep regulation and consolidation. Further experiments assessing the long-term effect of mCLAS in neurodegeneration may majorly impact the establishment of sleep-based therapies.

neuroscience↗

bioRxiv2023

Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease in vivo

BackgroundAbnormal alpha-synuclein and iron accumulation in the brain play an important role in Parkinsons disease (PD). Herein, we aim at visualizing alpha-synuclein inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. MethodsFluorescently labelled pyrimidoindole-derivative THK-565 was characterized by using recombinant fibrils and brains from 10-11 months old M83 mice, which subsequently underwent in vivo concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging. The in vivo results were verified against structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 Tesla and scanning transmission X-ray microscopy (STXM) of perfused brains. Brain slice immunofluorescence and Prussian blue staining were further performed to validate the detection of alpha-synuclein inclusions and iron deposition in the brain, respectively. ResultsTHK-565 showed increased fluorescence upon binding to recombinant alpha-synuclein fibrils and alpha-synuclein inclusions in post-mortem brain slices from patients with Parkinsons disease and M83 mice. i.v. administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 minutes post-injection by wide-field fluorescence compared to non-transgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. ConclusionWe demonstrated in vivo mapping of alpha-synuclein by means of non-invasive epifluorescence and vMSOT imaging assisted with a targeted THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo.

neuroscience↗

bioRxiv2021

Natural age-related sleep-wake alterations onset prematurely in the Tg2576 mouse model of Alzheimer disease

Sleep insufficiency or decreased quality have been associated with Alzheimers disease (AD) already in its preclinical stages. Whether such traits are also present in rodent models of the disease has been poorly addressed, somewhat disabling the preclinical exploration of sleep-based therapeutic interventions for AD. We investigated age-dependent sleep-wake phenotype of a widely used mouse model of AD, the Tg2576 line. We implanted electroencephalography/ electromyography headpieces into 6 months old (plaque-free, n=10) and 11 months old (moderate plaque-burdened, n=10) Tg2576 and age-matched wild-type (WT) mice and recorded vigilance states for 24 hours. Tg2576 mice exhibited significantly increased wakefulness and decreased non-rapid eye movement sleep over a 24-hour period compared to WT mice at 6, but not at 11 months of age. Concomitantly, delta power appeared decreased in 6-month old Tg2576 mice in comparison to age-matched WT controls, yielding a reduced slow-wave energy phenotype in the young mutants. Lack of genotype-related differences over 24 hours in overall sleep-wake phenotype at 11 months of age appears to be the result of the natural aging of WT mice. Therefore, our results indicate that at plaque-free stages of the disease, diminished sleep quality is present in Tg2576 mice which resembles aged healthy controls, suggesting an early-onset of sleep-wake deterioration in murine AD. Whether such disturbances in the natural patterns of sleep could in turn worsen disease progression warrants further exploration.

neuroscience↗

bioRxiv2021

Altered sleep intensity upon DBS to hypothalamic sleep-wake centers in rats

Deep brain stimulation (DBS) has been scarcely investigated in the field of sleep research. We hypothesize that DBS onto hypothalamic sleep- and wake-promoting centers will produce significant neuromodulatory effects, and potentially become a therapeutic strategy for patients suffering severe, drug-refractory sleep-wake disturbances. We aimed to investigate whether continuous electrical high-frequency DBS, such as that often implemented in clinical practice, in the ventrolateral preoptic nucleus (VLPO) or the perifornical area of the posterior lateral hypothalamus (PeFLH), significantly modulates sleep-wake characteristics and behavior. We implanted healthy rats with electroencephalographic/electromyographic electrodes and recorded vigilance states in parallel to bilateral bipolar stimulation of VLPO and PeFLH at 125 Hz at 90 A over 24 h to test the modulating effects of DBS on sleep-wake proportions, stability and spectral power in relation to baseline. We unexpectedly found that VLPO DBS at 125 Hz deepens slow-wave sleep as measured by increased delta power, while sleep proportions and fragmentation remain unaffected. Thus, the intensity, but not the amount of sleep or its stability, is modulated. Similarly, the proportion and stability of vigilance states remained altogether unaltered upon PeFLH DBS but, in contrast to VLPO, 125 Hz stimulation unexpectedly weakened SWS, evidenced by reduced delta power. This study provides novel insights into non-acute functional outputs of major sleep-wake centers in the rat brain in response to electrical high-frequency stimulation, a paradigm frequently used in human DBS. In the conditions assayed, while exerting no major effects on sleep-wake architecture, hypothalamic high-frequency stimulation arises as a provocative sleep intensity-modulating approach.

neuroscience↗

bioRxiv2021

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

AimAbnormal tau accumulation plays an important role in tauopathy diseases such as Alzheimers disease and Frontotemporal dementia. There is a need for high-resolution imaging of tau deposits at the whole brain scale in animal models. Here, we demonstrate non-invasive whole brain imaging of tau-targeted PBB5 probe in P301L model of 4-repeat tau at 130 m resolution using volumetric multi-spectral optoacoustic tomography (vMSOT). MethodsThe binding properties of PBB5 to 4-repeat K18 tau and A{beta}42 fibrils were assessed by using Thioflavin T assay and surface plasmon resonance assay. We identified the probe PBB5 suitable for vMSOT tau imaging. The imaging performance was first evaluated using postmortem human brain tissues from patients with Alzheimers disease, corticobasal degeneration and progressive supranuclear palsy. Concurrent vMSOT and epi-fluorescence imaging of in vivo PBB5 targeting (i.v.) was performed in P301L and wild-type mice. Ex vivo measurements on excised brains along with multiphoton microscopy and immunofluorescence staining of tissue sections were performed for validation. The spectrally-unmixed vMSOT data was registered with MRI atlas for volume-of-interest analysis. ResultsPBB5 showed specific binding to recombinant K18 tau fibrils, Alzheimers disease brain tissue homogenate by competitive binding against [11C]PBB3 and to tau deposits (AT-8 positive) in post-mortem corticobasal degeneration and progressive supranuclear palsy brain. i.v. administration of PBB5 in P301L mice led to retention of the probe in tau-laden cortex and hippocampus in contrast to wild-type animals, as also confirmed by ex vivo vMSOT, epi-fluorescence and multiphoton microscopy results. ConclusionvMSOT with PBB5 facilitates novel 3D whole brain imaging of tau in P301L animal model with high-resolution for future mechanistic studies and monitoring of putative treatments targeting tau.

neuroscience↗

bioRxiv2021

Closed-loop auditory stimulation method to modulate sleep slow waves and motor learning performance in rats

Slow waves and cognitive output have been modulated in humans by phase-targeted auditory stimulation. However, to advance its technical development and further our understanding, implementation of the method in animal models is indispensable. Here, we report the successful employment of slow waves phase-targeted closed-loop auditory stimulation (CLAS) in rats. To validate this new tool both conceptually and functionally, we tested the effects of up- and down-phase CLAS on proportions and spectral characteristics of sleep, and on learning performance in the single pellet-reaching task, respectively. Without affecting 24-h sleep-wake behavior, CLAS specifically altered delta (slow waves) and sigma (sleep spindles) power persistently over chronic periods of stimulation. Down-phase CLAS exerted a detrimental effect on overall engagement and success rate in the behavioral test, and overall CLAS-dependent spectral changes were positively correlated with learning performance. Altogether, our results provide proof-of-principle evidence that phase-targeted CLAS of slow waves in rodents is efficient, safe and stable over chronic experimental periods, enabling the use of this high-specificity tool for basic and preclinical translational sleep research.

neuroscience↗