Biology subjects

Moreira, C. G.

Publications and source records attributed to Moreira, C. G..

6 recordsLinked to original sources

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

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↗

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

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↗

bioRxiv2018

A novel role of VisP and Wzz system during O-antigen assembly in Salmonella Typhimurium pathogenesis

Salmonella enterica serovars are associated with diarrhea and gastroenteritis and are a helpful model for understanding host-pathogen mechanisms. Salmonella Typhimurium regulates the distribution of O-antigen (OAg) and presents a trimodal distribution based on Wzy polymerase, WzzST (long chain length OAg, L-OAg) and WzzfepE (very long chain length OAg, VL-OAg) co-polymerases; however, several mechanisms regulating this process remain unclear. Here, we report that LPS modifications modulate the infectious process and that OAg chain length determination plays an essential role during infection. An increase in VL-OAg is dependent on Wzy polymerase, which is promoted by a growth condition resembling the environment of Salmonella-containing vacuoles (SCVs). The virulence and stress-related periplasmic protein (VisP) participates in OAg synthesis, as {Delta}visP presents a semirough OAg phenotype. The {Delta}visP mutant has greatly decreased motility and J774 macrophage survival in a colitis model of infection. Interestingly, the phenotype is restored after mutation of the wzzST or wzzfepE gene in a {Delta}visP background. Loss of both the visP and wzzST genes promotes an imbalance in flagellin secretion. L-OAg may function as a shield against host immune systems in the beginning of an infectious process, and VL-OAg protects bacteria during SCV maturation and facilitates intramacrophage replication. Taken together, these data highlight the roles of OAg length in generating phenotypes during S. Typhimurium pathogenesis and show the periplasmic protein VisP as a novel protein in the OAg biosynthesis pathway.\n\nAuthor summarySalmonella modifies its LPS, specifically the O-antigen length, to adapt itself to distinct intestinal environments. These LPS modifications may provide a way for this bacterium to avoid complement activation in the intestinal lumen, improving Salmonella pathogenesis. This process is essential for a successful infection, and our investigation into these specific details regarding LPS in this foodborne pathogen will elucidate different aspects of the host-pathogen association.

microbiology↗