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Berteotti, C.

Publications and source records attributed to Berteotti, C..

4 recordsLinked to original sources

Lack of Consensus for Manual Mouse Sleep Scoring Limits Implementation of Automatic Deep Learning Models

Scientists have for decades attempted to automate the manual sleep staging problem not only for human polysomnography data but also for rodent data. No model has, however, succeeded in fully replacing the manual procedure across clinics and laboratories. We hypothesize that this is due to the models limited ability to generalize to data from unseen laboratories. Our findings show that despite the high performance of four state-of-the-art models reported in initial publications, the published models struggle to generalize to other laboratories. We further show a significant improvement in model performance across labs by re-training them on a diverse dataset from five different sites. To assess the contribution of variability in manual scoring, ten experts from five laboratories all labelled the same nine mouse sleep recordings. The result revealed substantial scoring variability, particularly for rapid eye movement (REM) sleep, both within and between labs. In conclusion our study demonstrates that key challenges in the generalizability of state-of-the-art sleep scoring models are signal variability and label noise. Our study highlights the need for a standardized set of mouse sleep scoring guidelines to enable consistency and collaboration across the field. Until such a consensus is reached, we present four sufficiently robust models trained on diverse datasets that can serve as standardized tools across labs.

neuroscience↗

EXPRESSION OF A SECRETABLE, CELL-PENETRATING CDKL5 PROTEIN ENHANCES THE EFFICACY OF AAV VECTOR-MEDIATED GENE THERAPY FOR CDKL5 DEFICIENCY DISORDER.

No therapy is currently available for CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the CDKL5 gene. Although delivery of a wild-type copy of the mutated gene to cells represents the most curative approach for a monogenic disease, proof-of-concept studies highlight significant efficacy caveats for brain gene therapy. Herein, we used a secretable TATk-CDKL5 protein to enhance the efficiency of a gene therapy for CDD. We found that, although AAVPHP.B_Igk-TATk-CDKL5 and AAVPHP.B_CDKL5 vectors had similar brain infection efficiency, the AAVPHP.B_Igk-TATk-CDKL5 vector led to a higher CDKL5 protein replacement due to secretion and transduction of the TATk-CDKL5 protein into the neighboring cells. Importantly, Cdkl5 KO mice treated with the AAVPHP.B_Igk-TATk-CDKL5 vector showed a behavioral and neuroanatomical improvement in comparison with vehicle-treated Cdkl5 KO mice or Cdkl5 KO mice treated with the AAVPHP.B_CDKL5 vector, indicating that a gene therapy based on a secretable recombinant TATk-CDKL5 protein is more effective at compensating Cdkl5-null brain defects than gene therapy based on the expression of the native CDKL5.

neuroscience↗

Paternally expressed imprinted Snord116 and Peg3 regulate hypothalamic orexin neurons

Imprinted genes are highly expressed in the hypothalamus; however, whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at chromosome 15q11-q13, is characterised by hypothalamic insufficiency. Here, we investigate the role of the paternally expressed Snord116 gene within the context of sleep and metabolic abnormalities of PWS, and we report a novel role of this imprinted gene in the function and organisation of the two main neuromodulatory systems of the lateral hypothalamus (LH), namely, the orexin (OX) and melanin concentrating hormone (MCH) systems. We observe that the dynamics between neuronal discharge in the LH and the sleep-wake states of mice with paternal deletion of Snord116 (PWScrm+/p-) are compromised. This abnormal state-dependent neuronal activity is paralleled by a significant reduction in OX neurons in the LH of mutants. Therefore, we propose that an imbalance between OX- and MCH-expressing neurons in the LH of mutants reflects a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake and temperature control.\n\nHighlightsO_LISnord116 regulates neuronal activity in the lateral hypothalamus (LH), which is time-locked with cortical states of sleep.\nC_LIO_LILoss of Snord116 reduces orexin neurons in the LH and affects sleep homeostasis and thermoregulation in mice.\nC_LIO_LISnord116 and Peg3 independently control orexin expression in the LH.\nC_LIO_LIPaternally expressed alleles maximize the patrilineal effects in the control of REM sleep by the LH in mammals.\nC_LI

neuroscience↗

Long-term cardiovascular re-programming by short-term perinatal exposure to nicotine‘s main metabolite cotinine

BackgroundCotinine - a nicotine by-product and biomarker of passive perinatal tobacco smoke exposure - is historically considered to lack significant health effects. We challenged this notion and sought \"proof-of-concept\" evidence of the adverse developmental potential of exposure to this substance at real-life levels.\n\nMethodsPregnant C57 mice drank nicotine or cotinine-laced water for 6wks from conception (NPRE = 2% saccharin+100g nicotine/ml; CPRE = 2% saccharin + 10g cotinine/ml) or for 3wks after birth (CPOST = 2% saccharin + 30g cotinine/ml). Controls drank 2% saccharin (CTRL). At 17{+/-}1weeks male pups (CTRL n=6; CPOST n=6; CPRE n=8; NPRE n=9) were instrumented for EEG and blood pressure (BP) telemetry. We evaluated (i) cardiovascular control during sleep (at rest / during stress); (ii) arterial reactivity ex vivo; (iii) expression of genes involved in arterial constriction/dilation.\n\nResultsBlood cotinine levels (ELISA) recapitulated passive smoker mothers-infants. Pups exposed only to cotinine exhibited (i) mild bradycardia - hypotension at rest (p<0.001); (ii) attenuated (CPRE, p<0.0001) or reverse (CPOST; p<0.0001) BP reactivity to asphyxia; (iii) pronounced adrenergic hypo-contractility (p<0.0003), low Protein Kinase C (p<0.001) and elevated adrenergic receptor mRNA (p<0.05) (all drug-treated arteries). NPRE pups also exhibited endothelium-mediated dysfunction.\n\nConclusionsCotinine has subtle, enduring developmental consequences. Some cardiovascular effects of nicotine can plausibly arise via conversion to cotinine. Low-level exposure to this metabolite may pose unrecognized perinatal risks. Adults must avoid inadvertently exposing a fetus or infant to cotinine as well as nicotine.

physiology↗