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Kornum, B. R.

Publications and source records attributed to Kornum, B. R..

5 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↗

Wheel running, but not home cage activity in Digital Ventilated Cages(R) is impaired in a mouse model of breast cancer-induced bone pain

IntroductionCancer-induced bone pain (CIBP) due to metastatic breast cancer is common and debilitating. Effective, long-term treatment options have side effects that reduce patients quality of life. Preclinical models are a valuable tool to test novel analgesics, but new methods that are translationally and clinically relevant are necessary. This study aimed to assess spontaneous pain-like behaviour of home cage activity and wheel running in Digital Ventilated Cages(R). MethodTwenty BALB/cAnNHsd mice were housed in Digital Ventilated Cages(R) from Tecniplast(R) with GYM500 home cage running wheels. Mice were assessed by limb use analysis and static weight bearing to determine the development of CIBP and this was compared to the dark-phase home cage activity and wheel running in the Digital Ventilated Cages(R). Ten mice underwent 4T1-Luc2 mammary gland adenocarcinoma cell inoculation into the right femur to establish CIBP and another ten mice underwent a sham surgical procedure. ResultsThe 4T1-inoculated mice displayed pain-like behaviour in limb use and weight bearing tests, demonstrating a preference for the contralateral limb. The limb use scores were compared with home cage activity and wheel running. A reduced wheel running distance corresponded to reduced limb use scores, with the shortest wheel running distances corresponding to the lowest limb use scores. However, this behavioural pattern was not observed in home cage activity, which remained consistent over the study period. DiscussionReduced wheel running corresponded with reduced limb use scores. This suggests that wheel running behaviour is affected by the development of metastatic breast cancer. However, the home cage activity was not influenced by disease development. Digital Ventilated Cage(R) wheel running may be a useful behavioural assessment of spontaneous pain-like behaviour of CIBP and may be useful to assess analgesic efficacy.

animal behavior and cognition↗

A sleep disturbance method by novel objects in the home cage to minimize stress

BackgroundThe increasing prevalence of low sleep quality is a significant issue, particularly among adolescents, necessitating a deeper understanding of its biological consequences. In sleep research, various protocols are used for sleep deprivation or disturbance, each presenting its own set of confounding factors crucial to consider. New MethodWe developed a standardized seven-day sleep disturbance (SD) protocol using daily four-hour exposures to novel objects to minimize rodent stress. Objects were selected and characterized for wake-promoting properties, and exposure timing was structured to reduce variability and enhance experimental reliability and reproducibility. ResultsDuring the four hours of SD, the mice were efficiently sleep-deprived on the first and seventh day of SD. Thus, the selected objects efficiently sleep restricted the mice. On the first day of SD, the protocol induced sleep deprivation effect when measured over 24h, but by the seventh day, the mice recovered the sleep loss. Thus, this method is a sub-chronic sleep disturbance and not sleep deprivation. Fecal corticosterone concentrations remained unchanged during the seven days of SD. Comparison with existing methodsThis approach reduced the risk of stress through voluntary rather than forced wakefulness. Previously, novel objects have been exchanged randomly during mouse sleep initiation causing protocol variability and very frequent disturbances. Our protocol minimizes this by introducing the novel object in a structured manner. ConclusionWe effectively disturbed the sleep of the mice during seven days without inflicting substantial stress. We further demonstrate the value of validating the efficiency of an SD protocol with 24h recordings. HighlightsO_LIStandardized sleep disruption method by object exposure in mice C_LIO_LIMice are sleep-restricted during the four-hour SD intervention all 7 days C_LIO_LIMice habituate to a subchronic sleep deprivation setup by recovering sleep outside of the SD period C_LIO_LIFecal corticosterone samples showed no difference before and after SD intervention C_LI

neuroscience↗

Molecular Consequences of Peripheral Influenza A Infection on Cell Populations in the Murine Hypothalamus

Infection with Influenza A virus (IAV) causes the well-known symptoms of the flu, including fever, loss of appetite and excessive sleepiness. These responses, mediated by the brain, will normally disappear once the virus is cleared from the system, but a severe respiratory virus infection may cause long-lasting neurological disturbances. These include encephalitis lethargica and narcolepsy. The mechanisms behind such long lasting changes are unknown. The hypothalamus is a central regulator of the homeostatic response during a viral challenge. To gain insight into the neuronal and non-neuronal molecular changes during an IAV infection, we intranasally infected mice with an H1N1 virus and extracted the brain at different time points. Using single-nucleus RNA sequencing (snRNA-seq) of the hypothalamus, we identify transcriptional effects in all identified cell populations. The snRNA-seq data showed the most pronounced transcriptional response at 3 days past infection, with a strong downregulation of genes across all cell types. General immune processes were mainly impacted in microglia, the brain resident immune cells, where we found increased numbers of cells expressing pro-inflammatory gene networks. In addition, we found that most neuronal cell populations downregulated genes contributing to the energy homeostasis in mitochondria and protein translation in the cytosol, indicating potential reduced cellular and neuronal activity. This might be a preventive mechanism in neuronal cells to avoid intracellular viral replication and attack by phagocytosing cells. The change of microglia gene activity suggest that this is complemented by a shift in microglia activity to provide increased surveillance of their surroundings.

neuroscience↗

GHB confers neuroprotection by stabilizing the CaMKIIα hub domain

Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII) is an abundant neuronal signaling protein involved in synaptic plasticity and memory formation1,2. The central hub domain regulates the activity of CaMKII by organizing the holoenzyme complex into functional oligomers3-6. Recent findings have suggested that the hub is also an allosteric determinant of kinase activity7, and is thus an emerging target for therapies to correct CaMKII dysregulation8,9. However, pharmacological modulation of the hub domain has never been demonstrated. Here we show that stabilization of the CaMKII hub domain confers neuroprotection. By combining photoaffinity labeling and chemical proteomics using small molecule analogs of the natural metabolite {gamma}-hydroxybutyrate (GHB)10 we reveal that CaMKII is the selective target for GHB. We further find that these GHB analogs bind to the hub interior by solving a 2.2 [A] crystal structure of CaMKII with bound ligand. Using differential scanning fluorimetry, we show that binding of ligands to the hub interior increases the thermal stability of hub oligomers in a concentration-dependent manner. Moreover, we demonstrate the functional significance of this hub stabilization by showing substantial neuroprotective effects in cellular excitotoxicity assays and in a mouse model of cerebral ischemia. Together, our results reveal that CaMKII hub stabilization is the mechanism by which GHB provides endogenous neuroprotection and that small-molecule CaMKII-selective ligands have therapeutic potential.

biochemistry↗