Alsmouritsen8223

-activated kinase (AMPK)/mammalian target of the rapamycin pathway, whereas chloroquine, AMPK silencing, and compound C blocked the inhibitory effect on pyroptosis. Conclusions BMSC-Exos can protect PC12 cells against OGD/R injury via attenuation of NLRP3 inflammasome-mediated pyroptosis by promoting AMPK-dependent autophagic flux.Biologically relevant large-scale computational models currently represent one of the main methods in neuroscience for studying information processing primitives of brain areas. However, biologically realistic neuron models tend to be computationally heavy and thus prevent these models from being part of brain-area models including thousands or even millions of neurons. The cerebellar input layer represents a canonical example of large scale networks. In particular, the cerebellar granule cells, the most numerous cells in the whole mammalian brain, have been proposed as playing a pivotal role in the creation of somato-sensorial information representations. Enhanced burst frequency (spiking resonance) in the granule cells has been proposed as facilitating the input signal transmission at the theta-frequency band (4-12 Hz), but the functional role of this cell feature in the operation of the granular layer remains largely unclear. This study aims to develop a methodological pipeline for creating neuron models tmputationally simple models. The proposed methodology represents a valuable tool for adjusting AdEx models according to a FF defined in the spiking regime and based on biological data. These models are appropriate for future research of the functional implication of bursting resonance at the theta band in large-scale granular layer network models.Virus-mediated gene therapy has the potential to deliver exogenous genetic material into specific cell types to promote survival and counteract disease. This is particularly enticing for neuronal conditions, as the nervous system is renowned for its intransigence to therapeutic targeting. Administration of gene therapy viruses into skeletal muscle, where distal terminals of motor and sensory neurons reside, has been shown to result in extensive transduction of cells within the spinal cord, brainstem, and sensory ganglia. This route is minimally invasive and therefore clinically relevant for gene therapy targeting to peripheral nerve soma. For successful transgene expression, viruses administered into muscle must undergo a series of processes, including host cell interaction and internalization, intracellular sorting, long-range retrograde axonal transport, endosomal liberation, and nuclear import. In this review article, we outline key characteristics of major gene therapy viruses-adenovirus, adeno-associated virus (AAV), and lentivirus-and summarize the mechanisms regulating important steps in the virus journey from binding at peripheral nerve terminals to nuclear delivery. Additionally, we describe how neuropathology can negatively influence these pathways, and conclude by discussing opportunities to optimize the intramuscular administration route to maximize gene delivery and thus therapeutic potential.Gene splicing modulates the potency of cell death effectors, alters neuropathological disease processes, influences neuronal recovery, but may also direct distinct mechanisms of secondary brain injury. Therapeutic targeting of RNA splicing is a promising avenue for next-generation CNS treatments. RNA-binding proteins (RBPs) regulate a variety of RNA species and are prime candidates in the hunt for druggable targets to manipulate and tailor gene-splicing responses in the brain. RBPs preferentially recognize unique consensus sequences in targeted mRNAs. Also, RBPs often contain multiple RNA-binding domains (RBDs)-each having a unique consensus sequence-suggesting the possibility that drugs could be developed to block individual functional domains, increasing the precision of RBP-targeting therapies. Empirical characterization of most RBPs is lacking and represents a major barrier to advance this emerging therapeutic area. There is a paucity of data on the role of RBPs in the brain including, identification of their unique mRNA targets, defining how CNS insults affect their levels and elucidating which RBPs (and individual domains within) to target to improve neurological outcomes. This review focuses on the state-of-the-art of the RBP tumor suppressor RNA binding motif 5 (RBM5) in the CNS. We discuss its potent pro-death roles in cancer, which motivated our interest to study it in the brain. We review recent studies showing that RBM5 levels are increased after CNS trauma and that it promotes neuronal death in vitro. Finally, we conclude with recent reports on the first set of RBM5 regulated genes identified in the intact brain, and discuss how those findings provide new clues germane to its potential function(s) in the CNS, and pose new questions on its therapeutic utility to mitigate CNS injury.Alzheimer's disease (AD) is characterized by the accumulation in the brain of intraneuronal aggregates of abnormally and hyperphosphorylated tau proteins and of extracellular deposits of amyloid-β surrounded by dystrophic neurites. Numerous experimental models have shown that tau pathology develops in the brain after intracerebral injection of brain homogenates or pathological tau [paired helical filaments (PHF)-tau)] from AD brains. Further investigations are however necessary to identify or exclude potential extracerebral routes of tau pathology transmission, e.g., through the intravascular route. In this study, we have analyzed the effect of intravenous injection of PHF-tau proteins from AD brains on the formation of tau and amyloid pathologies in the brain of wild-type (WT) mice and of 5XFAD mice (an amyloid model). find more We observed that 5XFAD mice with a disrupted blood-brain barrier showed increased plaque-associated astrogliosis, microgliosis, and increased deposits of Aβ40 and Aβ42 after intravenous injection of PHF-tau proteins. In addition, an increased phosphotau immunoreactivity was observed in plaque-associated dystrophic neurites. These results suggest that blood products contaminated by PHF-tau proteins could potentially induce an exacerbation of neuroinflammation and AD pathologies.Sensorineural hearing loss (SNHL) caused by noise exposure and attendant loss of glutamatergic synapses between cochlear spiral ganglion neurons (SGNs) and hair cells is the most common sensory deficit worldwide. We show here that systemic administration of a bisphosphonate to mice 24 h after synaptopathic noise exposure regenerated synapses between inner hair cells and SGNs and restored cochlear function. We further demonstrate that this effect is mediated by inhibition of the mevalonate pathway. These results are highly significant because they suggest that bisphosphonates could reverse cochlear synaptopathy for the treatment of SNHL.Speech perception in noisy environments depends on complex interactions between sensory and cognitive systems. In older adults, such interactions may be affected, especially in those individuals who have more severe age-related hearing loss. Using a data-driven approach, we assessed the temporal (when in time) and spatial (where in the brain) characteristics of cortical speech-evoked responses that distinguish older adults with or without mild hearing loss. We performed source analyses to estimate cortical surface signals from the EEG recordings during a phoneme discrimination task conducted under clear and noise-degraded conditions. We computed source-level ERPs (i.e., mean activation within each ROI) from each of the 68 ROIs of the Desikan-Killiany (DK) atlas, averaged over a randomly chosen 100 trials without replacement to form feature vectors. We adopted a multivariate feature selection method called stability selection and control to choose features that are consistent over a range of model parameters. parable level of group segregation (78.7% accuracy). Our results identify critical time-courses and brain regions that distinguish mild hearing loss from normal hearing in older adults and confirm a larger number of active areas, particularly in RH, when processing noise-degraded speech information.Abundant research has established the important role of ad-evoked feelings on consumers' reaction to advertising. However, measurement of feelings through explicit self-report is not without its limitations. The current study adds to previous work by showing a sophisticated way of first estimating how arousal is represented in the brain via an independent task (using EEG), and thereafter using this representation to measure arousal in response to advertisements. We then estimate the relationship between the identified process (arousal) and external measures of ad effectiveness (as measured by notability and attitude toward the ad). The results show that the neural measure of arousal is positively associated with notability of ads in the population at large, but may be negatively associated with attitude toward these ads. The implications for the application of EEG in ad testing and for understanding the relationship between arousal and effective advertising are discussed.Understanding how neural networks generate activity patterns and communicate with each other requires monitoring the electrical activity from many neurons simultaneously. Perfectly suited tools for addressing this challenge are genetically encoded voltage indicators (GEVIs) because they can be targeted to specific cell types and optically report the electrical activity of individual, or populations of neurons. However, analyzing and interpreting the data from voltage imaging experiments is challenging because high recording speeds and properties of current GEVIs yield only low signal-to-noise ratios, making it necessary to apply specific analytical tools. Here, we present NOSA (Neuro-Optical Signal Analysis), a novel open source software designed for analyzing voltage imaging data and identifying temporal interactions between electrical activity patterns of different origin. In this work, we explain the challenges that arise during voltage imaging experiments and provide hands-on analytical solutions. We demonstrate how NOSA's baseline fitting, filtering algorithms and movement correction can compensate for shifts in baseline fluorescence and extract electrical patterns from low signal-to-noise recordings. NOSA allows to efficiently identify oscillatory frequencies in electrical patterns, quantify neuronal response parameters and moreover provides an option for analyzing simultaneously recorded optical and electrical data derived from patch-clamp or other electrode-based recordings. To identify temporal relations between electrical activity patterns we implemented different options to perform cross correlation analysis, demonstrating their utility during voltage imaging in Drosophila and mice. All features combined, NOSA will facilitate the first steps into using GEVIs and help to realize their full potential for revealing cell-type specific connectivity and functional interactions.Neural implants that deliver multi-site electrical stimulation to the nervous systems are no longer the last resort but routine treatment options for various neurological disorders. Multi-site electrical stimulation is also widely used to study nervous system function and neural circuit transformations. These technologies increasingly demand dynamic electrical stimulation and closed-loop feedback control for real-time assessment of neural function, which is technically challenging since stimulus-evoked artifacts overwhelm the small neural signals of interest. We report a novel and versatile artifact removal method that can be applied in a variety of settings, from single- to multi-site stimulation and recording and for current waveforms of arbitrary shape and size. The method capitalizes on linear electrical coupling between stimulating currents and recording artifacts, which allows us to estimate a multi-channel linear Wiener filter to predict and subsequently remove artifacts via subtraction. We confirm and verify the linearity assumption and demonstrate feasibility in a variety of recording modalities, including in vitro sciatic nerve stimulation, bilateral cochlear implant stimulation, and multi-channel stimulation and recording between the auditory midbrain and cortex.