Experimental Neurobiology最新文献

Electroencephalography (EEG) provides high temporal resolution and noninvasiveness for a range of practical applications, including emotion recognition. However, inherent variability across subjects poses significant challenges to model generalizability. In this study, we systematically evaluated twelve approaches by combining four domain generalization (DG) techniques, Deep CORAL, GroupDRO, VREx, and DANN, with three representative deep learning architectures (ShallowFBCSPNet, EEGNet, and TSception) to enable improved subject-independent EEG-based emotion recognition. The performances of the DG-integrated deep learning models were quantitatively evaluated using two emotional EEG datasets collected by the authors. Data from each subject were treated as distinct domains in each model. Binary classification tasks were conducted to identify the valence or arousal state of each participant based on a ten-fold cross-validation strategy. The results indicated that the application of DG methods consistently enhanced classification accuracy across datasets. In one dataset, TSception combined with VREx achieved the highest performance for both valence and arousal classifications. In the other dataset, TSception with VREx still yielded the highest valence classification accuracy, while TSception combined with GroupDRO showed the best arousal classification performance among the twelve models, slightly outperforming TSception with VREx. These findings underscore the potential of DG approaches to mitigate distributional shifts caused by intersubject and intersession variabilities to implement robust subject-independent EEG-based emotion recognition systems.

Progressive neurodegeneration is a common pathological feature of synucleinopathies, which include dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA). Among mechanisms known to induce neurodegeneration, the presence of aggregated forms of α-synuclein (α-syn) has been extensively considered as a causal factor for cell death. These aggregates exist in multiple different physical forms, which might yield different disease phenotypes and explain the heterogeneity among these diseases. Here, we investigated the neurotoxic properties of structurally distinct and exogenous α-syn polymorphs. Most of the polymorphs at the concentrations we studied are neurotoxic, but dopamine stabilized α-syn oligomer induced greater levels of neurotoxicity at lower concentrations compared to other polymorphs. In addition, polymorphs commonly induced apoptotic neuronal death through autophagic impairment. Our results suggest that neurons have different sensitivities to different α-syn aggregates, which should be a consideration when developing disease markers and therapeutics.

Microglia exhibit a complex and context-dependent role in the post-ischemic brain, performing both neuroprotective and neurotoxic functions. Among the many factors contributing to pro-inflammatory microglia activation, NF-κB signaling plays a pivotal role. The NEMO (IKKγ)-binding domain (NBD) peptide, an 11-amino-acids cell-permeable peptide spanning the NBD of IKKα and IKKβ, acts as a highly specific inhibitor by preventing NEMO-IKKα/IKKβ complex formation. We investigated the neuroprotective effects of the NBD peptide in a post-ischemic brain using a transient middle cerebral artery occlusion (MCAO) animal model. In in vitro experiments, pre-treatment of BV2 cells (a microglia cell line) with NBD peptide significantly suppressed LPS-induced NEMO-IKKα/IKKβ complex formation, nuclear translocation of p65, and upregulation of numerous pro-inflammatory cytokines expressions. The anti-inflammatory effect was further confirmed in reporter gene assay following reporter plasmid transfection, demonstrating a NBD peptide dose-dependent response. In the post-ischemic brain, intranasal delivery of NBD peptide significantly suppressed NEMO-IKKα/IKKβ complex formation, IκB-α phosphorylation, microglial activation, and cytokine induction. Notably, intranasal administration of NBD peptide 3 h post-MCAO significantly reduced infarct volumes in a dose-dependent manner. A significant reduction in infarct volume was observed by 6 h post-administration, suggesting an extended therapeutic window for the NBD peptide. These neuroprotective effects were accompanied by the attenuation of neurological deficits and motor function impairment, as assessed by rota-rod, beam balance, and corner turn tests. Collectively, these results highlight a robust neuroprotective effect along with long-term outcomes of NBD peptide in the post-ischemic brain, with NBD peptide-mediated blocking of NEMO-IKKα/IKKβ complex formation serving as a key underlying molecular mechanism.

Celiac disease (CeD) is an autoimmune disorder triggered by gluten, primarily affecting the small intestine but potentially impacting other systems, including the nervous system through the gut-brain axis. This study employed Mendelian randomization (MR) to explore the causal relationships between CeD and several neurological disorders, with a particular focus on multiple sclerosis (MS). Utilizing genetic data from the OpenGWAS and Finngen databases, we applied various MR methods, including Inverse Variance Weighted (IVW), IVW-multiplicative random effects (MRE), weighted median (WM), MR-Egger, and robust adjusted profile score (RAPS), to investigate these associations. The analysis revealed no significant causal relationship between CeD and several other neurological disorders, but a significant positive association with MS was found (IVW OR=1.1919, 95% CI: 1.0851~1.3092, p=0.0002). Further analysis indicated that the mediator CCL19 plays a significant role in the pathway from CeD to MS, suggesting that CCL19 may be a key factor in the immune response linking these conditions. This mediation effect highlights the potential mechanism through which CeD increases the risk of developing MS. These findings emphasize the complexity of the relationship between CeD and MS, indicating the need for further research to understand these connections better and their clinical implications.

Impaired adult hippocampal neurogenesis is a key pathological mechanism contributing to memory deficits in Alzheimer's disease (AD). Recent studies have shown that elevating magnesium levels promotes neurogenesis by enhancing the neuronal differentiation of adult neural progenitor cells in vitro. Therefore, this in vivo study aims to determine if magnesium-L-threonate (MgT) can ameliorate cognitive deficit of AD mice by attenuating adult hippocampal neurogenesis impairment and to reveal the underlying mechanisms. APPswe/PS1dE9 mice were treated with different doses of MgT and ERK inhibitor PD0325901. The memory ability of each mouse was recorded by Morris Water Maze test. After cognitive test, hippocampus tissues were collected to measure the proportion of BrdU/doublecortin double-labeled cells using the flow cytometry test and assess the expression of doublecortin using PCR and Western blot. Furthermore, the activations of CREB, ERK, P38 and JNK were measured by Western blot to identify the involved mechanisms. The cognitive test confirmed that MgT treatment attenuated the memory impairment of APPswe/PS1dE9 mice. Flow cytometry test showed that Brdu/doublecortin labeled newborn neurons gradually increased following MgT administration. In line with the flow cytometry results, Western blot and PCR confirmed that MgT administration significantly increased doublecortin expression levels. Furthermore, the ratios of p-ERK/ERK and p-CREB/CREB increased with MgT elevation. In addition, these effects of MgT treatment were markedly reversed by PD0325901 supplementation. In conclusion, MgT treatment improved cognitive decline by ameliorating adult hippocampal neurogenesis impairment in this AD model, possibly via ERK/CREB activation.

Recent research has shed light on the metabolic changes in reactive astrocytes associated with Alzheimer's disease, contributing to disease pathology. In this article, we summarize key findings related to reactive astrogliosis and how the discovery of the role of the enzyme ornithine decarboxylase 1 can set us on the path to finding more effective therapeutic strategies against neurodegenerative diseases.

Brain functional connectivity has shown promise for developing objective biomarkers for autism spectrum disorder (ASD). Although many imaging studies have demonstrated its potential, most have focused on static measurements. In this study, we explored the dynamic changes in functional connectivity over time to uncover potential temporal dependencies. These dynamic patterns were abstracted into high-level representations and used as predictors to identify individuals at risk of ASD. To achieve this, we employed a deep learning framework that combines attention mechanism with long short-term memory (LSTM) neural network. Experiments were conducted using heterogeneous resting-state functional magnetic resonance imaging (rs-fMRI) data from the Autism Brain Imaging Data Exchange (ABIDE) database. The resulting classification achieved an accuracy of 74.9% and precision of 75.5% under intra-site cross-validation, outperforming traditional classifiers such as support vector machines (SVM), random forests (RF), and single LSTM network. Further analyses demonstrated the robustness and generalizability of our model, with classification performance less affected by subjects' gender or age. The optimal model's weights revealed atypical temporal dependencies in the brain functional connectivity of individuals with ASD, highlighting the potential for these patterns to serve as biomarkers. Our findings underscore the importance of dynamic functional connectivity in understanding ASD and suggest that our deep learning framework could aid in the development of more accurate and reliable diagnostic tools for this disorder.

Emerging evidence suggests that systemic inflammation may play a critical role in neurological disorders. Recent studies have shown the connection between inflammatory bowel diseases (IBD) and neurological disorders, revealing a bidirectional relationship through the gut-brain axis. Immunotherapies, such as Treg cells infusion, have been proposed for IBD. However, the role of adaptive immune cells in IBD-induced neuroinflammation remains unclear. In this study, we established an animal model for IBD in mice with severe combined immune-deficient (SCID), an adaptive immune deficiency, to investigate the role of adaptive immune cells in IBD-induced neuroinflammation. Mice were fed 1%, 3%, or 5% dextran sulfate sodium (DSS) for 5 days. We measured body weight, colon length, disease activity index (DAI), and crypt damage. Pro-inflammatory cytokines were measured in the colon, while microglial morphology, neuronal count, and inflammatory cytokines were analyzed in the brain. In the 3% DSS group, colitis symptoms appeared at day 7, with reduced colon length and increased crypt damage showing colitis-like symptoms. By day 21, colon length and crypt damage persisted, while DAI showed recovery. Although colonic inflammation peaked at day 7, no significant increase in inflammatory cytokines or microglial hyperactivation was observed in the brain. By day 21, neuroinflammation was detected, albeit with a slight delay, in the absence of adaptive immune cells. The colitis-induced neuroinflammation model provides insights into the fundamental immune mechanisms of the gut-brain axis and may contribute to developing immune cell therapies for IBD-induced neuroinflammation.

Maternal stress during pregnancy can profoundly affect offspring health, increasing the risk of psychiatric disorders, metabolic diseases, and gastrointestinal problems. In this study, the effects of high prenatal corticosterone exposure on gene expression in the brain and small intestine of rat offspring were investigated via RNA-sequencing analysis. Pregnant rats were divided into two groups: Corti.Moms were injected with corticosterone daily, while Nor.Moms were given saline injections. Their offspring were labeled as Corti.Pups and Nor.Pups, respectively. The brain tissue analysis of Corti.Pups showed that the expression levels of the genes linked to neurodegenerative conditions increased and enhanced mitochondrial biogenesis, possibly due to higher ATP demands. The genes associated with calcium signaling pathways, neuroactive ligand-receptor interactions, and IgA production were also upregulated in the small intestine of Corti.pups. Conversely, the genes related to protein digestion, absorption, and serotonergic and dopaminergic synaptic activities were downregulated. These findings revealed that gene expression patterns in both the brain and intestinal smooth muscle of offspring prenatally exposed to corticosterone were substantially altered. Thus, this study provided valuable insights into the effects of prenatal stress on neurodevelopment and gut function.

Recent studies have shown an increased abundance of Sphingomonas paucimobilis, an aerobic, Gram-negative bacterium with a distinctive cell envelope rich in glycosphingolipids, within the gut microbiome of individuals with Alzheimer Disease (AD). However, the fact that S. paucimobilis is a well-known pathogen associated with nosocomial infections presents a significant challenge in investigating whether its presence in the gut microbiome is detrimental or beneficial, particularly in the context of AD. This study examines the impact of S. paucimobilis-derived extracellular vesicles (Spa-EV) on Aβ-induced pathology in cellular and animal models of AD. Microarray analysis reveals that Spa-EV treatment modulates Aβ42-induced alterations in gene expression in both HT22 neuronal cells and BV2 microglia cells. Among the genes significantly affected by Spa-EV, notable examples include Bdnf, Nt3/4, and Trkb, which are key players of neurotrophic signaling; Pgc1α, an upstream regulator of mitochondrial biogenesis; Mecp2 and Sirt1, epigenetic factors that regulate numerous gene expressions; and Il1β, Tnfα, and Nfκb-p65, which are associated with neuroinflammation. Remarkably, Spa-EV effectively reverses Aβ42-induced alteration in the expression of these genes through the upregulation of Mecp2. Furthermore, administration of Spa-EV in Tg-APP/PS1 mice restores the reduced expression of neurotrophic factors, Pgc1α, MeCP2, and Sirt1, while suppressing the increased expression of proinflammatory genes in the brain. Our results indicate that Spa-EV has the potential to reverse Aβ-induced dysregulation of gene expression in neuronal and microglial cells. These alterations encompass those essential for neurotrophic signaling and neuronal plasticity, mitochondrial function, and the regulation of inflammatory processes.