Experimental Neurobiology最新文献

Graphene has emerged as a promising nanomaterial for brain-computer interface (BCI) applications due to its excellent electrical properties and biocompatibility. However, its long-term structural compatibility on the cerebral cortex requires further validation. This study assessed both functional compatibility and preservation of neural tissue architecture for graphene/parylene C composite electrodes implanted on the rat cortical surface, in accordance with ISO 10993-6 guideline weekly neurobehavioral assessments and comprehensive histopathological analyses were conducted for four weeks post-implantation. Our results revealed no significant differences in neurobehavioral outcomes between graphene-based and medical-grade silicone implants. Histopathological examination showed no noticeable inflammatory responses, changes in cellular morphology, myelination status, or neuronal degeneration. These findings indicate that graphene electrodes preserve tissue integrity comparable to medical‑grade silicone. Our study supports graphene's potential use in clinical neuroprosthetics and neuromodulation devices.

Neural tumors represent diverse malignancies with distinct molecular profiles and present particular challenges due to the blood-brain barrier, heterogeneous molecular etiology including epigenetic dysregulation, and the affected organ's critical nature. KCC-07, a selective and blood-brain barrier penetrable MBD2 (methyl CpG binding domain protein 2) inhibitor, can suppress tumor development by inducing p53 signaling, proven only in medulloblastoma. Here we demonstrate KCC-07 treatment's application to other neural tumors. KCC-07 treatment reduced proliferation rates of U-87MG (glioma cell line) and SH-SY5Y (neuroblastoma cell line). p53 stabilization occurred in these cell lines without significantly affecting programmed cell death factors under KCC-07 exposure. Furthermore, tumor cell growth inhibition was enhanced when combined with DNA damaging reagents. Both phleomycin (radiomimetic agent inducing DNA double strand breaks) and etoposide (topoisomerase II inhibitor inducing DNA double strand breaks) treatment activated p53-dependent signaling for apoptosis and cell cycle arrest, consequently suppressing tumor cell growth. Dual treatment with KCC-07 (epigenetic modifier) and DNA damaging reagents augmented tumor cell suppression, suggesting greater benefits of combinatorial therapy for neural tumors than previously demonstrated.

Aging correlates with alterations in metabolism and neuronal function, which affect the overall regulation of energy homeostasis. Recent studies have highlighted that protein O-GlcNAcylation, a common post-translational modification regulating metabolic function, is linked to aging. In particular, elevated O-GlcNAcylation increases energy expenditure, potentially due to alterations in the neuronal function of the hypothalamic arcuate nucleus (ARC), a key brain region for energy balance and metabolic processes. However, its impact on metabolism and hypothalamic neuronal activity in aged mice remains unknown. This study investigates the effect of elevated O-GlcNAcylation on metabolic rate, motor behaviors, glucose tolerance, and neuronal excitability within the hypothalamic ARC in 10-month-old mice. We demonstrate that Oga^+/- mice with elevated O-GlcNAcylation levels show increased energy expenditure, but do not show significant alterations in motor function or glucose tolerance. Our ex vivo electrophysiology experiments revealed that Oga^+/- mice exhibited a reduced firing rate of hypothalamic ARC neurons, suggesting that the increased metabolism in these mice could be attributed to the reduced activity of ARC neurons. These findings indicate that O-GlcNAcylation plays a crucial role in maintaining metabolic balance and neuronal function in the aging brain.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). The latter is a human organ-specific autoimmune disease of the central nervous system (CNS). EAE is characterized by systemic inflammation associated with increased blood levels of proinflammatory mediators that potentially trigger inflammation of both reproductive organs and the CNS. Pathological changes in the hypothalamus-pituitary gland-gonadal axis have occasionally been reported in both the MS and EAE contexts. Such changes may affect the reproductive organs. We used the phrase "EAE and hypothalamus-pituitary-gonads (testis and ovary)" to retrieve relevant papers from PubMed. We postulated that EAE might be associated with inflammation of the hypothalamus, pituitary gland and gonads, in turn indicating reproductive dysfunction. This paper overviews evidence supporting the roles of both hormonal and inflammatory alterations in animals with EAE. This aids our understanding of how certain autoimmune diseases are associated with infertility.

This study investigated the learning strategy preferences of 11-month-old APP/PS1 double transgenic (Tg) mice, a well-established murine model of Alzheimer's disease (AD). APP/PS1 Tg and non-Tg control mice were serially trained in visual and hidden platform tasks in the Morris water maze. APP/PS1 Tg mice performed poorly in visual platform training compared with non-Tg mice but performed as well as non-Tg mice in hidden platform training. Further analysis of their search paths for locating a hidden platform revealed that APP/PS1 Tg mice used more cued/response search patterns than place/spatial search patterns compared with non-Tg mice. Three months later, the object/location recognition memory of APP/PS1 Tg mice was assessed. Although their object recognition memory was intact, their object location memory was impaired. Neuropathological AD features of APP/PS1 transgenic mice were observed in the medial prefrontal cortex, retrosplenial cortex, and hippocampus, key brain regions involved in learning strategy shifts and spatial cognition. These results indicate that distinct search patterns and spatial memory deficits in APP/PS1 Tg mice are key features of AD animal models.

Changes in microglia, a specialized population of glial cells found in the central nervous system (CNS), is often associated with hyperglycemic conditions. It has been reported that exogenous administration of agmatine (agm) has neuroprotective effects in CNS injuries, including neurodegenerative diseases, while also being involved with modulating macrophage subdivision. In this study, the effects of agmatine on microglial polarization has been investigated and whether this effect can be related to the modulation of autophagy in neuroinflammatory conditions induced by high glucose (HG) concentrations. Neuroinflammatory conditions were mimicked through treatment to BV2 microglial cells. BV2 cells were mainly induced into proinflammatory M1 phenotype when treated with HG (100 mM), shown by the increase in M1 marker, CD86, and shifted to M2 phenotype in HG condition with agm (100 μM), indicated by the upregulation of mannose receptor CD206. When agm was treated with HG, the level of LC3-II was increased while p62/SQSTM1 level was downregulated, and the expression of LAMP1 was increased. In transmission electron microscopy, autophagosomes has shown that HG conditions led to severe mitochondrial damage while elongating phagophore membranes and autolysosomes were seen in cells treated with HG and agm, showing stimulated mitophagy. In a high-fat diet-induced T2DM metabolic dementia animal model, agmatine administration upregulated autophagy and shifted microglial polarization from proinflammatory to anti-inflammatory phenotype, improving cognitive function and alleviating neuroinflammation. In this study, it has been demonstrated that agm treatment can ameliorate neuroinflammation by upregulating autophagy on a cellular level and shifting microglia polarization from M1 to M2 phenotype, showing a therapeutic potential in metabolic AD.

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.