Experimental Neurobiology最新文献

Neurotrophic factors (NTFs) are secreted proteins that are crucial in neuronal growth, survival, and function. Individuals with neurodegenerative diseases, characterized by neuronal loss and various functional disorders, have been reported to exhibit altered levels of NTFs. This suggests that modulating NTF levels may offer a promising therapeutic strategy to alter the progression of neurodegenerative diseases. Although numerous efforts have been made to deliver NTFs to target regions, their clinical application remains challenging due to their inability to cross the blood-brain barrier (BBB) and the adverse side effects observed in clinical trials. Consequently, various delivery methods have been explored to overcome these limitations. In this review, we discuss recent therapeutic approaches utilizing NTFs and their signaling pathways as interventions against neurodegenerative diseases.

Parkinson's disease (PD) is a neurodegenerative disorder associated with neuroinflammation and gut dysfunction. The G protein-coupled estrogen receptor (GPER) has showed therapeutic potential in inflammatory bowel diseases (IBD), yet its role and underlying mechanisms in PD remain unclear. Here, we aimed to investigate the role and mechanisms of GPER in protecting PD. Female mice underwent bilateral ovariectomies (OVX) and were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD, followed by administration of GPER agonist G1. The expressions of tyrosine hydroxylase (TH) and α-synuclein (α-syn), as well as activations of inflammatory cells and NLRP3 inflammasome in the brain and ileum were evaluated. BV2 cells were pretreated with G1 and/or the antagonist G15, then treated with LPS and ATP to activate NLRP3 inflammasome. Activation of NLRP3 inflammasome in BV2 cells was assessed. Results demonstrated that G1 treatment increased TH expression, reduced α-syn expression, and suppressed inflammation and NLRP3 inflammasome in both the midbrain and ileum of MPTP-treated OVX mice. Pretreatment with G1 suppressed the activation of NLRP3 inflammasome in BV2 cells, while the effect was reversed by G15. These findings indicate that GPER activation exerts a protective effect in MPTP-induced OVX mice by modulating NLRP3 inflammasome in both brain and gut, which might provide novel insights into the pathogenesis and therapy of PD.

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.