Experimental Neurobiology最新文献

In Alzheimer's disease (AD), persistent microglial neuroinflammation and the poor brain exposure and durability of current therapies underscore the need for new, long-acting treatments. We developed a non-viral gene therapy that suppresses microglial Toll-like receptor 2 (TLR2) signaling using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with a plasmid encoding the anti-TLR2 single-chain variable fragment (scFv33). Following intra-cisterna magna delivery, PLGA NPs exhibited microglia-biased uptake and enabled brain-wide transgene expression in mice. In 5xFAD mice, a single administration of scFv33 NPs improved recognition memory in the novel object recognition (NOR) assay, outperforming 8 weeks of weekly recombinant scFv33-Fc dosing. Histology showed selective reduction of small hippocampal Aβ plaques and a shift toward a ramified microglial morphology, indicative of reduced activation. In primary neuron-microglia co-culture, scFv33 reduced microglial hypertrophy, restored process complexity, and enhanced Aβ phagocytosis. Together, these data indicate that sustained, local expression of an anti-TLR2 scFv via a clinically translatable PLGA platform recalibrates microglial state and preferentially limits early-stage plaque accumulation, yielding cognitive benefit after a single dose.

Glioblastoma (GBM) remains fatal despite maximal surgical resection, temozolomide chemotherapy, and radiotherapy. Within the GBM microenvironment, tumor-educated microglia and astrocytes adopt immunoregulatory-like STAT3-high and ARG1/TGF-β-high phenotypes, respectively, which shield GBM cells from adaptive immune attack. In this review, we examine emerging adjuvant strategies designed to molecularly reprogram glial cells toward pro-inflammatory C3-high and IFN/NF-κB-high states, amplifying antitumor immunity. First, we summarize key aspects of GBM pathobiology and identify why conventional treatments fail to achieve durable control. Next, we dissect the signaling networks that govern glial phase states, including NF-κB, STAT3, IRF3, NLRP3, and cGAS-STING axes. We then provide a mechanism-centric analysis of pattern-recognition receptor (PRR) agonists, inflammasome modulators, and cyclic-dinucleotide STING agonists, integrating quantitative preclinical data with early clinical trial results. For each adjuvant, we distinguish between direct astrocytic engagement and indirect cytokine-mediated reprogramming. Modulation of glial phase states holds considerable promise for enhancing personalized vaccine efficacy and for converting immunologically "cold" GBM into a T cell-inflamed tumor. Consequently, targeting glial cell phase modulation is a highly attractive strategy for GBM immunotherapy, with the potential to maximize therapeutic benefit. Despite advances in chemo-, radio-, and checkpoint-blockade therapies, the immunosuppressive tumor microenvironment (TME) of GBM and its failure to establish memory immunity limit their impact. Tumor-polarized astrocytes and microglia form a barrier to effective T cell-mediated attack. Emerging evidence shows that redirecting glia toward pro-inflammatory phenotypes can recondition the TME, creating a more permissive landscape for immunotherapy. This review highlights glial phase reprogramming as a promising immunoadjuvant approach, emphasizing molecular circuits, synthetic modulators, and translational prospects.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal-dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the ataxin-3 gene. The resulting mutant ataxin-3 protein forms intraneuronal inclusions that lead to neurodegeneration in the cerebellum and other brain regions. This study aimed to develop a novel nonhuman primate model of SCA3 to address the limitations of existing knock-in and transgenic models using an adeno-associated virus (AAV) to deliver the mutant gene. AAV viral vectors carrying mutant ataxin-3 were stereotaxically injected into the cerebellum of monkeys. The animals were monitored over an 8-week period, during which behavioral and neuroimaging assessments were conducted. This was followed by a detailed pathological examination. The AAV vector successfully spread throughout the cerebellum, and the expression of mutant ataxin-3 was confirmed. Neuroimaging revealed a reduction in N-acetylaspartate (NAA) levels, whereas histological analysis showed significant damage to the Purkinje cell layer. Notably, the monkeys exhibited sleep disturbances, a prodromal symptom commonly observed in human patients with SCA3. AAV-mediated delivery of mutant ataxin-3 can effectively replicate the key pathological and clinical features of SCA3 in primates. This approach offers a promising new model for studying disease mechanisms and evaluating potential therapies.

Early-life stress (ELS) is a major contributor to neurodevelopmental vulnerability, particularly within the dentate gyrus (DG), where oxidative burden and microglial activation disrupt adult neurogenesis. Here, we examined whether N-acetylcysteine (NAC), a cysteine prodrug and glutathione precursor, could counteract impaired neurogenesis induced by neonatal maternal separation (NMS). Adolescent NAC administration restored the number of Ki67⁺ proliferating progenitors and DCX⁺ immature neurons in the DG of NMS rats, accompanied by reduced reactive oxygen species, suppressed iNOS induction, and attenuated microglial activation. NAC also normalized EAAC1 expression, indicating enhanced neuronal antioxidant capacity. Notably, NAC rescued diminished neurogenesis in EAAC1 knockout mice, demonstrating its efficacy under both stress-induced and transporter-deficient redox imbalance. These findings identify NAC as a potent modulator of hippocampal neuroplasticity, acting through the restoration of redox and inflammatory homeostasis, and support its potential as an early therapeutic strategy to mitigate long-lasting neurodevelopmental consequences of ELS.

The ability to cope with changing environments is critical for healthy functioning, yet this flexibility is impaired in many neuropsychiatric disorders. However, neural mechanisms underlying flexible behavior remain elusive. Here, we report that oscillatory dynamics in the medial prefrontal cortex (mPFC) support learning to flexibly overcome established behavioral bias. Mice performed a delayed non-match-to-sample task that required trial-by-trial adjustment of arm choice strategy despite persistent arm bias. Decoding analysis of delay-period local field potentials (LFPs) and single-unit activities revealed evolving neural representations across trials as mice adapted to the task. Notably, mPFC neurons modulated by theta (4~12 Hz) bursts selectively encoded upcoming choice information after acquiring the new rule. In contrast, beta (12~30 Hz) bursts correlated with perseverative behavior and appeared to inhibit theta-modulated neuronal firing in mice showing adaptive behavior. These theta and beta bursts were temporally separated over the delay period, reflecting a dynamic gating mechanism. Thus, beta bursts shape neuronal ensembles that are modulated by theta bursts to facilitate flexible learning. This dynamic interaction provides a mechanistic basis for cognitive flexibility and provides insights into cognitive rigidity seen in neuropsychiatric disorders such as schizophrenia and autism.

Dynamic facial expressions carry a wide range of signals, encompassing emotional but also more conversational content important for social interaction, for which the dynamic aspect is crucial. Likewise, we know from previous behavioral and neuroimaging studies that processing of emotional stimuli changes across aging - little, however, is known about how age may impact brain activity for dynamic facial expressions. To address this open issue, here we used two cohorts of older and younger adults (total N=77) within a whole-brain MVPA decoding paradigm in fMRI. We used a range of dynamic and conversational expressions as stimuli shown with a foil task in the scanner and had participants rate these post-scanning in terms of their affective content along 12 dimensions (including valence and arousal). The behavioral ratings were used to cluster the facial expressions and the resulting similarity matrix was used in a searchlight decoding paradigm to identify common areas. Using robust bootstrap analyses, we identified the insula as a common brain region able to decode the wide range of emotional and conversational dynamic facial expressions for both participants groups. We also discuss additional brain areas specific to the younger group. Our study adds to the growing literature on neural processing of dynamic expressions in the context of aging.

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.