Neuroscience Research最新文献

Neurodegenerative diseases (ND) affect distinct populations of neurons and manifest various clinical and pathological symptoms. A subset of ND prognoses has been linked to vascular risk factors. Consequently, the current study investigated retinal vascular abnormalities in a murine model of Lafora neurodegenerative disease (LD), a fatal and genetic form of progressive myoclonus epilepsy that affects children. Here, arterial rigidity was evaluated by measuring pulse wave velocity and vasculature deformations in the retina. Our findings in the LD mouse model indicate altered pulse wave velocity, retinal vascular thinning, and convoluted retinal arteries.

Studies have demonstrated that the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) extensively affects brain function. Although cognitive dysfunction is considered a common manifestation in COVID-19 patients during the recovery period, the potential changes in decision-making ability, are not yet clear. Decision-making functions are essential to the work of healthcare workers. However, there is a lack of a multidimensional assessment of its functioning in COVID-19 cases. Here, we used tests combined with the resting-state functional magnetic resonance imaging (rs-fMRI) stabilization feature amplitude of low-frequency fluctuations (ALFF) to explore decision-making behavior and brain neural activity changes in healthcare workers after mild COVID-19. Participants were divided into the SARS-CoV-2 infected group (SI, n = 41) and healthy controls (HC, n = 42). All participants underwent a series of neuropsychological tests. They performed the Iowa Gambling Task (IGT) and the Game of Dice Task (GDT), followed by fMRI (n = 20) to assess their decision-making ability under ambiguous and risky conditions and changes in brain neural activity. The SI group performed worse in verbal memory than the HC group. Furthermore, the SI group performed worse in the IGT, whereas no significant difference was observed in the GDT. In addition, rs-fMRI showed enhanced spontaneous neural activity in the postcentral gyrus and inferior parietal lobe in the SI group compared to the HC group.

The central neuropeptide GLP-1 is synthesized by preproglucagon (PPG) neurons in the brain. GLP-1 receptors are widely distributed in central nervous system. Hippocampus is a key component of the limbic system which is involved in learning, memory, and cognition. Previous studies have shown that overexpression of GLP-1 receptors in the hippocampus could improve the process of learning and memory. However, up to now, the direct electrophysiological effects and possible molecular mechanisms of GLP-1 in hippocampal CAl neurons remain unexplored. The present study aims to evaluate the effects and mechanisms of GLP-1 on the spontaneous firing activity of hippocampal CAl neurons. Employing multibarrel single-unit extracellular recordings, the present study showed that micro-pressure administration of GLP-1 receptor agonist, exendin-4, significantly increased the spontaneous firing rate of hippocampal CA1 neurons in rats. Furthermore, application of the specific GLP-1 receptor antagonist, exendin(9−39), alone significantly decreased the firing rate of CA1 neurons, suggesting that endogenous GLP-1 modulates the firing activity of CA1 neurons. Co-application of exendin(9−39) completely blocked exendin-4-induced excitation of hippocampal CA1 neurons. Finally, the present study demonstrated for the first time that the transient receptor potential canonical 4 (TRPC4)/TRPC5 channels may be involved in exendin-4-induced excitation. The present studies may provide a rationale for further investigation of the modulation of GLP-1 on learning and memory as well as its possible involvement in Alzheimer's disease.

Dendritic spines are unique postsynaptic structures that emerge from the dendrites of neurons. They undergo activity-dependent morphological changes known as structural plasticity. The changes involve actin cytoskeletal remodeling, which is regulated by actin-binding proteins. CaMKII is a crucial molecule in synaptic plasticity. Notably, CaMKIIβ subtype is known to bind to filamentous-actin and is closely involved in structural plasticity. We have shown that CaMKIIβ binds to drebrin, and is localized in spines as both drebrin-dependent and drebrin-independent pools. However, the nanoscale relationship between drebrin and CaMKIIβ within dendritic spines has not been clarified. In this study, we used stochastic optical reconstruction microscopy (STORM) to examine the detailed localization of these proteins. STORM imaging showed that CaMKIIβ co-localized with drebrin in the core region of spines, and localized in the submembrane region of spines without drebrin. Interestingly, the dissociation of CaMKIIβ and drebrin in the core region was induced by NMDA receptor activation. In drebrin knockdown neurons, CaMKIIβ was decreased in the core region but not in the submembrane region. Together it indicates that the clustering of CaMKIIβ in the spine core region is dependent on drebrin. These findings suggest that drebrin-dependent CaMKIIβ is in a standby state before its activation.

Bone mesenchymal stem cell (BMSC)-derived exosome (BMSC-Exo) could be a treatment method for ischemic injury. In ischemic cerebrovascular disease (IC), microglia is pivotal in neuronal damage and remodeling. This study explores the mechanisms of BMSC-Exo miR-148b-3p in regulating oxygen-glucose deprivation/reoxygenation (OGD/R)-induced human microglial clone 3 (HMC3) cell activation. Transmission electron microscopy (TEM) and qNano were used to assess BMSC-Exo features. The functions of BMSC-Exo miR-148 b-3p in OGD/R-induced HMC3 cell activation were explored via MTT assay, flow cytometry, scratch, transwell, and enzyme-linked immunosorbent assay (ELISA) assays. A dual-luciferase reporter assay was performed to determine the relationship between miR-148b-3p and Delta-like ligand 4(DDL4) or neurogenic locus notch homolog protein 1 (Notch1). OGD/R decreased miR-148b-3p expression in HMC3 cells. After BMSC-Exo treatment, miR-148b-3p expression was upregulated, cell viability and migration were inhibited, cell cycles remained in the G0/G1 phase, and proinflammatory cytokines were decreased in OGD/R-induced HMC3 cells. More importantly, BMSC-Exo miR-148b-3p could further strengthen BMSC-Exo effects. DDL4 and Notch1 are direct targets of miR-148b-3p, respectively. Moreover, the knockdown of DLL4 or Notch1 could inhibit OGD/R-induced HMC3 cell activation. BMSC-Exo miR-148b-3p inhibited OGD/R-induced HMC3 cell activation via inhibiting DLL4 and Notch1 expression, which provided a new strategy for treating cerebral ischemia.

Dopamine neurons have long been thought to facilitate learning by broadcasting reward prediction error (RPE), a teaching signal used in machine learning, but more recent work has advanced alternative models of dopamine’s computational role. Here, I revisit this critical issue and review new experimental evidences that tighten the link between dopamine activity and RPE. First, I introduce the recent observation of a gradual backward shift of dopamine activity that had eluded researchers for over a decade. I also discuss several other findings, such as dopamine ramping, that were initially interpreted to conflict but later found to be consistent with RPE. These findings improve our understanding of neural computation in dopamine neurons.

SUMO (small ubiquitin-like modifier) conjugation or SUMOylation, a post-translational modification, is a crucial regulator of protein function and cellular processes. In the context of neural stem cells (NSCs), SUMOylation has emerged as a key player, affecting their proliferation, differentiation, and survival. By modifying transcription factors, such as SOX1, SOX2, SOX3, SOX6, Bmi1, and Nanog, SUMOylation can either enhance or impair their transcriptional activity, thus impacting on NSCs self-renewal. Moreover, SUMOylation regulates neurogenesis and neuronal differentiation by modulating key proteins, such as Foxp1, Mecp2, MEF2A, and SOX10. SUMOylation is also crucial for the survival and proliferation of NSCs in both developing and adult brains. By regulating the activity of transcription factors, coactivators, and corepressors, SUMOylation acts as a molecular switch, inducing cofactor recruitment and function during development. Importantly, dysregulation of NSCs SUMOylation has been implicated in various disorders, including embryonic defects, ischemic cerebrovascular disease, glioma, and the harmful effects of benzophenone-3 exposure. Here we review the main findings on SUMOylation-mediated regulation of NSCs self-renewal, differentiation and survival. Better understanding NSCs SUMOylation mechanisms and its functional consequences might provide new strategies to promote neuronal differentiation that could contribute for the development of novel therapies targeting neurodegenerative diseases.

The purpose of this study was to analyze and elucidate the mechanisms of non-obese diabetes-experimental autoimmune encephalomyelitis (NOD-EAE), an animal model of progressive multiple sclerosis (MS), and to compare the pathological features with those observed in human progressive MS. Pathological analysis, flow cytometry analysis, immunohistochemical staining, and transcriptome analysis were performed at each pathological stage of the NOD-EAE mice to characterize each pathological stage in the lesion. The NOD-EAE mice showed a biphasic pattern of disease progression once in remission. The longitudinal profile of demyelination and inflammatory cell infiltration in the spinal cord was consistent with the pathological score. In the chronic phase of the disease, fibrosis and lymph follicle formation, characteristic of progressive human MS, were observed. Here we describe the pathological profile and transcriptome analysis of the NOD-EAE mice and verify that this model has similar features to those of human progressive MS. Our findings suggest that this model recapitulates lymph follicle formation, a disease hallmark of progressive MS, and fibrosis, a feature complicating the pathogenesis of MS in the chronic phase. This model may be useful for evaluating the efficacy of therapeutic agents and for mechanistic analysis.

Epilepsy is a common neurological disorder worldwide. Hydrogen sulfide (H₂S) has been found to have anti-seizure effects. However, its mechanism remains to be explored. In the present study, we showed that a novel H₂S donor attenuated neuroinflammation by up-regulating ATP-sensitive potassium channel (K_ATP) expression to reduce seizures. The novel H₂S donor significantly reduced the expression of TNF-α and increased the expression of IL-10 in LPS-treated BV2 cells and the hippocampus of pilocarpine-induced epileptic mice. The modulatory effects of the H₂S donor on inflammatory cytokines were prevented by glibenclamide, a common K_ATP channels blocker. The H₂S donor promoted the expression of K_ATP channel subunits SUR2 and Kir6.1 in LPS-treated BV2 cells and the hippocampus of pilocarpine-induced epileptic mice. In addition, the H₂S donor reduced the electroencephalography amplitude of hippocampal epileptic waves and reduced seizures in pilocarpine-induced epileptic mice, which were also attenuated by glibenclamide. These results indicated that the novel H₂S donor reduced seizures and regulated microglial inflammatory cytokines by activating K_ATP channels, which may provide a prospective therapeutic strategy for the anti-seizure effects of H₂S donor.

Histones organize DNA within cellular nuclei, but they can be released from damaged cells. In peripheral tissues extracellular histones act as damage-associated molecular patterns (DAMPs) inducing pro-inflammatory activation of immune cells. Limited studies have considered DAMP-like activity of histones in the central nervous system (CNS); therefore, we studied the effects of extracellular histones on microglia, the CNS immunocytes, and on neuronal cells. Both the linker histone H1 and the core histone H3 induced pro-inflammatory activation of microglia-like cells by upregulating their secretion of NO and cytokines, including interferon-γ-inducible protein 10 (IP-10) and tumor necrosis factor-α (TNF). The selective inhibitors MMG-11 and TAK-242 were used to demonstrate involvement of toll-like receptors (TLR) 2 and 4, respectively, in H1-induced NO secretion by BV-2 microglia. H1, but not H3, downregulated the phagocytic activity of BV-2 microglia. H1 was also directly toxic to all neuronal cell types studied. We conclude that H1, and to a lesser extent H3, when released extracellularly, have the potential to act as a CNS DAMPs. Inhibition of the DAMP-like effects of extracellular histones on microglia and their neurotoxic activity represents a potential strategy for combating neurodegenerative diseases that are characterized by the adverse activation of microglia and neuronal death.