Frontiers in Cellular Neuroscience最新文献

Objective: To investigate the effects of bone marrow mesenchymal stem cells (BMSCs) on extrapyramidal neural network of Wilson disease (WD).

Methods: 27 6-month-old toxic milk mice (TX mice, WD animal model) and 15 C57 mice were selected. Corrected phase (CP) value on susceptibility weighted imaging (SWI), fractional anisotropy (FA) on diffusion tensor imaging (DTI) were performed. The volume of fiber connections was determined. BMSCs was transplanted though tail vein injection (1 × 10⁶, 0.5 mL). The myelin basic protein (MBP), amyloid precursor protein (β-APP), nitric oxide (NO), glutathione (GSH) and interleukin (IL-1β) were determined at 1, 2, 4 and 8 weeks after transplantation.

Results: The CP value of TX mice increased at 4 (p = 0.029) and 8 weeks (p = 0.037) after transplantation. FA values (p = 0.026, 0.020, 0.037) and the volume of neural fibers (p = 0.016, 0.023, 0.018) increased at 2, 4 and 8 weeks after transplantation. The pathological indexes of demyelination (MBP) and axon injury (β-APP) improved after BMSCs transplantation. The brain copper content decreased at 4 and 8 weeks after transplantation (p = 0.024, 0.038). The indexes of oxidative stress (NO and GSH) and inflammation (IL-1β) of TX mice were improved after transplantation.

Conclusion: BMSCs can ameliorate WD extrapyramidal neural network injury. The mechanism may be related to reducing copper deposition and alleviating oxidative stress and inflammatory response.

Neuroscience drug discovery is challenged by the brain's structural and cell-type complexity, which is difficult to model in cellular systems compatible with high-throughput screening methods. Calcium oscillation assays, that harness neurons' intrinsic capability to develop functional neural networks in cell culture, are currently the closest cellular models with a relevant functional endpoint to model human neuronal circuitry in a dish. Here we further developed this useful assay towards scalable drug discovery applications. We show the importance of defined neuron-to-astrocyte ratios for optimal cellular distribution and surface adherence in HTS-compatible cell culture vessels and how the cell type ratios affect network firing patterns. Increasing the neuron density resulted in decreased network spike frequencies, but increased network spike amplitudes. We identified DAPT, a molecule previously shown to promote neuronal maturation and synapse formation, as a negative regulator of astrocyte viability. Furthermore, inclusion of GABAergic neurons in the cocultures increased the network spike frequency while reducing network spike amplitudes. The GABA_A receptor antagonist bicuculline did not affect network spike frequency, but increased network spike amplitudes. In order to access local field activity in an automated and scalable calcium imaging environment, we developed a pixel-based analysis for plate reader data. This method revealed that the effect of GABAergic neurons and bicuculline was restricted to local field calcium activity that coincided with synchronized network spikes. Our observations are consistent with previous findings suggesting that the presence of GABAergic neurons decreases synchronization and network spike participation of local neuronal activity, thus potentially echoing aspects of GABA action in vivo, and dysregulation thereof in pathological conditions.

Background: Alzheimer's disease (AD) has long been associated with hallmark protein aggregates, yet increasing evidence suggests immune involvement may contribute to its progression. Prior studies have found increased T cell presence in AD brain tissue, raising the possibility of neuroimmune crosstalk.

Methods: We used single-nucleus RNA sequencing data from the Religious Orders Study and Memory and Aging Project (ROSMAP), the largest available postmortem AD cohort, to investigate T cell dynamics in prefrontal cortex (PFC) and hippocampus.

Results: Contrary to prior findings, we observed no significant increase in T cell frequency in individuals with pathologically confirmed AD in either region. We replicated these findings in dorsolateral PFC (DLPFC) using the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD). Notably, although we confirmed a prior finding of T cell expansion in middle temporal gyrus (MTG), the strength of this association was affected by donor age. Additionally, we detected no change in gene expression in T cells in the brain parenchyma from individuals with AD.

Impact: These results suggest that T cell enrichment in AD may be regionally restricted and not as widespread as previously assumed. Our findings underscore the importance of brain region selection, analytical approach, and dataset composition in interpreting immune cell dynamics in neurodegenerative disease.

Neurodegenerative diseases are frequently accompanied by inflammatory responses and alterations in lipid metabolism, both of which are believed to negatively affect neural regeneration in mammals. In addition to immune cells, glial cells such as astrocytes and microglia contribute significantly to these inflammatory processes, and it is now recognized that lipid droplet accumulation and cholesterol metabolism are dysregulated in these glial cells. Consequently, recent studies have examined inflammation and lipid metabolism from the standpoint of glial cell function; however, effective therapeutic strategies remain unestablished. By contrast, in zebrafish, a teleost species, robust neural regeneration occurs within a short period after injury to the telencephalon or spinal cord. In this review, we aimed to identify candidate functional factors by comparing mouse and zebrafish disease models and to explore molecules with potential therapeutic relevance for mammalian neurological disorders.

Microglia can selectively phagocytose live neurons during normal development and also in response to stress, injury or disease by recognizing phagocytic cues to target cells for elimination. In the developing retina at embryonic stages we previously found that microglia refine retinal ganglion cell (RGC) numbers by targeting non-apoptotic newborn RGCs for phagocytosis, utilizing complement receptor 3 (CR3) to recognize and eliminate RGCs. Here, we investigate additional phagocytic mechanisms and cues that microglia utilize to clear a subset of viable RGCs. Our findings indicate that both Mer tyrosine kinase (Mertk) and CR3 are required for clearance of a subpopulation of embryonic RGCs. In Mertk/CR3 double knockouts, we show that C1q-tagged RGCs accumulate and excess RGCs persist indicating failure of normal clearance by microglia. We also show that microglia target RGCs that have phosphorylated c-JUN (p-cJUN) expression, suggesting stress pathway activation. RGCs with p-cJUN expression also accumulate in Mertk/CR3 double knockout retinas, but this appears to resolve by P0, suggesting this is a transient stress state exhibited by a subset of RGCs that remain viable. By depleting microglia we establish that microglia are not required for p-cJUN induction in RGCs but show that they are the sole source of complement protein C1q, which marks these cells for elimination. Altogether the data suggests that a subset of stressed RGCs are recognized by local microglia that tag them with opsonins for removal using specific recognition receptors.

Purpose: To investigate the impact of low-dose, long-term aspirin use on neovascular age-related macular degeneration (nAMD).

Methods: Adult C57BL/6J or Thbs-1^-/- mice were treated with daily aspirin (1.25 mg/kg) for 8 weeks before being subjected to laser-induced choroidal neovascularization (CNV). The animals were left for 7-10 days with continued aspirin use before the eyes were collected for further investigations. Bone marrow-derived macrophages (BMDMs) and primary retinal pigment epithelial (RPE) cells were treated with different concentrations of aspirin (1, 10, 100 μM) for two days before being subjected to LPS+IFNγ for 16 h. The expression of cytokine genes was evaluated by qRT-PCR. The concentrations of thrombospondin-1 (TSP-1) were measured by ELISA.

Results: Aspirin treatment did not affect circulating immune cell profiles in normal mice but significantly increased CD11b⁺ cells in laser-induced CNV mice. The treatment significantly increased the severity of laser-induced CNV and reduced serum levels of TSP-1. In vitro aspirin treatment upregulated Tnfa and Ccl22, down-regulated Thbs-1 mRNA expression, and reduced TSP-1 production in LPS+IFNγ-treated M1 BMDMs but not RPE cells. Thbs-1^-/- mice developed severe laser-induced CNV, which was not affected by aspirin intervention. nAMD patients had significantly lower serum levels of TSP-1 than healthy controls, although no significant difference was found between nAMD patients with and without aspirin use.

Conclusion: Low-dose long-term aspirin use promoted the severity of laser-induced CNV by down-regulating TSP-1. Lower serum levels of TSP-1 may be a risk factor for nAMD. The long-term ocular safety of aspirin should be validated in prospective cohorts.

tRNA-derived small RNAs (tsRNAs) have recently gained attention as important regulatory non-coding RNAs (ncRNAs). Among these, tRNA-derived fragments (tRFs) constitute a distinct and well-defined subset. These small molecules play essential roles in maintaining cellular homeostasis and have been increasingly implicated in disease pathogenesis. This comprehensive review specifically concentrates on tRFs, takes a closer look at their diverse mechanisms of action and their impact on key cellular processes. Specific focus is placed on their functions within the central nervous system (CNS) and their involvement in the molecular pathways driving neurological diseases and neurodevelopmental disorders. Besides their pathological roles, the review covers fundamental aspects of tRFs, including their biogenesis, classification, and structural features. It also describes latest methods for tRFs detection, prediction, and validation. Overall, the review points out the ongoing need for research in this area, especially when it comes to applying these findings clinically. Importantly, it highlights their potential as useful biomarkers and even targets for treatment in neurological diseases.

Neuroglia, comprising three cell types (astrocytes, oligodendrocytes and microglia), interact with neurons and extracellular components in brain physiology. Astroglia, having as main function the control of homeostasis, modulate dynamic processes in the nervous system, including mental functions; they are crucially involved in all neurological, psychiatric and degenerative disorders and diseases. How to change the century-old neuron-centered paradigm used to explain experimental phenomena in the clinical domain? This is the question addressed in this paper. I review a new explanatory paradigm based on an "endogenous feedback" between astroglial and neuronal networks: neuronal bioelectricity generates Local Field Potentials, which are synchronized, generating a dynamic field that impacts on a multi-ion population, releasing 'shuttles' that induce amplitude-modulated spatiotemporal patterns on astroglial 'calcium waves'. The 'calcium wave' activates other signaling processes, as the release of ions in the "synaptic cradle," to control the temporal dynamics of spike trains of the post-synaptic neuron and metabolic processes determining behavioral and endocrine responses. The "endogenous feedback" theoretical hypothesis can be tested by means of a combination of new techniques of visualization and analysis of amplitude-modulated spatiotemporal patterns present in astroglia in vivo, registers of behavioral patterns and subjective reports (in the case of alert persons under invasive brain surgery procedures), addressing the issue of how astroglial 'calcium waves' modulate neuronal dynamics, mediating brain processing of stimuli to produce adaptive responses.

The corpus callosum (CC) is the largest interhemispheric commissure in the eutherian brain, enabling inter-hemispheric sensory integration and higher-order cognitive functions. Historically viewed through a neuron- and axon-centric lens, extensive research has established that glial cells (astrocytes, oligodendrocytes, and microglia) are essential regulators of CC ontogenesis. Astrocytic guidepost cells sculpt midline architecture and secrete axonal guidance cues; oligodendrocytes drive callosal axonal maturation and myelination; and microglia regulate their fasciculation and pruning, myelination patterns, and synaptic refinement. In addition to these cell-specific roles, coordinated bidirectional signaling between neurons and glia ensures that axon targeting, maturation, and interhemispheric integration proceed in a precisely orchestrated manner. Disruptions to these glial functions are implicated in congenital and developmental brain pathologies, including malformations and CC agenesis. This review integrates molecular, developmental, and translational insights to provide a comprehensive, mechanistic understanding of glial contributions to CC development and how their dysfunction shapes pathology.