Frontiers in Cellular Neuroscience最新文献

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.

Astrocytes are the most abundant glial cells in the central nervous system. They detect neuronal activity through Ca²⁺ signals and thereby regulate synaptic plasticity, integrate neuronal information, and maintain extracellular homeostasis. Growing evidence indicates that aberrant astrocytic Ca²⁺ signaling is an important pathological factor in the onset and progression of many neurological disorders. In this review, we systematically summarize the sources, classifications, detection methods, and functional significance of astrocyte Ca²⁺ signaling, with the aim of improving understanding of astrocyte function and providing new perspectives and rationale for therapeutic strategies targeting related diseases.

The essential role of the lungs in gas exchange necessitates exposure to possible threats from a dynamic external environment. To protect life-critical functions the airways contain multiple systems that monitor the inhaled environment and elicit appropriate defensive responses. As such the airways represent a key sensory surface with multiple signaling pathways to the brain. Despite the presence of rich and diverse bacterial communities in both upper and lower airways, the respiratory tract has been relatively overlooked compared to the gut regarding its potential as an interface between microbes and the central nervous system. This review draws attention to the respiratory system, specifically the nasal cavity and lungs, and the evidence supporting a microbiota-airway-brain axis. We highlight the olfactory system and the role of the lungs as a sensory organ, monitoring the inhaled environment, as clear examples of airway-brain communication and identify how these communication pathways can be engaged by microbes. We also outline the relationship between the airways and mental health and present the case that the nasal and lung microbiota should be considered alongside that of the gut as potential influencers of brain function, mood, and behavior.

We offer an integrative perspective on how the air-pollution exposome shapes fetal development during the first 1,000 days and reverberates across mental health and behavior. Pregnant individuals and young children are disproportionately exposed to particulate matter (PM2.5), nitrogen dioxide (NO₂), ozone (O₃), and volatile organic compounds (VOCs) with social disadvantage amplifying risk. We bridge exposure to biology through three conduits. First, the placenta acts as a sensor and recorder, transducing signals that alter growth, immune tone, and neuroendocrine programming. Second, fetal autonomic control-captured by beat-to-beat fetal heart rate variability (fHRV) offers a relevant biomarker of neurodevelopmental integrity; the absence of direct ambient-pollution-fHRV studies is a pressing gap. Third, maternal immune activation, oxidative and endoplasmic reticulum (ER) stress, and disrupted morphogenesis reshape developing circuits, changes now traceable in utero by advanced fetal MRI. These pathways fit a developmental-programming frame: epigenetic remodeling, gene-environment interplay, endocrine-disrupting co-exposures, and gut-microbiome shifts create durable susceptibility. Clinically, the result is structural and functional brain alterations and child phenotypes spanning attention, executive control, affecting regulation, and learning, with clear pediatric and educational implications. We propose an exposome-based research agenda coupling high-resolution exposure assessment with placental molecular profiling, fetal/neonatal autonomic biomarkers (including fHRV), fetal/child neuroimaging, and longitudinal microbiome readouts in harmonized cohorts. In parallel, multisectoral actions-clean air urban design, targeted protection of pregnancy and early childhood, chemical regulation, and risk communication-should narrow exposure inequities while trials test biomarker-guided prevention. Aligning placental biology, autonomic metrics, and exposome science may transform risk stratification and safeguard the developing brain.