ABSTRACTIron is essential for life and plays a key role in multiple fundamental cellular functions. The brain has the highest rate of energy consumption, and within the brain, oligodendrocytes have the highest level of oxidative metabolism per volume. Oligodendrocytes also stain the strongest for iron. The high requirement for iron is related to an oligodendrocyte's primary function to produce the myelin sheath, which requires iron as a cofactor. In addition to the high‐energy demands that accompany the production of such dense and extensive membranous sheaths, iron is also required for lipid synthesis. Although the involvement of iron in oligodendrocyte functioning is clear, how iron is specifically acquired and utilized by oligodendrocytes is not completely understood. The purpose of this review is to provide a complete and thorough overview of the role of iron in oligodendrocytes. Here, we discuss in detail what is currently known about key iron transport proteins that participate in the balance of iron in oligodendrocytes. Understanding how oligodendrocytes utilize iron is beneficial in understanding dysmyelinating diseases, and the knowledge could be utilized to develop treatment options.

ABSTRACTOligodendrogenesis and myelin formation are important processes in the central nervous system (CNS) of jawed vertebrates, underpinning the highly efficient neural computation within the compact CNS architecture. Myelin, the dense lipid sheath wrapped around axons, enables rapid signal transmission and modulation of neural circuits. Oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), which are widely distributed in the adult CNS and continue to produce new oligodendrocytes throughout life. Adult oligodendrogenesis is integral to adaptive myelination, which fine‐tunes neural circuits in response to neuronal activity, contributing to neuroplasticity, learning, and memory. Emerging evidence also highlights the role of oligodendrogenesis in specialized brain regions, linking oligodendrocytes to metabolic and homeostatic functions. In the aging and diseased brain, dysregulated oligodendrogenesis exacerbates myelin loss and may contribute to pathogenesis. In addition, maladaptive myelination driven by aberrant neuronal activity could sustain a dysfunction in conditions such as epilepsy. This review summarizes the current understanding of oligodendrogenesis, with insights into its evolution, regulation, and impact on aging and disease.

The Nucleus Accumbens (NAc) is a critical brain region for the effects of psychostimulant drugs. Type-1 cannabinoid receptors (CB1), the main elements of the endocannabinoid system (ECS) in the brain, participate in these effects and modulate synaptic functions in the NAc. Besides their neuronal expression, CB1 receptors are also present in astrocytes, where they contribute to the regulation of synaptic plasticity and behavior. However, the impact of astroglial CB1 receptors on synaptic plasticity in the NAc and on psychostimulant-induced synaptic and behavioral effects is currently unknown. This study shows that the psychostimulant amphetamine impairs a form of astroglial CB1 receptor-dependent synaptic plasticity in the NAc of male, but not female mice. Consistently, locomotor effects of amphetamine require astroglial CB1 receptors in male, but not female mice. These results, by revealing unforeseen mechanisms underlying sex-dependent effects of amphetamine, pave the way to a better understanding of the diverse impact of psychostimulants in women and men.

Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression invivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.

Subarachnoid hemorrhage (SAH) is a devastating neurological disorder that results from the accumulation of blood in the brain's subarachnoid space, leading to significant challenges in neurological recovery. This study explores the molecular interactions between Connexin 43 (Cx43) and Atypical Chemokine Receptor 3 (ACKR3) in astrocytes following SAH, with a focus on their roles in neuroinflammation and neuronal apoptosis. Through transcriptome sequencing and a range of functional assays, we have identified crucial alterations in astrocytic gene expression triggered by the modulation of these proteins. Our results indicate that the Cx43-ACKR3 axis plays a pivotal role in exacerbating neuroinflammatory responses and enhancing neuronal apoptosis, which are key contributors to the pathology of SAH. The data reveal that disrupting this axis could serve as a therapeutic target, suggesting potential interventions to mitigate neuroinflammation, restore astrocytic functionality, and ultimately protect against neuronal damage. This study contributes to the understanding of glial cell dynamics in SAH and opens avenues for novel therapeutic approaches to treat this severe condition.

ABSTRACTThe mammalian suprachiasmatic nucleus (SCN) orchestrates daily (circadian) rhythms of physiology and behavior by broadcasting timing cues generated autonomously by its mutually reinforcing network of ~10,000 neurons and ~3000 astrocytes. Although astrocytic control of extracellular glutamate and GABA has been implicated in driving circadian oscillations in SCN gene expression and neuronal activity, the full scale of the network‐level signaling mechanisms is unknown. To understand better how this astrocyte‐neuron network operates, we adopted a multi‐omics approach, first using SILAC‐based mass spectrometry to generate an SCN proteome where ~7% of identified proteins were circadian. This circadian proteome was analyzed bioinformatically alongside existing single‐cell RNAseq transcriptomic data to identify the cell‐types and processes to which they contribute. This highlighted “S100 protein binding,” tracked to astrocytes, and revealed annexin‐A2 (Anxa2) as an astrocyte‐enriched circadian protein for further investigation. We show that Anxa2 and its partner S100a10 are co‐expressed and enriched in SCN astrocytes. We also show that pharmacological disruption of their association acutely and reversibly dysregulated the circadian cycle of astrocytic calcium levels and progressively compromised SCN neuronal oscillations. Anxa2 and S100a10 interaction therefore constitutes an astrocytic cellular signaling axis that regulates circadian neuronal excitability and ultimately SCN network coherence necessary for circadian timekeeping.

Individual protoplasmic astrocytes have very complex and diverse spongiform shapes. The morphological diversity of astrocytes is determined by the structural and functional interactions of the astrocyte with its microenvironment. When faced with pathological conditions, astrocytes reorganize their morphology. Yet, little is known about the astrocytic response in pure tauopathies and its evolution over time. Here, we aimed to investigate the consequences of a primary neuronal tau pathology on astrocyte fine morphology at three stages of the disease using the transgenic Thy-Tau22 mouse model. We first showed that hippocampal astrocytes in Thy-Tau22 mice progressively accumulate hyperphosphorylated tau with age. We then developed a pipeline of analyses, including 3D reconstruction of hippocampal tdTomato-labeled astrocytes via a PHP.eB adeno-associated virus, confocal microscopy, Imaris software morphometric analysis, and an advanced statistical analysis. During normal aging, the complexity of astrocyte morphology peaked at adulthood, then declined. In contrast, in Thy-Tau22 mice, tauopathy was associated with a simpler initial morphology, followed by the appearance of a cluster of complex cells at the most advanced stage. Using principal component analysis and hierarchical clustering based on 10 morphological features, we were able to identify different astrocyte morphotypes whose relative proportion varies differently with age between WT and Thy-Tau22 mice. Interestingly, we revealed that a fraction of astrocytes with a complex morphology re-emerges late in tauopathy-affected animals. Our data highlight the concept of significant and reversible structural plasticity of astrocytes when faced with chronic pathological conditions.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, characterized by memory decline and behavioral changes. Its pathological features include senile plaques, neurofibrillary tangles, and reactive gliosis, comprising abnormal accumulations of β-amyloid peptide (Aβ) and hyperphosphorylated tau protein surrounded by reactive astrocytes and microglia. Recently, it has emerged that severe reactive astrocytes and MAOB-dependent production of GABA and H2O2 are the real causes of learning and memory impairment and neurodegeneration. Diverse mouse models for AD have been developed to clarify pathological mechanisms and discover therapeutic strategies and drugs. However, there are many shortfalls and discrepancies among them. A new AD mouse model named FAD4T has been developed to overcome various shortcomings. Here, we employed astrocyte-focused screening procedures to examine the pathological features of FAD4T as an AD model. Our results revealed that the FAD4T mice showed abnormal accumulation of Aβ plaques in overall brain regions at 6 and 12 months. We found astrocytic hypertrophy with a significant elevation of GFAP and LCN2. However, the expressions of MAOB and iNOS, a severe reactive astrocyte marker, were unchanged. Electrophysiological and behavioral analysis indicated aberrant tonic GABA release, reduced neuronal activity, and impaired CA1-specific memory. These findings demonstrate that FAD4T mice mimic pathological and functional features of AD, different from other AD mouse models. These findings demonstrate that FAD4T mimics some features of AD patients but lacks other important features, such as severe reactive astrocytes and neurodegeneration. This astrocyte-focused screening method offers valuable tools for advancing AD research and developing new therapeutic strategies.

The myelination is a critical process during brain development. This study aimed to explore the impact of volatile anesthetic sevoflurane on developing myelination and the role of microglial activation in this process. Neonatal C57BL/6J mice were exposed to sevoflurane at their postnatal 6-8 days. Neurobehavioral tests were used to assess fine motor and cognitive functions. Myelination of hippocampus (HC) and corpus callosum (CC), as well as microglial activation, were determined by western blotting and immunostaining. Lipid droplets were assessed by Oil-Red-O and Bodipy staining. Further, primary microglia were co-cultured with oligodendrocyte precursor cell (OPC) to determine the role of microglia in the proliferation and differentiation of OPC. And microglial inhibitor minocycline and CSF1R inhibitor PLX5622 were administered to assess the effects of microglial activation on developing myelination. The results showed that repeated sevoflurane exposure impaired both fine motor and cognitive functions and induced abnormal expressions of myelin-related proteins myelin basic protein (MBP) and platelet-derived growth factor α receptor (PDGFR-α). And accumulations of lipid droplets were found in the microglia of HC and CC after sevoflurane exposure. Further, the spatiotemporal response to repeated sevoflurane exposure in glial cells exhibited an aberrant myelination process and microglial polarization. The conditioned medium from sevoflurane-treated microglia inhibited the OPC proliferation and differentiation, while minocycline or PLX5622 alleviated sevoflurane-induced neuroinflammation and hypomyelination. Therefore, repeated sevoflurane exposure negatively affected OPC differentiation and myelination trajectory through hyperactivating microglia in developing brain, leading to motor and cognitive impairments, while microglial inhibition/depletion could protect against sevoflurane-induced damage on developing myelination.