Alzheimer's disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence of curative treatments. The current therapeutic strategies, primarily based on cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, offer limited symptomatic relief without halting disease progression, highlighting an urgent need for novel research directions that address the key mechanisms underlying Alzheimer's disease. Recent studies have provided insights into the critical role of glycolysis, a fundamental energy metabolism pathway in the brain, in the pathogenesis of Alzheimer's disease. Alterations in glycolytic processes within neurons and glial cells, including microglia, astrocytes, and oligodendrocytes, have been identified as significant contributors to the pathological landscape of Alzheimer's disease. Glycolytic changes impact neuronal health and function, thus offering promising targets for therapeutic intervention. The purpose of this review is to consolidate current knowledge on the modifications in glycolysis associated with Alzheimer's disease and explore the mechanisms by which these abnormalities contribute to disease onset and progression. Comprehensive focus on the pathways through which glycolytic dysfunction influences Alzheimer's disease pathology should provide insights into potential therapeutic targets and strategies that pave the way for groundbreaking treatments, emphasizing the importance of understanding metabolic processes in the quest for clarification and management of Alzheimer's disease.

Myelin is a multilamellar membrane that surrounds axons in the vertebrate nervous system. Properly functioning myelin is essential for the rapid conduction of nerve impulses, and it metabolically supports axonal integrity. Emerging evidence indicates that myelin is also involved in various aspects of cognition, with adaptive myelination playing a critical role in memory consolidation and motor learning. However, these physiological processes can be disrupted in various diseases. Understanding the mechanisms underlying myelin pathology is therefore essential for the development of targeted therapies for associated medical conditions. This review provides a comprehensive overview of the role of myelin in neural function, with a particular focus on adaptive myelination in cognition. We also highlight myelin dysfunction and the underlying mechanisms in the aging brain, as well as in diverse brain disorders and neurological conditions, including neurodegenerative diseases, psychiatric conditions, brain injuries, chemotherapy-related cognitive impairment, and neurological symptoms associated with COVID-19. Furthermore, we discuss the therapeutic potential of recently identified pro-myelinating compounds in aging-associated cognitive decline and brain disorders, as well as the future of remyelination therapies. Current evidence suggests that restoring functional myelin may serve as a therapeutic strategy for various medical conditions associated with myelin dysfunction.

The Fragile X Messenger Ribonucleoprotein (FMRP) is an RNA binding protein that regulates the translation of multiple mRNAs and is expressed by neurons and glia in the mammalian brain. Loss of FMRP leads to fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. While most research has been focusing on the neuronal contribution to FXS pathophysiology, the role of glia, particularly oligodendrocytes, is largely unknown. FXS individuals are characterized by white matter changes, which imply impairments in oligodendrocyte differentiation and myelination. We hypothesized that FMRP regulates oligodendrocyte maturation and myelination during postnatal development. Using a combination of human pluripotent stem cell-derived oligodendrocytes and an Fmr1 knockout rat model, we studied the role of FMRP on mammalian oligodendrocyte development. We found that the loss of FMRP leads to shared defects in oligodendrocyte morphology in both rat and human systems in vitro, which persist in the presence of FMRP-expressing axons in chimeric engraftment models. Our findings point to species-conserved, cell-autonomous defects during oligodendrocyte maturation in FXS.

Chromatin remodeling complexes (CRCs) participate in oligodendrocyte (OL) differentiation, survival, and maintenance. We asked whether CRCs also control the proliferation of OL precursors (OPs)-focusing on the INO80 complex, which is known to regulate the proliferation of a variety of other cell types during development and disease. CRISPR/Cas9-mediated inactivation of Ino80 in vitro, or Cre-mediated deletion in vivo, slowed the OP cell cycle substantially by prolonging G1. RNAseq analysis revealed that E2F target genes were dysregulated in OPs from INO80-deficient mice, but correlated RNAseq and ATAC-seq uncovered no general correlation between gene expression and altered nucleosome positioning at transcription start sites. Fluorescence photobleaching experiments in cultured OPs demonstrated that histone H2A.Z mobility increased following the loss of INO80, suggesting that INO80 regulates the cell cycle machinery in OPs through H2A.Z/H2A exchange. We also present evidence that INO80 associates with OLIG2, a master regulator of OL development.

There is increasing recognition that blood oxygenation level dependent (BOLD) signals are detectable in white matter (WM) and reflect an important, heretofore overlooked functional activity in the brain, but their biophysical origins remain understudied and poorly understood. By integrating several disparate, multimodal data sets, we established the associations of resting state BOLD signals with key microstructural, hemodynamic and metabolic features in WM. In particular, we identified the roles of myelination and fiber type in modulating BOLD effects, and derived relationships between measurements of BOLD signal power and cerebral blood volume, flow, oxygen extraction and metabolic rate of oxygen consumption, which are predicted using a simple theory and then verified empirically. Our findings demonstrate that myelin selectively influences the fractional amplitude of low-frequency fluctuations (fALFF) in BOLD signals, and that differences in myelin content account for variations in their temporal spectra and hemodynamic response functions, but these in turn are qualitatively different in association versus projection fibers. Other determinants of BOLD in WM are further revealed by converging biological, genomic and neurochemical evidence, including measurements of neurite and mitochondrial densities. Moreover, analyses of images of the optic nerve from human subjects confirm that BOLD activations evoked by visual stimuli are preferentially localized to unmyelinated portions, with minimal responses in fully myelinated regions of the same nerve, suggesting a myelin-dependent requirement for BOLD effects in WM.

Metabolism is fundamental to functional brain imaging. While functional MRI (fMRI) has greatly benefited neuroscience, 13C-MRS measures coupling between neuroenergetics and neurotransmission. However, a hyperpolarized 13C-MRI study in human brain shows increased 13C-lactate (i.e., cytosolic aerobic glycolysis) with no 13C-bicarbonate change (i.e., mitochondrial oxidation) within fMRI-defined activated areas. We discuss (dis)advantages of hyperpolarized vs. non-hyperpolarized 13C experiments and metabolic implications regarding the lactate increase: Is lactate a fuel for oligodendrocytes, astrocytes, or neurons? Is lactate a neuromodulator or a vasomodulator? Is lactate a byproduct of astrocytic glycogenolysis? Caveats aside, there is great enthusiasm for hyperpolarized 13C-fMRI.

Neurons rely on tightly regulated metabolic networks to sustain their high-energy demands, particularly through the coupling of glycolysis and oxidative phosphorylation. Here, we investigate the role of pyruvate kinase (PyK), a key glycolytic enzyme, in maintaining axonal and synaptic integrity in the Drosophila melanogaster neuromuscular system. Using genetic deficiencies in PyK, we show that disrupting glycolysis induces progressive synaptic and axonal degeneration and severe locomotor deficits. These effects require the conserved dual leucine zipper kinase (DLK), Jun N-terminal kinase (JNK), and activator protein 1 (AP-1) Fos transcription factor axonal damage signaling pathway and the SARM1 NADase enzyme, a key driver of axonal degeneration. As both DLK and SARM1 regulate degeneration of injured axons (Wallerian degeneration), we probed the effect of PyK loss on this process. Consistent with the idea that metabolic shifts may influence neuronal resilience in context-dependent ways, we find that pyk knockdown delays Wallerian degeneration following nerve injury, suggesting that reducing glycolytic flux can promote axon survival under stress conditions. This protective effect is partially blocked by DLK knockdown and fully abolished by SARM1 overexpression. Together, our findings help bridge metabolism and neurodegenerative signaling by demonstrating that glycolytic perturbations causally activate stress response pathways that dictate the balance between protection and degeneration depending on the system's state. These results provide a mechanistic framework for understanding metabolic contributions to neurodegeneration and highlight the potential of metabolism as a target for therapeutic strategies.

Chronic excessive alcohol (ethanol) consumption induces neuroadaptations in the brain's reward system, including biochemical and structural abnormalities in white matter that are implicated in addiction phenotypes. Here, we demonstrate that long-term (12 week) voluntary ethanol consumption enhances myelination in the nucleus accumbens (NAc) of female and male adult mice, as evidenced by molecular, ultrastructural, and cellular alterations. Specifically, transmission electron microscopy analysis showed increased myelin thickness in the NAc following long-term ethanol consumption, while axon diameter remained unaffected. These changes were paralleled by increased mRNA transcript levels of key transcription factors essential for oligodendrocyte (OL) differentiation, along with elevated expression of critical myelination-related genes. In addition, diffusion tensor imaging revealed increased connectivity between the NAc and the prefrontal cortex, reflected by a higher number of tracts connecting these regions. We also observed ethanol-induced effects on OL lineage cells, with a reduction in the number of mature OLs after 3 weeks of ethanol consumption, followed by an increase after 6 weeks. These findings suggest that ethanol alters OL development prior to increasing myelination in the NAc. Finally, chronic administration of the promyelination drug clemastine to mice with a history of heavy ethanol consumption further elevated ethanol intake and preference, suggesting that increased myelination may contribute to escalated drinking behavior. Together, these findings suggest that heavy ethanol consumption disrupts OL development, induces enhanced myelination in the NAc, and may drive further ethanol intake, reinforcing addictive behaviors.

In the mammalian central nervous system, axonal myelination, executed by mature oligodendrocytes (MOLs), enables rapid neural transmission. Conversely, myelin deficiencies are hallmark features of multiple sclerosis, optic neuromyelitis, and some leukodystrophies. Recent studies have highlighted that MOLs are heterogeneous; however, how MOL subpopulations are specified and balanced in physiological settings is poorly understood. Previous works have demonstrated an essential role of the small GTPases R-Ras1 and R-Ras2 in the survival and myelination of oligodendrocytes. In this study, we aimed to determine how R-Ras1 and R-Ras2 contribute to the heterogeneity of MOL subpopulations. Our results evidence that R-Ras1 and R-Ras2 affect specification into the distinct subpopulations MOL1, MOL2, and MOL5/6, which in turn vary in their dependence of these GTPases. In R-Ras1 and/or R-Ras2 mutant mice, we observed an increase in the MOL1 subpopulation and a decrease in the MOL2 and MOL5/6 subpopulations. We identified R-Ras1 and R-Ras2 as key elements in balancing the heterogeneity of MOLs. Our results contribute to the understanding of the molecular mechanisms underlying the heterogeneity of MOLs and the myelination processes, which is crucial for innovating regenerative therapies for nervous system disorders.

Endothelial cell glycolysis plays a novel and significant role in Schwann cells and peripheral nerve injury repair, which represents an emerging and important area of research. Glycolysis in endothelial cells is a conserved and tightly regulated biological process that provides essential energy (ATP) and intermediates by ultimately converting glucose into lactate. This metabolic pathway is crucial for maintaining the normal function of endothelial cells. During peripheral nerve injury repair, endothelial cell glycolysis influences the function of Schwann cells and the efficiency of nerve regeneration. Beyond glycolysis, endothelial cells also secrete various factors, including growth factors and extracellular vesicles, which further modulate Schwann cell activity and contribute to the repair process. This review will summarize the role of endothelial cell glycolysis in Schwann cell function and peripheral nerve injury repair, aiming to provide new insights for the development of novel strategies for peripheral nerve injury treatment.

Epilepsy is a chronic neurological disorder marked by recurrent seizures, significantly impacting individuals worldwide. Current treatments are often ineffective for a third of patients and can cause severe side effects, necessitating new therapeutic approaches. Glial cells, particularly astrocytes, microglia, and oligodendrocytes, are emerging as crucial targets in epilepsy management. Astrocytes regulate neuronal homeostasis, excitability, and synaptic plasticity, playing key roles in maintaining the blood-brain barrier (BBB) and mediating neuroinflammatory responses. Dysregulated astrocyte functions, such as reactive astrogliosis, can lead to abnormal neuronal activity and seizure generation. They release gliotransmitters, cytokines, and chemokines that may exacerbate or mitigate seizures. Microglia, the innate immune cells of the CNS, contribute to neuroinflammation, glutamate excitotoxicity, and the balance between excitatory and inhibitory neurotransmission, underscoring their dual role in seizure promotion and protection. Meanwhile, oligodendrocytes, primarily involved in myelination, also modulate axonal excitability and contribute to the neuron-glia network underlying seizure pathogenesis. Understanding the dynamic interactions of glial cells with neurons provides promising avenues for novel epilepsy therapies. Targeting these cells may lead to improved seizure control and better clinical outcomes, offering hope for patients with refractory epilepsy.

Neuroglial cells serve as the master regulators of the central nervous system, making it imperative for glial development to be tightly regulated both spatially and temporally to ensure optimal brain function. In this chapter, we will discuss the origin and development of the three major glia cells such as astrocytes, oligodendrocytes, and microglia in the central nervous system. While much of our understanding of neuroglia development stems from studies using animal models, we will also explore recent insights into human glial development and potential differences from rodent models. Finally, the extensive crosstalk between glia cells will be highlighted, discussing how interactions among astrocyte, oligodendrocyte, and microglial influence their respective developmental pathways.

Mature myelinating oligodendrocytes, the cells that produce the myelin sheath that insulates axons in the central nervous system, have distinct energetic and metabolic requirements compared to neurons. Neurons require substantial energy to execute action potentials, while the energy needs of oligodendrocytes are directed toward building the lipid-rich components of myelin and supporting neuronal metabolism by transferring glycolytic products to axons as additional fuel. The utilization of energy metabolites in the brain parenchyma is tightly regulated to meet the needs of different cell types. Disruption of the supply of metabolites can lead to stress and oligodendrocyte injury, contributing to various neurological disorders, including some demyelinating diseases. Understanding the physiological properties, structures, and mechanisms involved in oligodendrocyte energy metabolism, as well as the relationship between oligodendrocytes and neighboring cells, is crucial to investigate the underlying pathophysiology caused by metabolic impairment in these disorders. In this review, we describe the particular physiological properties of oligodendrocyte energy metabolism and the response of oligodendrocytes to metabolic stress. We delineate the relationship between oligodendrocytes and other cells in the context of the neurovascular unit, and the regulation of metabolite supply according to energetic needs. We focus on the specific bioenergetic requirements of oligodendrocytes and address the disruption of metabolic energy in demyelinating diseases. We encourage further studies to increase understanding of the significance of metabolic stress on oligodendrocyte injury, to support the development of novel therapeutic approaches for the treatment of demyelinating diseases.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cognitive dysfunction, memory decline, and behavioral disturbance, and it is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Although various hypotheses have been proposed to explain the pathogenesis of AD, including the amyloid beta hypothesis, oxidative stress hypothesis, and abnormal phosphorylation of tau proteins, the exact pathogenic mechanisms underlying AD remain largely undefined. Furthermore, effective curative treatments are very limited. Epidemiologic studies provide convincing evidence for a significant association between type 2 diabetes and AD. Here, we showed energy metabolism using glucose, lactate, ketone bodies, and lipids as energy substrates in a normal brain, and changes in such energy metabolism due to type 2 diabetes. We also showed the influences of such altered energy metabolism due to type 2 diabetes on the pathology of AD. Furthermore, we comprehensively searched for risk factors related with type 2 diabetes for AD and showed possible therapeutic interventions based on considering risk factors and altered brain energy metabolism due to type 2 diabetes for the development of AD.

To explore the therapeutic role of arginine vasopressin (AVP) and its possible mechanisms in autism.

Mid-trimester pregnant rats treated with valproate on embryonic day 12.5 and their offspring were selected as autism model. The autism rats were randomly assigned to autism group and AVP treatment group that given AVP by inhalation per day from postnatal days 21 to 42. The changes in social behavior and the hippocampus transcriptome were compared, and the hub genes were confirmed by quantitative real-time polymerase chain reaction (qPCR) and Mendelian randomization (MR).

403 genes were found to be differentially expressed in the autism model, with the majority of these genes being involved in oligodendrocyte development and myelination. Only 11 genes associated with myelination exhibited statistically significant alterations following AVP treatment when compared to the autism group. Gene set enrichment, expression patterns, and weighted gene co-expression network analysis (WGCNA) analysis consistently indicated that the biological processes of oligodendrocyte development and myelination were markedly enriched in the autism group and exhibited improvement following treatment. The variation trend of various nerve cells demonstrated a notable increase in the proportion of oligodendrocytes and oligodendrocyte precursor cells in the autism group, which subsequently exhibited a significant decline following treatment. Five hub genes (MBP, PLIP, CNP, GFAP, and TAOK1) were verified by qPCR. Finally, MR studies have confirmed a causal relationship between hippocampal myelination-related gene expression and the risk of autism.

AVP could markedly enhance social interaction abilities in the autism rat model, possibly due to the significantly improved hippocampus oligodendrocytes development and myelination.

Autism spectrum disorder (ASD) is characterized by social and neurocognitive impairments, with mutations of the SHANK3 gene being prominent in patients with monogenic ASD. Using the InsG3680 mouse model with a Shank3 mutation seen in humans, we revealed an unknown role for Shank3 in postsynaptic oligodendrocyte (OL) features, similar to its role in neurons. This was shown by impaired molecular and physiological glutamatergic traits of InsG3680-derived primary OL cultures. In vivo, InsG3680 mice exhibit significant reductions in the expression of key myelination-related transcripts and proteins, along with deficits in myelin ultrastructure, white matter, axonal conductivity, and motor skills. Last, we observed significant impairments, with clinical relevance, in induced pluripotent stem cell-derived OLs from a patient with the InsG3680 mutation. Together, our study provides insight into Shank3's role in OLs and reveals a mechanism of the crucial connection of myelination to ASD pathology.

The myelination of axons has evolved to enable fast and efficient transduction of electrical signals in the vertebrate nervous system. Acting as an electric insulator, the myelin sheath is a multilamellar membrane structure around axonal segments generated by the spiral wrapping and subsequent compaction of oligodendroglial plasma membranes. These oligodendrocytes are metabolically active and remain functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of metabolites and macromolecules to and from the internodal periaxonal space under the myelin sheath. Increasing evidence indicates that oligodendrocyte numbers, specifically in the forebrain, and myelin as a dynamic cellular compartment can both respond to physiological demands, collectively referred to as adaptive myelination. This review summarizes our current understanding of how myelin is generated, how its function is dynamically regulated, and how oligodendrocytes support the long-term integrity of myelinated axons.

Cytokines including tumor necrosis factor, interleukins, interferons, and chemokines are abundantly produced in various diseases. As pleiotropic factors, cytokines are involved in nearly every aspect of cellular functions such as migration, survival, proliferation, and differentiation. Oligodendrocytes are the myelin-forming cells in the central nervous system and play critical roles in the conduction of action potentials, supply of metabolic components for axons, and other functions. Emerging evidence suggests that both oligodendrocytes and oligodendrocyte precursor cells are vulnerable to cytokines released under pathological conditions. This review mainly summarizes the effects of cytokines on oligodendrocyte lineage cells in central nervous system diseases. A comprehensive understanding of the effects of cytokines on oligodendrocyte lineage cells contributes to our understanding of central nervous system diseases and offers insights into treatment strategies.

The brain's high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformations, with mitochondria playing a central role in ATP production via oxidative phosphorylation. Dysregulation of this metabolic interplay is implicated in Alzheimer's disease (AD), where compromised glucose metabolism, oxidative stress, and mitochondrial dysfunction contribute to disease progression. This review explores the intricate bioenergetic crosstalk between astrocytes and neurons, highlighting the function of mitochondrial uncoupling proteins (UCPs), particularly UCP4, as important regulators of brain metabolism and neuronal function. Predominantly expressed in the brain, UCP4 reduces the membrane potential in the inner mitochondrial membrane, thereby potentially decreasing the generation of reactive oxygen species. Furthermore, UCP4 mitigates mitochondrial calcium overload and sustains cellular ATP levels through a metabolic shift from mitochondrial respiration to glycolysis. Interestingly, the levels of the neuronal UCPs, UCP2, 4 and 5 are significantly reduced in AD brain tissue and a specific UCP4 variant has been associated to an increased risk of developing AD. Few studies modulating the expression of UCP4 in astrocytes or neurons have highlighted protective effects against neurodegeneration and aging, suggesting that pharmacological strategies aimed at activating UCPs, such as protonophoric uncouplers, hold promise for therapeutic interventions in AD and other neurodegenerative diseases. Despite significant advances, our understanding of UCPs in brain metabolism remains in its early stages, emphasizing the need for further research to unravel their biological functions in the brain and their therapeutic potential.

Multiple sclerosis (MS) is an autoimmune disease, governed by oligodendrocyte (OL) dystrophy and central nervous system (CNS) demyelination manifesting variable neurological impairments. Mitochondrial mechanisms may drive myelin biogenesis maintaining the axo-glial unit according to dynamic requisite demands imposed by the axons they ensheath. The promotion of OL maturation and myelination by actively transporting thyroid hormone (TH) into the CNS and thereby facilitating key transcriptional and metabolic pathways that regulate myelin biogenesis is fundamental to sustain the profound energy demands at each axo-glial interface. Deficits in regulatory functions exerted through TH for these physiological roles to be orchestrated by mature OLs, can occur in genetic and acquired myelin disorders, whereby mitochondrial efficiency and eventual dysfunction can lead to profound oligodendrocytopathy, demyelination and neurodegenerative sequelae. TH-dependent transcriptional and metabolic pathways can be dysregulated during acute and chronic MS lesion activity depriving OLs from critical acetyl-CoA biochemical mechanisms governing myelin lipid biosynthesis and at the same time altering the generation of iron metabolism that may drive ferroptotic mechanisms, leading to advancing neurodegeneration.

We established a longitudinal acute slice preparation of transgenic mouse optic nerve to characterize membrane properties and coupling of glial cells by patch-clamp and dye-filling, complemented by immunohistochemistry. Unlike in cortex or hippocampus, the majority of EGFP + cells in optic nerve of the hGFAP-EGFP transgenic mouse, a tool to identify astrocytes, were characterized by time and voltage dependent K+-currents including A-type K+-currents, properties previously described for NG2 glia. Indeed, the majority of transgene expressing cells in optic nerve were immunopositive for NG2 proteoglycan, whereas only a minority show GFAP immunoreactivity. Similar physiological properties were seen in YFP + cells from NG2-YFP transgenic mice, indicating that in optic nerve the transgene of hGFAP-EGFP animals is expressed by NG2 glia instead of astrocytes. Using Cx43kiECFP transgenic mice as another astrocyte-indicator revealed that astrocytes had passive membrane currents. Dye-filling showed that hGFAP-EGFP+ cells in optic nerve were coupled to none or few neighboring cells while hGFAP-EGFP+ cells in the cortex form large networks. Similarly, dye-filling of NG2-YFP+ and Cx43-CFP+ cells in optic nerve revealed small networks. Our work shows that identification of astrocytes in optic nerve requires distinct approaches, that the cells express membrane current patterns distinct from cortex and that they form small networks.

In people with multiple sclerosis (MS), newborn and surviving oligodendrocytes (OLs) can contribute to remyelination, however, current therapies are unable to enhance or sustain endogenous repair. Low intensity repetitive transcranial magnetic stimulation (LI-rTMS), delivered as an intermittent theta burst stimulation (iTBS), increases the survival and maturation of newborn OLs in the healthy adult mouse cortex, but it is unclear whether LI-rTMS can promote remyelination. To examine this possibility, we fluorescently labelled oligodendrocyte progenitor cells (OPCs; Pdgfrα-CreER transgenic mice) or mature OLs (Plp-CreER transgenic mice) in the adult mouse brain and traced the fate of each cell population over time. Daily sessions of iTBS (600 pulses; 120 mT), delivered during cuprizone (CPZ) feeding, did not alter new or pre-existing OL survival but increased the number of myelin internodes elaborated by new OLs in the primary motor cortex (M1). This resulted in each new M1 OL producing ~ 471 µm more myelin. When LI-rTMS was delivered after CPZ withdrawal (during remyelination), it significantly increased the length of the internodes elaborated by new M1 and callosal OLs, increased the number of surviving OLs that supported internodes in the corpus callosum (CC), and increased the proportion of axons that were myelinated. The ability of LI-rTMS to modify cortical neuronal activity and the behaviour of new and surviving OLs, suggests that it may be a suitable adjunct intervention to enhance remyelination in people with MS.

Glioblastoma cell lines derived from different patients are widely used in tumor biology research and drug screening. A key feature of glioblastoma is the high level of inter- and intratumor heterogeneity that accounts for treatment resistance. Our aim was to investigate whether intratumor heterogeneity is maintained in cell models. Single-cell RNA sequencing was used to investigate the cellular composition of a tumor sample and six patient-derived glioblastoma cell lines. Three cell lines preserved the mutational profile of the original tumor, whereas three others differed from their precursors. Copy-number variation analysis showed significantly rearranged genomes in all the cell lines and in the tumor sample. The tumor had the most complex cell composition, including cancer cells and microenvironmental cells. Cell lines with a conserved genome had less diverse cellularity, and during cultivation, a relative increase in the stem-cell-derived progenitors was noticed. Cell lines with genomes different from those of the primary tumors mainly contained neural progenitor cells and microenvironmental cells. The establishment of cell lines without the driver mutations that are intrinsic to the original tumors may be related to the selection of clones or cell populations during cultivation. Thus, patient-derived glioblastoma cell lines differ substantially in their cellular profile, which should be taken into account in translational studies.

Since the beautiful images of Santiago Ramón y Cajal provided a first glimpse into the immense diversity and complexity of cell types found in the cerebral cortex, neuroscience has been challenged and inspired to understand how these diverse cells are generated and how they interact with each other to orchestrate the development of this remarkable tissue. Some fundamental questions drive the field's quest to understand cortical development: what are the mechanistic principles that govern the emergence of neuronal diversity? How do extrinsic and intrinsic signals integrate with physical forces and activity to shape cell identity? How do the diverse populations of neurons and glia influence each other during development to guarantee proper integration and function? The advent of powerful new technologies to profile and perturb cortical development at unprecedented resolution and across a variety of modalities has offered a new opportunity to integrate past knowledge with brand new data. Here, we review some of this progress using cortical excitatory projection neurons as a system to draw out general principles of cell diversification and the role of cell-cell interactions during cortical development.

The corpus callosum-the largest commissural fiber system connecting the two cerebral hemispheres-is considered essential for bilateral sensory integration and higher cognitive functions. Most studies exploring the corpus callosum have examined either the anatomical, physiological, and neurochemical organization of callosal projections or the functional and/or behavioral aspects of the callosal connections after complete/partial callosotomy or callosal lesion. There are no works that address the intrinsic organization of the corpus callosum. We review the existing information on the activities that take place in the commissure in three sections: I) the topographical and neurochemical organization of the intracallosal fibers, II) the role of glia in the corpus callosum, and III) the role of the intracallosal neurons.

Environmental deprivation can have deleterious effects on adaptive myelination and oligodendroglia function. Early stage Huntington disease (HD) is characterised by white-matter myelin abnormalities in both humans and animal models. However, whether deprived environments exacerbate myelin-related pathological features of HD is not clearly understood. Here, we investigated the impact of deprivation and social isolation on ultrastructural features of myelin in the corpus callosum of the YAC128 mouse model of HD and wildtype (WT) mice using transmission electron microscopy. HD pathology on its own leads to increased representation of altered myelin features, such as thinner sheaths and compromised morphology. Interestingly, deprivation mirrors these effects in WT mice but does not greatly exacerbate the already aberrant myelin in HD mice, indicating a disease-related floor effect in the latter animals. These novel findings indicate that environmental deprivation causes abnormalities in myelin ultrastructure in the otherwise healthy corpus callosum of wild-type mice but has distinct effects on HD mice, where compromised myelin integrity is manifest from early stages of the disease.

The central nervous system (CNS) exhibits remarkable adaptability throughout life, enabled by intricate interactions between neurons and glial cells, in particular, oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs). This adaptability is pivotal for learning and memory, with OLs and OPCs playing a crucial role in neural circuit development, synaptic modulation, and myelination dynamics. Myelination by OLs not only supports axonal conduction but also undergoes adaptive modifications in response to neuronal activity, which is vital for cognitive processing and memory functions. This review discusses how these cellular interactions and myelin dynamics are implicated in various neurocircuit diseases and disorders such as epilepsy, gliomas, and psychiatric conditions, focusing on how maladaptive changes contribute to disease pathology and influence clinical outcomes. It also covers the potential for new diagnostics and therapeutic approaches, including pharmacological strategies and emerging biomarkers in oligodendrocyte functions and myelination processes. The evidence supports a fundamental role for myelin plasticity and oligodendrocyte functionality in synchronizing neural activity and high-level cognitive functions, offering promising avenues for targeted interventions in CNS disorders.

In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of neuronal networks. The maintenance of myelin and the well-organized subtle process of myelin plasticity requires cooperation among myelin-forming cells, glial cells, and neural networks. The process of cooperation is fragile, and the balance is highly susceptible to disruption by microenvironment influences. Reactive microglia play a critical and complicated role in the demyelination and remyelination process. Recent studies have shown that the voltage-gated proton channel Hv1 is selectively expressed in microglia in CNS, which regulates intracellular pH and is involved in the production of reactive oxygen species, underlying multifaceted roles in maintaining microglia function. This paper begins by examining the molecular mechanisms of demyelination and emphasizes the crucial role of the microenvironment in demyelination. It focuses specifically on the role of Hv1 in myelin repair and its therapeutic potential in CNS demyelinating diseases.

Hexaconazole is a highly effective triazole fungicide that is frequently applied in various countries to elevate crop productivity. Given its long half-life and high water solubility, this fungicide is frequently detected in the environment, including water sources. Moreover, hexaconazole exerts hazardous effects on nontarget organisms. However, little is known about the toxic effects of hexaconazole on animal development. Thus, this study aimed to investigate the developmental toxicity of hexaconazole to zebrafish, a valuable animal model for toxicological studies, and elucidate the underlying mechanisms. Results showed that hexaconazole affected the viability and hatching rate of zebrafish at 96 h postfertilization. Hexaconazole-treated zebrafish showed phenotypic defects, such as reduced size of head and eyes and enlarged pericardiac edema. Moreover, hexaconazole induced apoptosis, DNA fragmentation, and inflammation in developing zebrafish. Various organ defects, including neurotoxicity, cardiovascular toxicity, and hepatotoxicity, were observed in transgenic zebrafish models olig2:dsRed, fli1:eGFP, and l-fabp:dsRed. Furthermore, hexaconazole treatment altered the Akt and MAPK signaling pathways, which possibly triggered the organ defects and other toxic mechanisms. This study demonstrated the developmental toxicity of hexaconazole to zebrafish and elucidated the underlying mechanisms.

Interest in myelin and its roles in almost all brain functions has been greatly increasing in recent years, leading to countless new studies on myelination, as a dominant process in the development of cognitive functions. Here, we explore the unique role myelin plays in the central nervous system and specifically discuss the results of altered myelination in neurodevelopmental disorders. We present parallel developmental trajectories involving myelination that correlate with the onset of cognitive impairment in neurodevelopmental disorders and discuss the key challenges in the treatment of these chronic disorders. Recent developments in drug repurposing and nano/micro particle-based therapies are reviewed as a possible pathway to circumvent some of the main hurdles associated with early intervention, including patient's adherence and compliance, side effects, relapse, and faster route to possible treatment of these disorders. The strategy of drug encapsulation overcomes drug solubility and metabolism, with the possibility of drug targeting to a specific compartment, reducing side effects upon systemic administration.

Objective. In recent studies, network control theory has been applied to clarify transitions between brain states, emphasizing the significance of assessing the controllability of brain networks in facilitating transitions from one state to another. Despite these advancements, the potential alterations in functional network controllability associated with Alzheimer's disease (AD), along with the underlying genetic mechanisms responsible for these alterations, remain unclear.Approach. We conducted a comparative analysis of functional network controllability measures between patients with AD (n= 64) and matched normal controls (NCs,n= 64). We investigated the association between altered controllability measures and cognitive function in AD. Additionally, we conducted correlation analyses in conjunction with the Allen Human Brain Atlas to identify genes whose expression was correlated with changes in functional network controllability in AD, followed by a set of analyses on the functional features of the identified genes.Main results. In comparison to NCs, patients with AD exhibited a reduction in average controllability, predominantly within the default mode network (DMN) (63% of parcellations), and an increase in average controllability within the limbic (LIM) network (33% of parcellations). Conversely, AD patients displayed a decrease in modal controllability within the LIM network (27% of parcellations) and an increase in modal controllability within the DMN (80% of parcellations). In AD patients, a significant positive correlation was found between the average controllability of the salience network and the mini-mental state examination scores. The changes in controllability measures exhibited spatial correlation with transcriptome profiles. The significant genes identified exhibited enrichment in neurobiologically relevant pathways and demonstrated preferential expression in various tissues, cell types, and developmental periods.Significance. Our findings have the potential to offer new insights into the genetic mechanisms underlying alterations in the controllability of functional networks in AD. Additionally, these results offered perspectives for a deeper understanding of the pathogenesis and the development of therapeutic strategies for AD.

The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs). To determine how OLs detect axonal spiking and how rapid axon-OL metabolic coupling is regulated in the white matter, we studied activity-dependent calcium (Ca2+) and metabolite fluxes in the mouse optic nerve. We show that fast axonal spiking triggers Ca2+ signaling and glycolysis in OLs. OLs detect axonal activity through increases in extracellular potassium (K+) concentrations and activation of Kir4.1 channels, thereby regulating metabolite supply to axons. Both pharmacological inhibition and OL-specific inactivation of Kir4.1 reduce the activity-induced axonal lactate surge. Mice lacking oligodendroglial Kir4.1 exhibit lower resting lactate levels and altered glucose metabolism in axons. These early deficits in axonal energy metabolism are associated with late-onset axonopathy. Our findings reveal that OLs detect fast axonal spiking through K+ signaling, making acute metabolic coupling possible and adjusting the axon-OL metabolic unit to promote axonal health.

Spinal cord injury (SCI) is a devastating disease that causes extensive damage to oligodendrocytes and neurons leading to demyelination and axonal degeneration. In this study, we co-transplanted cell grafts containing oligodendrocyte progenitor cells (OPCs) derived from human-induced pluripotent stem cells (iPSCs) combined with human umbilical vein endothelial cells (HUVECs), which were reported to promote OPCs survival and migration, into rat contusion models to promote functional recovery after SCI.

OPCs were derived from iPSCs and identified by immunofluorescence at different time points. Functional assays in vitro were performed to evaluate the effect of HUVECs on the proliferation, migration, and survival of OPCs by co-culture and migration assay, as well as on the neuronal axonal growth. A combination of OPCs and HUVECs was transplanted into the rat contusive model. Upon 8 weeks, immunofluorescence staining was performed to test the safety of transplanted cells and to observe the neuronal repairment, myelination, and neural circuit reconstruction at the injured area; also, the functional recovery was assessed by Basso, Beattie, and Bresnahan open-field scale, Ladder climb, SEP, and MEP. Furthermore, the effect of HUVECs on grafts was also determined in vivo.

Data showed that HUVECs promote the proliferation, migration, and survival of OPCs both in vitro and in vivo. Furthermore, 8 weeks upon engraftment, the rats with OPCs and HUVECs co-transplantation noticeably facilitated remyelination, enhanced functional connection between the grafts and the host and promoted functional recovery. In addition, compared with the OPCs-alone transplantation, the co-transplantation generated more sensory neurons at the lesion border and significantly improved the sensory functional recovery.

Our study demonstrates that transplantation of OPCs combined with HUVECs significantly enhances both motor and sensory functional recovery after SCI. No significance was observed between OPCs combined with HUVECs group and OPCs-alone group in motor function recovery, while the sensory function recovery was significantly promoted in OPCs combined with HUVECs groups compared with the other two groups. These findings provide novel insights into the field of SCI research.

Traumatic brain injury (TBI) and opioid use disorder (OUD) comprise twin plagues causing considerable morbidity and mortality worldwide. As interactions between TBI and OUD are to our knowledge uncharted, we review the possible mechanisms by which TBI may stimulate the development of OUD and discuss the interaction or crosstalk between these two processes. Central nervous system damage due to TBI appears to drive adverse effects of subsequent OUD and opioid use/misuse affecting several molecular pathways. Pain, a neurological consequence of TBI, is a risk factor that increases the likelihood of opioid use/misuse after TBI. Other comorbidities including depression, anxiety, posttraumatic stress disorder, and sleep disturbances are also associated with deleterious outcomes. We examine the hypothesis that a TBI "first hit" induces a neuroinflammatory process involving microglial priming, which, on a second hit related to opioid exposure, exacerbates neuroinflammation, modifies synaptic plasticity, and spreads tau aggregates to promote neurodegeneration. As TBI also impairs myelin repair by oligodendrocytes, it may reduce or degrade white matter integrity in the reward circuit resulting in behavioral changes. Along with approaches focused on specific patient symptoms, understanding the CNS effects following TBI offers a promise of improved management for individuals with OUD.

Experience sculpts brain structure and function. Activity-dependent modulation of the myelinated infrastructure of the nervous system has emerged as a dimension of adaptive change during childhood development and in adulthood. Myelination is a richly dynamic process, with neuronal activity regulating oligodendrocyte precursor cell proliferation, oligodendrogenesis and myelin structural changes in some axonal subtypes and in some regions of the nervous system. This myelin plasticity and consequent changes to conduction velocity and circuit dynamics can powerfully influence neurological functions, including learning and memory. Conversely, disruption of the mechanisms mediating adaptive myelination can contribute to cognitive impairment. The robust effects of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, indicates that dysregulated or 'hijacked' mechanisms of myelin plasticity could similarly promote growth in this devastating group of brain cancers. Indeed, neuronal activity promotes the pathogenesis of many forms of glioma in preclinical models through activity-regulated paracrine factors and direct neuron-to-glioma synapses. This synaptic integration of glioma into neural circuits is central to tumour growth and invasion. Thus, not only do neuron-oligodendroglial interactions modulate neural circuit structure and function in the healthy brain, but neuron-glioma interactions also have important roles in the pathogenesis of glial malignancies.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is one of the most common diseases of the male urological system while the etiology and treatment of CP/CPPS remain a thorny issue. Cumulative research suggested a potentially important role of glial cells in CP/CPPS. This narrative review retrospected literature and grasped the research process about glial cells and CP/CPPS. Three types of glial cells showed a crucial connection with general pain and psychosocial symptoms. Microglia might also be involved in lower urinary tract symptoms. Only microglia and astrocytes have been studied in the animal model of CP/CPPS. Activated microglia and reactive astrocytes were found to be involved in both pain and psychosocial symptoms of CP/CPPS. The possible mechanism might be to mediate the production of some inflammatory mediators and their interaction with neurons. Glial cells provide a new insight to understand the cause of complex symptoms of CP/CPPS and might become a novel target to develop new treatment options. However, the activation and action mechanism of glial cells in CP/CPPS needs to be further explored.

Methamphetamine (METH) addiction causes a huge burden on society. The prefrontal cortex (PFC), associated with emotion and cognitive behaviours, is also involved in addiction neurocircuitry. Although bulk RNA sequencing has shown METH-induced gene alterations in the mouse PFC, the impact on different cell types remains unknown.

To clarify the effects of METH treatment on different cell types of the PFC and the potential pathways involved in METH-related disorders.

We performed single-nucleus RNA sequencing (snRNA-seq) to examine the transcriptomes of 20 465 nuclei isolated from the PFC of chronic METH-treated and control mice. Main cell types and differentially expressed genes (DEGs) were identified and confirmed by RNA fluorescence in situ hybridization(FISH).

Six main cell types were identified depending on the single-cell nucleus sequencing; of particular interest were the mature oligodendrocytes in the PFC. The DEGs of mature oligodendrocytes were enriched in the myelin sheath, adenosine triphosphate (ATP) metabolic process, mitochondrial function and components, and so on. The messenger RNA levels of Aldoc and Atp5l (FISH) and the protein level of the mitochondrial membrane pore subunit TOM40 (immunofluorescence) decreased in the mature oligodendrocytes. Fast blue staining and transmission electron microscopy image indicated myelin damage, and the myelin thickness decreased in METH brains.

snRNA-seq reveals altered transcriptomes of different cell types in mouse PFC induced by chronic METH treatment, underscoring potential relationships with psychiatric disorders.

Previous work has shown that motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursor cells (OLPs) in the brains of adult mice. In the present study we ask whether OL production is also required for non-motor learning and cognition, using T-maze and radial-arm-maze tasks that tax spatial working memory. We find that maze training stimulates OLP proliferation and OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation of adult male mice; myelin sheath formation is also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impairs training-induced improvements in maze performance. We find a strong positive correlation between the performance of individual wild type mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos+ neurons in their mPFC, underscoring the important role played by OL lineage cells in cognitive processing.