Frontiers in Molecular Neuroscience最新文献

Introduction: Spinal cord injury (SCI) frequently leads to severe motor impairments and psychological issues, particularly depression, which negatively affects overall quality of life. This study seeks to clarify the relationship between SCI and depression by employing a comprehensive approach that includes behavioral assessments, transcriptomic profiling, and molecular analyses.

Methods: We established a weight-drop model of SCI and randomly assigned mice to Sham and SCI groups. Behavioral assessments included the Open Field Test (OP), Sucrose Preference Test (SP), and Tail Suspension Test (TS). We conducted transcriptomic analyses using datasets related to SCI and major depressive disorder (MDD) sourced from the GEO database. The hub gene, Nfkbia, was identified with Cytoscape software and validated through RT-PCR. Western blotting was utilized to measure the protein levels of IκB-α (encoded by Nfkbia) and phosphorylated p65 (p-p65). Additionally, we examined hippocampal histopathology and measured pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α).

Results: Following SCI, mice displayed abnormal behaviors in the OP, SP, and TS, suggesting the development of depression-like symptoms. In light of these observations, we analyzed publicly available transcriptomic datasets related to SCI and depression, identifying 16 common differentially expressed genes. Functional enrichment analysis showed that these genes were primarily associated with biological processes linked to inflammatory responses. We constructed a protein-protein interaction network that highlighted four potential key genes (Nfkbia, Fkbp5, Sgk1, and Cdkn1a). Subsequent molecular biology experiments confirmed that Nfkbia was downregulated after SCI, resulting in an increase in inflammatory factor production and the emergence of depression-like behaviors in mice.

Discussion: Our results suggest that neuroinflammation plays a crucial role in the onset of depression after SCI. This is supported by the activation of the IκB/p65 signaling pathway and the dysregulation of inflammatory cytokines. These findings align with clinical observations of mood disorders in patients with SCI and reflect known patterns of inflammatory cytokine dysregulation. This study underscores the significance of anti-inflammatory treatments and comprehensive neuropsychiatric management strategies in the rehabilitation of SCI patients.

Introduction: Stress involves complex interactions between the brain and endocrine systems, but the gene-level processes and genetic factors mediating these responses remain unclear. This study investigates gene expression patterns and allele-specific expression (ASE) in key limbic, diencephalon and endocrine tissues to better understand stress adaptation at the molecular level.

Methods: We performed RNA sequencing on 48 samples from six distinct tissues: amygdala, hippocampus, thalamus, hypothalamus, pituitary gland, and adrenal gland. These tissues were categorized into three functionally and anatomically distinct groups: limbic (amygdala, hippocampus), diencephalon (thalamus, hypothalamus), and endocrine (pituitary, adrenal). Differential expression analyses were conducted both between individual tissues and across these tissue groups. Weighted Gene Co-expression Network Analysis (WGCNA) was applied exclusively at the tissue group level to identify group-specific gene networks. Allele-specific expression (ASE) was analyzed at the individual tissue level to capture cis-regulatory variation with high resolution.

Results: Thirty-three candidate genes were differentially expressed across all tissues, indicating a core set involved in stress responses. Weighted Gene Co-expression Network Analysis revealed limbic and diencephalon modules enriched in neural signaling pathways such as neuroactive ligand-receptor interaction and synaptic functions, while endocrine modules were enriched for hormone biosynthesis and secretion, including thyroid and growth hormone pathways. Over 1,000 genes per tissue showed ASE, with 37 genes consistently colocalized. Ten of these displayed differences in allelic ratios, with seven (PINK1, TTLL1, SLA-DRB1, HEBP1, ANKRD10, LCMT1, and SDF2) identified as eQTLs in pig brain tissue within the FarmGTEx database.

Conclusion: The findings reveal significant genetic regulation differences between brain and endocrine tissues, emphasizing the complexity of stress adaptation. By identifying key genes and pathways, this study provides insights that could aid in enhancing animal welfare and productivity through targeted modulation of stress-related molecular pathways.

Clinical features of the fragile X syndrome (FXS) phenotype include intellectual disability, repetitive behaviors, social communication deficits, and, commonly, auditory hypersensitivity to acoustic stimuli. Electrophysiological studies have shown that FXS patients and Fmr1KO mice exhibit improper processing of auditory information in the cortical areas of the brain and the spiral ganglion of the cochlea. Synapses formed by spiral ganglion neurons on sensory hair cells (HC) are the first connection on the path that conveys the auditory information from the sensory cells to the brain. We confirmed the presence of fragile X mental retardation protein (FMRP) in the inner hair cells of the cochlea. Next, we analyzed the morphology of IHC ribbon synapses in early stages of postnatal development (P5, P14) and detected their delayed structural maturation in Fmr1 KO mice. Interestingly, the ultrastructure of inner hair cell ribbon synapses, studied by electron microscopy in adult mice (P48), has shown no specific dysmorphologies. Delayed structural maturation of presynaptic ribbons of auditory hair cells in Fmr1 KO mice may contribute to abnormal development of circuits induced by auditory experience.

Peroxisomes are membrane-bounded organelles that contribute to a range of physiological functions in eukaryotic cells. In the central nervous system (CNS), peroxisomes are implicated in several vital homeostatic functions including, but not limited to, reactive oxygen species signaling and homeostasis; generation of critical myelin sheath components (including ether phospholipids); biosynthesis of neuroprotective docosahexaenoic acid; breakdown of neurotoxic metabolites (such as very-long chain fatty acids); and, intriguingly, glial activation and response to inflammatory stimuli. Indeed, peroxisomes play a critical role in modulating inflammatory responses and are key regulators of the mitochondrial antiviral signaling (MAVS) protein-mediated response to infections. The importance of peroxisomes in CNS physiology is exemplified by the peroxisome biogenesis disorders (PBDs), a spectrum of inherited disorders of peroxisome assembly and/or abundance, that are characterized in part by neurological manifestations ranging from severe cerebral malformations to vision and hearing loss, depending on the individual disorder. Recently, peroxisome dysfunction has been implicated in neurological diseases associated with neuroinflammation including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease while also contributing to the pathogenesis of neurotropic viruses including SARS-CoV-2, Human Pegivirus, HIV-1 and Zika virus. In the present review, we examine the diverse roles that peroxisomes serve in CNS health before reviewing more recent studies investigating peroxisome dysfunction in inflammatory brain disorders and also highlight potential peroxisomal targets for diagnostic biomarkers and therapeutic interventions.

Gliomas are the most common type of malignant primary central nervous system (CNS) tumors, resulting in significant morbidity and mortality in children and adolescent and young adult (AYA) patients. The discovery of mutations in isocitrate dehydrogenase (IDH) genes has dramatically changed the classification and understanding of gliomas. IDH mutant gliomas have distinct clinical, pathological, and molecular features including a favorable prognosis and response to therapy compared to their wildtype counterparts. Although more common in adults, 5-15% of pediatric gliomas have IDH mutations. In this review, we provide a comprehensive summary of the current knowledge on IDH mutant high-grade gliomas (HGG), including their biology, clinical features, diagnosis, treatment, and prognosis. We also discuss future directions in research and clinical management with particular attention to the AYA cohort.

Introduction: Endothelial-to-mesenchymal transition (EndoMT), cell death, and fibrosis are increasingly recognized as contributing factors to Alzheimer's disease (AD) pathology, but the underlying transcriptomic mechanisms remain poorly defined. This study aims to elucidate transcriptomic changes associated with EndoMT, diverse cell death pathways, and fibrosis in AD using the 3xTg-AD mouse model.

Methods: Using RNA-seq data and knowledge-based transcriptomic analysis on brain tissues from the 3xTg-AD mouse model of AD. This included pathway-level analysis of gene expression changes across multiple brain cell types. Mechanistic insights were further validated using single-cell RNA sequencing (scRNA-Seq) dataset from human AD brain.

Results: Our analysis showed that in the 3xTg-AD model: (i) multiple brain cell type genes are altered, promoting EndoMT through upregulation of RGCC and VCAN; (ii) genes related to various types of cell death, including apoptosis, ferroptosis, necrosis, anoikis, mitochondrial outer membrane permeability programmed cell death, mitochondrial permeability transition-driven necrosis, NETotic, and mitotic cell death, are upregulated in the several brain cell types; (iii) fibrosis-related genes are upregulated across multiple brain cell types. Further mechanistic analysis revealed: (1) mitochondrial stress through upregulation of mitochondrial genes in the brain cells; (2) upregulation of cellular, oxidative, and endoplasmic reticulum (ER) stress genes; (3) nuclear stress via upregulation of nuclear genes, transcription factors (TFs), and differentiation TFs FOSB and MEOX1; (4) metabolic reprogramming/stress through the upregulation of genes related to lipid and lipoprotein metabolism, fatty acid oxidation (FAO), glucose metabolism, and oxidative phosphorylation (OXPHOS); (5) catabolic stress via upregulation of catabolic genes. Single-cell RNA-Seq data indicated that many of these were also increased in AD patients' brain cells. These changes were reversed by knockdown of the ER stress kinase PERK (EIF2AK3) and deficiencies in FOSB and MEOX1.

Discussion: This study uncovers previously unrecognized molecular signatures of organelle stress and bioenergetic reprogramming that drive EndoMT, cell death, and fibrosis in AD. The reversal of these changes via PERK, FOSB, and MEOX1 inhibition highlights potential therapeutic targets for mitigating neurodegenerative processes in AD.

[This corrects the article DOI: 10.3389/fnmol.2025.1625943.].

Introduction: The potassium chloride co-transporter 2 (KCC2) is the principal Cl^- extrusion mechanism employed by mature neurons in the central nervous system (CNS) and plays a critical role in determining the efficacy of fast synaptic inhibition mediated by type A γ-aminobutyric acid receptors (GABA_ARs) to protect against epileptogenesis. It has previously been demonstrated that epileptic seizures down-regulate KCC2 and induce neuronal apoptosis through the extrinsic apoptotic pathway. However, the mechanism by which neuronal death is induced by KCC2 loss remains unknown. We have previously demonstrated that C1q copurifies with KCC2 in comparable amounts. C1q is responsible for synaptic elimination in the brain during development, aging and neurodegeneration.

Methods: Here, we studied apoptotic induction in models of KCC2 loss of function and demonstrated the importance of C1q in this process using a constitutive C1qKO mouse model. We characterized the activation of different apoptotic pathways by measuring caspase 8 and caspase 9 cleavage as markers of extrinsic and intrinsic apoptosis, respectively.

Results: This study demonstrates in vitro, ex vivo and following seizures in vivo, that reduced KCC2 function coincides with neuronal death by activating the extrinsic apoptotic pathway, which is contingent upon complement C1q. Moreover, kainic acid (KA)- and glutamate-induced excitotoxicity also selectively activates the extrinsic apoptotic pathway which is contingent upon C1q.

Discussion: These results strongly support the hypothesis that the KCC2/C1q protein complex plays a critical role in the apoptotic process that occurs following loss of KCC2 function.