Frontiers in Molecular Neuroscience最新文献

Chronic pain and depression often co-occur, exhibiting a complex, bidirectional relationship that significantly exacerbates the clinical burden and complicates treatment strategies. Recent studies have identified neurochemical mechanisms as the fundamental biological basis for this interaction. Specifically, the imbalance between excitatory glutamate and inhibitory γ-aminobutyric acid (GABA), dysfunction of the endogenous opioid system, and dysregulation of various neuropeptides and non-classical neurotransmitters collectively constitute the neurobiological foundation of disturbances in pain perception and emotional regulation. Glutamate-mediated synaptic excitation and the reduction of GABA's inhibitory function contribute to central sensitization and the abnormal processing of negative emotions. The endogenous opioid system plays a critical role in alleviating pain and emotional disturbances by regulating descending pain control pathways and the limbic system, with receptor dysfunction and expression imbalance being key mechanisms in the comorbidity. Additionally, neuropeptides such as substance P, corticotropin-releasing factor (CRF), and oxytocin participate in stress responses, reward modulation, and emotional control, thereby exacerbating the pathological connection between chronic pain and depression. This review collects the most recent findings on neurochemical interactions in the comorbidity of chronic pain and depression. The goal of this summary is to further our understanding of the molecular mechanisms in this comorbidity, as well as provide theoretical support for intervening in the neurotransmitter system in a targeted way.

[This corrects the article DOI: 10.3389/fnmol.2025.1603619.].

[This corrects the article DOI: 10.3389/fnmol.2022.848185.].

Epilepsy, a prevalent neurological disorder affecting millions globally, manifests as recurrent synchronous neuronal discharges that disrupt normal cerebral function. Emerging evidence characterizes this condition as a network-level hyperexcitability disorder driven by aberrant neuroelectrical synchronization. At the molecular level, intracellular calcium (Ca²⁺) overload is increasingly recognized as a key contributor to seizure initiation and propagation. The regulation of neuronal Ca²⁺ homeostasis involves multiple Ca²⁺ - permeable cation channels, with transient receptor potential (TRP) channels emerging as critical mediators of pathological ion flux. These non-selective transmembrane conduits facilitate Ca²⁺ permeation and contribute to epileptogenic ionic dysregulation through subtype-specific mechanisms. Current research efforts focus on elucidating TRP channel pathophysiology across epilepsy subtypes while identifying potent pharmacological modulators. This systematic investigation of TRP channel biology and targeted therapeutic development promises to revolutionize antiepileptic drug discovery by addressing current treatment limitations in seizure prevention and disease modification. The present review synthesizes recent advances in TRP channel research and evaluates emerging strategies for therapeutic targeting in epilepsy management.

Postoperative cognitive dysfunction (POCD), which often affects elderly patients after anesthesia and surgery, is characterized by memory loss, trouble concentrating, and difficulties with thinking and decision-making. Propofol is a commonly used intravenous anesthetic. Its effects on the brain are complex, and researchers have been paying closer attention to them. While it can protect nerve cells in some situations, it may also cause damage. Emerging evidence suggests that mechanosensitive Piezo ion channels may serve as critical mediators. These channels allow cells to detect mechanical forces and turn them into biological signals. They may act as a link between propofol use and cognitive decline. This review highlights new findings on how propofol may affect Piezo channel function. It shows that propofol changes the physical properties of cell membranes. It makes the membranes stiffer and less fluid. These changes may change how Piezo channels react to mechanical forces. They can disturb calcium signals and synaptic function in the brain. This problem can increase inflammation and damage to mitochondria. It can weaken synaptic connections and cause cognitive decline, especially in older adults. Additionally, calcium entering through Piezo1 channels has been linked to inflammation, which may be another mechanism by which propofol and Piezo channels together cause POCD. However, clear proof of how propofol interacts with Piezo channels is still lacking. More research with molecular simulations, genetic models, and calcium imaging is needed to better understand these processes.

Introduction: Intervertebral disc degeneration (IVDD) and non-alcoholic fatty liver disease (NAFLD) represent major global health burdens. Although recent evidence points to a potential association between these two conditions, the underlying molecular mechanisms remain poorly understood. This study aims to elucidate their shared molecular landscape using integrated bioinformatics approaches.

Methods: Three IVDD and two NAFLD datasets were acquired from the Gene Expression Omnibus (GEO). We performed differential expression analysis (DEGs), weighted gene co-expression network analysis (WGCNA), and machine learning to identify shared hub genes. The diagnostic relevance of these genes was further assessed using ROC curves and nomograms. Single-cell sequencing analysis was employed to examine gene expression patterns across cell clusters in intervertebral disk and liver tissues. In vivo experiments were conducted to evaluate the influence of NAFLD on IVDD progression and the therapeutic potential of exercise intervention.

Results: Six shared genes were identified between IVDD and NAFLD. Among these, ME1, HAS2, and ADRB2 were highlighted as potential biomarkers. Validation confirmed consistent expression patterns and strong predictive performance for both diseases. KEGG pathway and immune infiltration analyses indicated significant involvement of these biomarkers in disease-related pathways and immune cell interactions. Single-cell sequencing revealed distinct expression profiles and functional roles of ME1, HAS2, and ADRB2 across relevant cell types. In vivo studies demonstrated that NAFLD exacerbates IVDD progression, and intervention through swimming exercise ameliorated NAFLD and exerted protective effects on IVDD under high-fat diet conditions.

Discussion: This study identifies ME1, HAS2, and ADRB2 as pivotal shared biomarkers for IVDD and NAFLD, providing new insights into their molecular interconnection. The findings enhance our understanding of the comorbid mechanisms and highlight the potential of exercise as a therapeutic strategy for both conditions. These results pave the way for further mechanistic and clinical research into common pathways and integrated treatment approaches.

Introduction: Central neuroinflammation is pivotal in neuropathic pain pathogenesis, with blood-spinal cord barrier (BSCB) dysfunction recognized as a trigger for neuroinflammation and pain, though molecular mechanisms remain poorly understood.

Methods: Through comparative clinical studies measuring serum endoglin in postherpetic neuralgia (PHN) patients versus healthy controls, and animal investigations using spared nerve injury (SNI) rat models with recombinant endoglin intervention, we assessed mechanical/thermal hyperalgesia, microglial activation, inflammatory cytokines, BSCB permeability, and TGF-βRI/Smad2/NR2B phosphorylation.

Results: PHN patients exhibited lower serum endoglin versus controls; SNI rats showed reduced spinal endoglin compared to sham controls. Recombinant endoglin alleviated hyperalgesia while reversing microglial activation, inflammation, BSCB impairment, and NR2B phosphorylation. SNI decreased spinal TGF-βRI expression and Smad2 phosphorylation.

Discussion: These findings demonstrate that endoglin reduction disrupts BSCB integrity via TGF-β/Smad2 pathway inhibition in endothelial cells, driving microglial activation, neuroinflammation, and NR2B phosphorylation, thereby elucidating a key pain mechanism and identifying endoglin as a therapeutic target.

Chronic exposure to elevated levels of manganese (Mn) causes a neurological disorder referred to as manganism, resembling pathological symptoms of Parkinson's disease (PD). The repressor element-1 silencing transcription factor (REST) induces neuroprotection in several neurological disorders, including PD and Mn toxicity. Tamoxifen (TX), a selective estrogen receptor modulator, has been shown to afford neuroprotective effects in various experimental models and increase REST expression via the non-genomic estrogen receptor (ER)/Wnt signaling in Cath. a-differentiated (CAD) neuronal cultures. The present study investigated whether TX enhances REST transcription through the genomic estrogen receptor (ER) pathway in CAD cells, using a combination of Western blotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), promoter activity assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and site-directed mutagenesis. The findings showed that the REST promoter sequences contained half-site estrogen response elements (ERE) motifs. The ER-α pathway primarily upregulated REST, as the ER-α selective agonist propylpyrazole triol (PPT) (1 μM) predominantly increased REST transcription and attenuated Mn (250 μM)-induced REST reduction in CAD cells. TX induced REST upregulation by activation of the genomic ER-α pathway, as it increased nuclear ER-α's interaction with cyclic adenosine monophosphate (AMP) response element (CREB)-binding protein and Sp1 and promoted ER-α binding to the half-site ERE in the REST promoter. Moreover, the ERE mutation in the REST promoter reduced TX-induced REST promoter activity, and TX reversed Mn-induced REST transcriptional repression. Our novel findings suggest that the genomic ER-α pathway plays a critical role in TX-induced REST upregulation and mitigation of Mn-induced decreases in REST expression.

Major depressive disorder (MDD) is one of the most prevalent mental disorders, posing a significant socioeconomic burden worldwide. Its development involves both genetic and environmental factors, among which chronic stress is considered a major contributor. The amygdala, a key brain region for emotional regulation, is critically implicated in MDD pathophysiology. Given its complex subnuclear architecture, it is essential to characterize stress-induced molecular changes at the level of individual subnuclei. To investigate subnucleus-specific molecular adaptations to chronic stress, we performed RNA sequencing on fluorescence-guided micropunch samples from five amygdala-related subnuclei in mice exposed to chronic corticosterone (CORT): the basolateral amygdala (BLA), the lateral and medial central amygdala (CeL, CeM), and the oval and fusiform bed nuclei of the stria terminalis (BNSTov, BNSTfu). Comparative transcriptomic analysis revealed highly divergent and subnucleus-resolved gene expression responses to chronic CORT exposure. Each subregion exhibited unique profiles of differentially expressed genes, implicating alterations in excitatory-inhibitory synaptic balance, glial functions involving oligodendrocytes or astrocytes, and neuropeptide signaling. Our results uncover the molecular heterogeneity of subnucleus-specific responses within the amygdala. These findings highlight the importance of anatomically resolved analyses in elucidating the biological basis of stress-related mental disorders such as MDD, thereby paving the way for more targeted therapeutic strategies.