Neuroreport最新文献

Background: Altered homotopic functional connectivity in primary angle-closure glaucoma (PACG) and their underlying molecular mechanisms remain poorly understood. In our study, we investigated voxel-mirrored homotopic connectivity (VMHC) alterations in patients with PACG and the molecular mechanisms of VMHC.

Methods: In this study, we investigated alterations in VMHC among 47 patients with PACG and 45 matched healthy controls. We then integrated these spatial patterns with cortical transcriptomic data from the Allen Human Brain Atlas using partial least squares (PLS) regression to identify gene expression profiles associated with VMHC alterations.

Results: In this study, we identified widespread reductions in interhemispheric functional connectivity in patients with PACG using VMHC analysis. Multivariate spatial correlation with gene expression data revealed that VMHC alterations were significantly associated with a distinct transcriptional signature captured by the first PLS component. Functional enrichment of these genes indicated downregulation of pathways related to synaptic and metabolic maintenance, and upregulation of immune, stress, and chromatin regulatory processes. Cell-type analysis showed that astrocytes and endothelial cells were selectively enriched with VMHC-related genes, reflecting glial and vascular involvement. Moreover, spatial alignment with neurotransmitter receptor maps highlighted significant associations with serotonergic, dopaminergic, GABAergic, cholinergic, and opioidergic pathways, suggesting a neuromodulatory basis for VMHC disruption.

Conclusion: Together, these findings suggest that interhemispheric dysconnectivity in PACG is not only a reflection of functional brain changes but is also grounded in molecular and cellular mechanisms. This integrative approach advances our understanding of PACG as a brain-wide neurodegenerative condition and offers new perspectives for targeting glial, vascular, and neuromodulatory pathways in future therapeutic interventions.

Objective: Chronic psychological stress is a major cause of various psychiatric disorders, such as depression and anxiety; however, the pathophysiological features of these disorders remain largely unknown. Polysialic acid (PSA), a linear homopolymer of α2-8-linked sialic acid residues, binds to the neural cell adhesion molecule (NCAM) and is involved in cell-to-cell interactions during neural cell migration and neurite outgrowth. Decreased PSA and PSA-NCAM expression have been observed in the brains of patients with psychiatric disorders. Nevertheless, the relationship between psychological stress and PSA has not been clarified. Thus, we examined whether chronic social defeat stress (cSDS), a well-established psychosocial stress model in rodents, affects PSA levels in the male mouse brain.

Methods: Male C57BL/6J mice were exposed to social defeat stress for 10 consecutive days, after which their whole brains were collected. PSA and NCAM protein levels in the hippocampus and prefrontal cortex were analyzed by western blotting. In addition, we measured the expression of genes involved in PSA metabolism by real-time quantitative PCR analysis.

Results: Exposure to cSDS decreased PSA and NCAM protein levels in the hippocampus, but not in the prefrontal cortex. We also found that the expression of genes involved in removing sialic acid from NCAM, such as neuraminidase 3 and 4, was significantly elevated in the hippocampus of mice exposed to cSDS.

Conclusion: We provide evidence showing that psychosocial stress disrupts PSA metabolism in adult mice brains. These findings advance our understanding of the mechanisms underlying the onset of stress-related psychiatric disorders.

Objective: This study aimed to examine the potential of repetitive transcranial magnetic stimulation (rTMS) to alleviate myocardial injury in a rat model of vascular dementia (VaD) by restoring renin-angiotensin system (RAS) balance and inhibiting apoptosis.

Methods: The VaD was induced in rats using a modified two-vessel occlusion protocol. The effects of rTMS on cognitive function, myocardial injury, and RAS equilibrium were also evaluated. Cellular apoptosis was evaluated using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and the expression of RAS components was analyzed using western blotting.

Results: The application of rTMS in VaD rats resulted in decreased apoptosis of both cortical and myocardial cells, an increase in neuronal nuclei positive cell populations, and a reduction in TUNEL-positive cells, thereby demonstrating neuroprotective and cardioprotective effects. Furthermore, western blot analysis indicated that rTMS modulated RAS levels by downregulating the expression of components associated with the classical RAS axis while upregulating those related to the alternative axis.

Conclusion: rTMS may mitigate myocardial injury in VaD rat models by re-establishing the balance of RAS and suppressing apoptotic processes. This study offers valuable insights into the prospective therapeutic application of rTMS in managing cardiocerebral comorbidities linked to RAS dysregulation.

Objective: This study investigated miR-7b's regulatory role in the nucleus accumbens (NAc) and its interaction with gamma-aminobutyric acid A receptor alpha 4 (GABRA4) during cue-induced heroin-seeking reinstatement.

Methods: A heroin self-administration model (4 h/day) was established in rats. Cue-induced reinstatement was assessed postextinction. Dual-luciferase reporter assays validated miR-7b/GABRA4 binding. Gain- and loss-of-function approaches via adeno-associated virus (AAV)-mediated miR-7b overexpression (AAV-miR-7b-OE) and GABRA4 knockdown [AAV-small interfering RNA (siRNA)-GABRA4] were applied in the NAc.

Results: Reinstatement correlated with reduced miR-7b (P < 0.05) and elevated GABRA4 expression in the NAc. Luciferase assays confirmed miR-7b's direct regulation of the GABRA4 3'-untranslated region (3'-UTR) (P < 0.01). NAc-targeted AAV-miR-7b-OE significantly increased reinstatement behavior (P < 0.01), concomitant with decreased GABRA4 mRNA. Meanwhile, AAV-siRNA-GABRA4-mediated GABRA4 silencing increased reinstatement responses postextinction (P < 0.05).

Conclusion: MiR-7b suppression and GABRA4 upregulation form a feedback loop promoting cue-induced heroin-seeking reinstatement. These findings identify a compensatory miR-7b/GABRA4 axis in the NAc that counteracts relapse vulnerability, proposing novel targets for addiction intervention.

Background: Neuropathic pain is a chronic condition involving microglial pyroptosis mediated by the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome. Current treatments are limited, prompting the need for new therapies targeting these mechanisms. This study evaluates Procaine's effects on microglial pyroptosis and its underlying pathways.

Methods: BV-2 cells were exposed to lipopolysaccharide (LPS) to induce pyroptosis. NLRP3 O-GlcNAcylation was assessed using wheat germ agglutinin pull-down and co-immunoprecipitation assays. ELISA was employed to measure interleukin (IL)-1β and IL-18 secretion levels. The transcriptional regulation of O-GlcNAc transferase (OGT) by signal transducer and activator of transcription 3 (STAT3) was investigated through dual-luciferase reporter and chromatin immunoprecipitation assays.

Results: Procaine treatment markedly inhibited LPS-induced pyroptosis in BV-2 cells while promoting the viability. NLRP3 O-GlcNAcylation contributed to LPS-induced microglial pyroptosis. Mechanistically, the Janus kinase 2 (JAK2)/STAT3 signaling pathway promoted LPS-induced microglial pyroptosis by transcriptionally activating OGT expression. In addition, procaine inhibited LPS-induced microglial pyroptosis by repressing OGT-mediated NLRP3 O-GlcNAcylation through inactivating the JAK2/STAT3 pathway.

Conclusion: Procaine alleviated LPS-induced microglial pyroptosis by inhibiting OGT-mediated O-GlcNAcylation of NLRP3 through inactivating the JAK2/STAT3 signaling pathway. Our research provides a potential therapeutic strategy for neuropathic pain.

Background: Neuroinflammation plays a critical role in the pathogenesis and progression of Parkinson's disease. Verminoside (VMS) is a natural iridoid exhibiting anti-inflammatory properties. We aimed to investigate the effects of VMS on neuroinflammation and neuronal death in lipopolysaccharide (LPS)-treated BV2 microglial cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse models.

Methods: The production of inflammatory mediators, including nitric oxide, inducible nitric oxide synthase, tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, were measured by Griess assay, ELISA, or real-time PCR. The protein levels of IκBα and nuclear factor kappa B (NF-κB) were determined by western blot. Cell viability and apoptotic rate were assessed using a cell viability assay and flow cytometry, respectively. Immunofluorescence was employed to label Iba-1-positive microglia and tyrosine hydroxylase-positive dopaminergic neurons. In addition, the motor function of mice was evaluated using the rotarod and traction tests.

Results: Our results demonstrated that VMS effectively suppressed the upregulation of inflammatory mediators induced by LPS in BV2 cells. VMS also inhibited the nuclear translocation of NF-κB and eliminated NF-κB activity. Moreover, VMS mitigated the toxicity of conditioned media from LPS-treated BV2 cells. In MPTP-treated mice, VMS decreased the number of Iba-1-positive microglia, reduced the production of inflammatory mediators, preserved tyrosine hydroxylase-positive dopaminergic neurons, and ameliorated motor deficits.

Conclusion: In summary, VMS prevents dopaminergic neuron degeneration and alleviates behavioral impairments by suppressing NF-κB-mediated neuroinflammation, highlighting its potential as a therapeutic drug for Parkinson's disease.

Background: Diabetes significantly elevates the risk of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, indicating shared pathophysiological mechanisms. While ferroptosis is increasingly implicated in neurodegeneration, microglia - highly vulnerable to ferroptosis - may mediate this link. However, it remains unknown whether high glucose (HG) directly induces microglial ferroptosis.

Methods: Using HG-treated BV2 microglia, we integrated multiomics profiling (RNA-seq and targeted lipidomics), functional assays, and genetic manipulation of pyruvate dehydrogenase kinase 4 (PDK4) to investigate its role in HG-associated ferroptosis.

Results: HG-induced microglial ferroptosis, characterized by iron overload, elevated malondialdehyde and mitochondrial reactive oxygen species, glutathione peroxidase 4 (GPX4) downregulation, and mitochondrial damage, including loss of membrane potential and ultrastructural disintegration. This was accompanied by upregulated PDK4 expression. PDK4 overexpression attenuated ferroptosis by preserving GPX4, reducing lipid peroxidation, and maintaining mitochondrial integrity; these protective effects were reversed by n-6 polyunsaturated fatty acid (PUFA) supplementation. Conversely, PDK4 knockdown exacerbated ferroptosis via amplified n-6 PUFA synthesis and oxidative stress. Mechanistically, PDK4 acts as a metabolic gatekeeper by restricting acetyl-CoA availability for the synthesis of pro-ferroptotic PUFAs, thereby curtailing iron-dependent lipid peroxidation.

Conclusion: PDK4 is a critical regulator of HG-induced microglial ferroptosis, thereby bridging hyperglycemia-induced metabolic dysfunction and neurodegeneration. Our findings nominate PDK4 as a promising therapeutic target for diabetes-linked neurodegenerative diseases.

Objectives: Acid-sensing ion channels (ASICs) are rapidly inactivated following activation by acidic extracellular pH. Consequently, mechanisms beyond ASICs are likely involved in modulating neuronal excitability under sustained acidic conditions. Therefore, this study investigated the impact of sustained acidic pH on neuronal excitability.

Methods: Membrane current and voltage changes induced by acidic pH were recorded from acutely isolated rat medullary dorsal horn neurons using the whole-cell patch-clamp technique.

Results: The steady-state inactivation relationship for extracellular pH revealed that most ASICs were completely inactivated at pH ≤ 6.5. Acidic pH depolarized medullary dorsal horn neurons with high affinity (EC50 of pH 6.9), a process mediated by ASIC activation. Acidic pH (≤6.9) also generated instantaneous action potentials; however, they immediately disappeared owing to the inactivation of voltage-gated Na⁺ channels. Action potentials reemerged depending on pH level, even under sustained acidic conditions. This reappearance of action potentials correlated with the extent to which acidic pH inhibited the persistent Na⁺ current mediated by voltage-gated Na⁺ channels.

Conclusion: These findings suggest that under pathological conditions characterized by sustained extracellular pH reduction, such as inflammation, a persistent Na⁺ current may serve as a sensor for modulating neuronal excitability in response to prolonged acidic pH levels.

Objective: This study investigated abnormal short- and long-range functional connectivity density (FCD) and resting-state functional connectivity (rsFC) within and outside the cortico-striatal-thalamic (CST) loop in patients with obsessive-compulsive disorder (OCD).

Methods: Ninety-two patients with OCD and 75 healthy controls underwent multimodal MRI. Clinical assessments included the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Beck Anxiety Inventory, and Beck Depression Inventory. Voxel-based FCD analysis explored local and distant nodal changes, followed by seed-based rsFC analysis and correlation with clinical variables.

Results: Compared with healthy controls, patients with OCD showed decreased short-range FCD in the bilateral postcentral gyrus, left superior temporal gyrus, and right insula, but increased short-range FCD in the left caudate nucleus. Long-range FCD increased in the right orbitofrontal gyrus and left middle frontal gyrus. Seed-based analysis revealed enhanced rsFC between the right orbitofrontal gyrus and right calcarine fissure and surrounding cortex, and between the left middle frontal gyrus and right anterior cingulate and paracingulate gyri, as well as the right paracentral lobule. Left caudate FCD values negatively correlated with Y-BOCS scores, while left middle frontal gyrus FCD values positively correlated with illness duration.

Conclusion: Patients with OCD exhibit widespread connectivity abnormalities in multiple brain regions within and beyond the classic CST loop, involving sensorimotor networks, emotion-cognitive regulation, executive control, error monitoring, and visual processing systems. These findings suggest that OCD pathophysiology extends beyond the traditional CST loop, providing new insights into the neural mechanisms underlying this disorder.

Objective: Butyrate, a short-chain fatty acid produced by intestinal microbial fermentation of dietary fiber, serves as an endogenous ligand for the G protein-coupled receptors. Previous studies have confirmed the neuroprotective effects of sodium butyrate (NaB) in ischemic stroke, but its role in subarachnoid hemorrhage (SAH) remains unclear. Here, we investigated the potential therapeutic efficacy and underlying mechanisms of NaB in a rat SAH model.

Methods: NaB was administered intranasally 1 h post-SAH, and neurological function and neuronal apoptosis were evaluated 24 h post-SAH.

Results: During the early brain injury (EBI) phase after SAH, GPR41 was predominantly expressed in neuronal cells, and its expression levels increased significantly, peaking at 24 h post-SAH. NaB treatment attenuated neurological deficits after SAH, reduced brain edema, and alleviated neuronal damage and apoptosis. Furthermore, NaB elevated the levels of GPR41, phosphorylated Akt, and the antiapoptotic protein Bcl-2, while suppressing the expression of the proapoptotic protein Bax. Notably, the neuroprotective effects of NaB were partially reversed by GPR41 siRNA knockdown and pharmacological inhibition of PI3K with LY294002.

Conclusions: These findings suggest that NaB may mitigate EBI after SAH by inhibiting neuronal apoptosis, with the underlying mechanism potentially involving activation of the GPR41/PI3K/Akt signaling pathway.