Neuroreport最新文献

Objective: This study aims to clarify the protective effect of miR-766-3p on brain injury caused by intracerebral hemorrhage (ICH), and to reveal the mechanisms by which it regulates neural function, neuroinflammation, and brain edema.

Methods: An ICH rat model was constructed and PC12 cells were treated with hemin to simulate neuronal injury. Quantitative reverse transcription PCR was used to detect the expression of miR-766-3p and inflammatory factors. Cell counting kit-8 and flow cytometry were used to assess cell viability and apoptosis. Brain edema was evaluated by the dry-wet method. Neurological function was assessed through the Garcia score, forelimb placement test, and corner turn test. The dual-luciferase reporter assay and RNA immunoprecipitation were employed to validate the targeting relationship between miR-766-3p and bradykinin receptor B2 (BDKRB2).

Results: The expression of miR-766-3p was significantly downregulated in the brain tissue surrounding the hematoma and PC12 cells. Overexpression of miR-766-3p increased the survival rate of neuronal cells, inhibited apoptosis, and reduced the release of inflammatory factors. In vivo experiments demonstrated that this intervention measure improved neurological function scores and placement rate of the forelimbs while alleviating turning disorders, brain edema, and neuroinflammation. miR-766-3p directly targets BDKRB2 and inhibits its expression. Overexpression of BDKRB2 completely reversed the neuroprotective effects of miR-766-3p.

Conclusion: miR-766-3p alleviates neuroinflammation, cerebral edema, and neuronal damage caused by ICH by targeting and inhibiting BDKRB2.

Objectives: Schwann cells have therapeutic potential for central nervous system repair, but their limited posttransplant survival remains a major challenge. Because histone deacetylase inhibitors (HDACIs) can enhance genes involved in myelination potential and neurotrophic support, this study investigated whether sodium butyrate (NaB), an HDACI, promotes the expression and sustained regulation of myelin‑associated and neurotrophic genes in cultured Schwann cells.

Methods: Cultured Schwann cells were treated with 1 or 10 mM NaB for either 48 h (prolonged treatment) or 24 h followed by reagent washout (transient treatment). Expression of myelin-associated genes, neurotrophic factors, and apoptosis marker were quantified using quantitative reverse transcription PCR. Cell viability was assessed via Cell Counting Kit-8 assay.

Results: Prolonged treatment with NaB increased the expression of myelin-associated genes (Mbp and Mpz) and neurotrophic genes (Igf-1 and Gdnf). Furthermore, transient NaB treatment increased these gene expressions for up to 24 h after reagent washout and attenuated NaB‑induced apoptosis. Specifically, transient treatment with a high dose of NaB strongly sustained the enhanced expression of the myelin marker, Mpz.

Conclusion: Transient pre‑treatment with NaB enhanced and sustained the expression of certain key myelin‑associated and neurotrophic genes in Schwann cells while reducing cytotoxic effects. These findings suggest a potential strategy to improve certain Schwann cell functions and support further investigation of HDACI‑based approaches in regenerative therapy.

Objective: We investigated whether transcranial direct current stimulation (tDCS) applied to the supplementary motor area (SMA) modulates mirror activity induced by transcranial magnetic stimulation (TMS) during a unilateral precision pinch task.

Methods: Healthy subjects performed a left-hand precision pinch task during the delivery of single-pulse TMS to the left primary motor cortex (M1) to evoke mirror activity in the right hand. Anodal, cathodal, and sham tDCS were applied over the SMA via a randomized crossover design. Motor-evoked potentials recorded from the right first dorsal interosseous muscle were used to quantify mirror activity. Pinch performance variability was evaluated.

Results: Although anodal tDCS tended to increase mirror activity, the effect did not differ significantly from that of sham tDCS. In contrast, cathodal tDCS significantly reduced mirror activity compared with the effects of sham and anodal tDCS. Pinch performance variability did not differ among the tDCS conditions, indicating that mirror activity changed independently of motor performance. Resting motor-evoked potential amplitudes elicited by single-pulse TMS were not significantly altered by tDCS targeting the SMA.

Conclusion: Mirror activity is modulated by SMA excitability. The findings indicate that cathodal tDCS applied to the SMA reduces mirror activity, potentially through alterations in cortical network interactions between the SMA and M1.

Background: Altered degree centrality, a measure of brain network connectivity, has been linked to Parkinson's disease symptoms. However, it is unclear whether regional degree centrality differences between Parkinson's disease patients and healthy controls relate to spatial patterns of gene expression. The associated biological pathways and cell types also remain to be clarified.

Objective: To investigate regional degree centrality differences between Parkinson's disease and healthy controls, and to explore their associations with brain-wide gene expression, enriched pathways, and specific cell types.

Methods: Voxel-wise degree centrality maps were computed for each participant and compared between groups using two-sample t-tests. Partial least squares (PLS) regression was applied to link degree centrality alterations to gene expression data from the Allen Human Brain Atlas. Enrichment analyses were conducted using Metascape, and cell-type specificity was assessed to identify key cellular contributors.

Results: Parkinson's disease patients showed significant degree centrality alterations relative to controls. These changes were spatially correlated with a gene expression pattern captured by PLS component 2 (PLS2). Enrichment analysis revealed that the associated genes were predominantly expressed in astrocytes, excitatory neurons, and inhibitory neurons, and were involved in synapse organization.

Conclusion: This study links functional network disruptions in Parkinson's disease to specific transcriptomic signatures, highlighting astrocytes and neurons as key contributors. These findings offer insight into the cellular and molecular mechanisms underlying brain connectivity changes in Parkinson's disease.

Background: Spinal cord injury (SCI) lacks effective treatments. Ferroptosis contributes to SCI pathology. We investigated the therapeutic potential of 20-deoxyingenol (20-DOI), a natural diterpene, focusing on its role in inhibiting ferroptosis.

Methods: We used ventral spinal cord 4.1 motor neurons in vitro, challenged with H2O2 or erastin. Assessments included cell viability, proliferation, autophagy, lysosomal function, and ferroptosis. Transcription factor EB (TFEB) knockdown validated its involvement. In vivo, a mouse SCI model assessed functional recovery (Basso mouse scale score), tissue damage, and ferroptosis markers.

Results: 20-DOI restored cell viability and proliferation, enhanced autophagy and lysosomal activity. It suppressed ferroptosis, reducing lipid peroxidation and reactive oxygen species, and preserving mitochondrial function. These benefits required TFEB; its knockdown abolished the protection and reduced NRF2/GPX4 levels. In mice, 20-DOI improved motor function, preserved neurons, and attenuated ferroptosis.

Conclusion: 20-DOI promotes recovery after SCI by activating TFEB to inhibit ferroptosis. Our work identifies TFEB as a key target and 20-DOI as a promising therapeutic agent.

Background: Ferroptosis is emerging as a crucial type of cellular demise involved in intracerebral hemorrhage (ICH). Cysteine desulfurase (NFS1) is a key gene involved in the regulation of ferroptosis; however, its role in modulating neuronal ferroptosis in ICH remains unclear. This work aimed to explore whether NFS1 influences neuronal ferroptosis in ICH and to explore the underlying molecular mechanisms.

Methods: We established an ICH animal model using collagenase injection and a cellular model by treating neurons with hemin. Neurons with NFS1 overexpression or knockdown were generated using adenoviral vectors. Ferroptosis was evaluated by measuring typical indicators such as lipid peroxidation and ferrous iron levels. In-vivo NFS1 overexpression was achieved via adeno-associated virus constructs. Neurobehavioral function was assessed using Rotarod, Cylinder, and Corner tests.

Results: A marked decrease in NFS1 levels was revealed in both animal and cellular models. Overexpression of NFS1 inhibited hemin-induced neuronal damage and ferroptosis. The exacerbating impact of NFS1 silencing on hemin-induced neuronal damage could be reversed by inhibiting ferroptosis. NFS1 overexpression suppressed hemin-induced neuronal ferroptosis by inhibiting the iron-responsive element-binding protein 2-mediated iron-starvation response. Blocking the iron-starvation response reversed the promoting effect of NFS1 silencing on neuronal ferroptosis. In the animal model, NFS1 overexpression significantly reduced hemorrhage volume and improved neurobehavioral function, accompanied by lower levels of iron-starvation response and ferroptosis.

Conclusion: NFS1 may alleviate ICH damage by suppressing neuronal ferroptotic death via the downregulation of the iron-starvation response, suggesting a prospective therapeutic target for the treatment of this disorder.

Objective: This study focused on clarifying whether methyltransferase3 (METTL3) participates in the polarization and activation of microglia in Alzheimer's disease (AD) by mediating the N6-methyladenosine (m6A) modification level of TP53-induced glycolysis and apoptosis regulator (TIGAR).

Methods: Human microglia HMC3 cells were transfected with overexpression or knockdown lentivirus of METTL3, TIGAR, or TIGAR before being induced by Aβ treatment to establish an in-vitro AD cell model. The expression of TIGAR and METTL3 was measured by real-time quantitative PCR and western blot. Microglial polarization was assessed by detecting the expression of M1 microglia marker CD86 and M2 marker CD206 using immunofluorescence and measuring the protein expression of M1-associated iNOS and IL-1β, and M2-associated Arg-1 and IL-10 using western blot. PAR-CLIP was employed to examine the binding of METTL3 to TIGAR mRNA, and MeRIP was used to measure the m6A level of TIGAR mRNA. The stability of TIGAR mRNA was evaluated by an actinomycin D assay.

Results: In Aβ-induced HMC3 cells, both METTL3 and TIGAR expressions were reduced. Aβ treatment in HMC3 cells increased M1 polarization and decreased M2 polarization. But this effect was partially reversed by overexpression of either METTL3 or TIGAR. METTL3 binds to TIGAR mRNA and increases its m6A level, thereby promoting TIGAR mRNA stability.

Conclusion: METTL3 modulates the balance of Aβ-induced polarization and microglia activation in HMC3 cells by upregulating TIGAR, promoting polarization toward an anti-inflammatory profile.

Objective: While the p75 neurotrophin receptor (p75NTR) is critically implicated in the aggregation of α-synuclein (α-syn), a defining pathological hallmark of Parkinson's disease, the distinct functional contributions of its structural domains remain largely unresolved.

Methods: To investigate this, we employed a rotenone-induced cellular Parkinson's disease model utilizing SH-SY5Y neuroblastoma cells transfected with plasmids encoding specific p75NTR truncation mutants.

Results: Overexpression of a mutant representing the p75NTR extracellular domain (HA-p75Δ151, lacking residues 277-427) significantly exacerbated both α-syn expression levels and its aggregation phenotype. This effect is potentially attributable to the aberrant activation of caspase-1. Conversely, unlike full-length p75NTR which enhanced α-syn ubiquitination, the HA-p75Δ151 truncation failed to modulate ubiquitination dynamics. Furthermore, expression of this extracellular domain fragment induced cell cycle dysregulation and promoted cell death.

Conclusion: These findings delineate the p75NTR extracellular domain-induced α-syn proteotoxic stress. This domain-specific mechanism advances our understanding of Parkinson's disease pathogenesis and highlights the therapeutic potential of targeting specific p75NTR domains.

Background: Intracerebral hemorrhage (ICH) causes a severe form of stroke characterized by high morbidity, mortality, and long-term disability. Neuronal cell death is influenced at the posttranscriptional level. Certain microRNAs influence neuronal cell death at the posttranscriptional level by regulating receptor-interacting protein kinase 3 (RIPK3), a key mediator of necroptosis. The specific mechanism by which miR-873 mediates neuronal necroptosis following ICH remains unclear. Epigenetic abnormalities, particularly N6-methyladenosine (m6A) modification, are increasingly recognized as critical contributors to ICH pathophysiology.

Methods: ICH mice model was established, followed by intracerebroventricular injection for gene manipulation. Brain water content was measured to assess cerebral edema. Neurological function was evaluated using the Morris water maze and neurological deficit scoring. Molecular and cellular analyses included Western blotting, quantitative real-time PCR, immunofluorescence, and luciferase reporter assays. Primary neuronal cultures, plasmid construction, and m6A RNA methylation quantification were performed to investigate underlying mechanisms. Differential gene expression was analyzed using microarray profiling, and data were statistically evaluated with appropriate analytical methods.

Results: The m6A modification is upregulated and positively involved in the functional role of miR-873 in ICH. miR-873 rescued necroptosis in ICH. miR-873 targets RIPK3. RRACH (R = G or A; H = A, C, or U) m6A sequence motifs predominantly contribute to the m6A modification of miR-873. The m6A modification regulates necroptosis in ICH. Knockdown of methyltransferase-like 3 improved the neurological function prognosis of ICH in mice.

Conclusion: m6A modification modulates miR-873 expression, thereby influencing RIPK3-mediated necroptosis in ICH. These findings provide potential therapeutic targets for mitigating neuronal injury after hemorrhagic stroke.

Objective: The transition from wakefulness to sleep depends on dynamic thalamocortical interactions that regulate arousal and sensory gating. While thalamic coordination of cortical activity during sleep is well established, little is known about how presleep thalamocortical connectivity relates to subsequent sleep architecture. This study examined whether short-term changes in thalamocortical coupling during the early evening predict polysomnographically measured sleep later that night.

Methods: Twenty adults (8 men, 12 women; age 19-39 years) with clinically significant insomnia symptoms completed two resting-state functional MRI scans ~2 hours apart (~6 : 30 and 8 : 30 p.m.) before an overnight in-lab sleep study. Whole-brain seed-to-voxel analyses using a bilateral thalamic region of interest assessed changes in functional connectivity between scans, which were then correlated with polysomnographic sleep-stage metrics [i.e. time in wake, N1, N2, N3, rapid eye movement (REM)].

Results: Increased thalamocortical connectivity with occipital, posterior middle temporal, and left frontal cortices before sleep predicted greater time in N2 sleep, whereas decreased connectivity with insula, putamen, and frontal regions predicted more N3 sleep. Reduced thalamic coupling with the left lateral occipital gyrus predicted greater REM sleep, and decreased thalamocerebellar connectivity was associated with increased wake time while in bed. No associations were observed for N1, total sleep time, or sleep efficiency.

Conclusion: Fluctuations in presleep thalamocortical connectivity predicted distinct features of subsequent sleep architecture. These findings suggest that presleep thalamocortical network dynamics may facilitate some aspects of later restorative sleep the same night, providing insight into how waking brain patterns influence subsequent sleep quality and continuity.