Stroke leads to widespread brain connectivity changes, impacting areas both close and remote to the lesion. Post-stroke recovery dynamics are not fully understood. Investigating structural network reorganization over time can thus provide valuable information on adaptive and maladaptive neural plasticity changes on a subject-specific level. Four first-time ischemic stroke patients (3 M, aged 50-69 years) with upper-extremity motor impairment were examined using ultra-high field 7T MRI structural imaging protocols. For each patient, we performed longitudinal lesion quantification and white matter connectivity analysis at three critical timepoints associated with post-stroke recovery: within 1 week, at ~ 1 month, and at ~ 3 months. Using the structural MRI images, we generated patient-specific weighted structural connectivity matrices at each timepoint. We utilized the Schaefer-Yeo and Automated Anatomical Labeling atlases to derive both anatomical regions and resting-state networks based on pre-defined parcel assignments. We examined lesion evolution and white matter connectivity changes as disconnections, re-emerging connections, and existing connections with an increase in estimated connectivity strength over time. We further conducted exploratory edge-level analyses to examine the connectivity strength changes for each patient. Across all patients and timepoints, an increase in estimated connectivity strength of pre-existing connections dominated structural reorganization. Temporally, the four patients revealed distinct neural reorganization patterns. Patient 1 exhibited robust structural changes in the late ~1 to ~ 3 months stage, whereas Patient 2 in the early < 1 week to ~ 1 month stage. Patient 3 had continuous network growth, while Patient 4 demonstrated stable network reorganization. In our sample, the somatomotor and attention networks underwent the most dynamic reorganization. Somatomotor and salience/ventral attention regions exhibited increased connectivity strength, and in cortical stroke cases, dorsal attention regions demonstrated decreased connectivity strength. In this longitudinal case series, post-stroke neural network reorganization appears to be driven by an increase in estimated connectivity strength of surviving white matter connections, suggesting compensatory neuroplasticity. Adaptive changes were most evident in the somatomotor and salience/ventral attention networks within this sample, while the dorsal attention network suggested a more limited contribution to adaptive network changes. Individual differences in the timing and pattern or reorganization highlight the potential need for further research into personalized treatment approaches to promote adaptive recovery.

Spinal cord injury (SCI) is a devastating condition with high rates of disability and mortality, and secondary injury mechanisms such as ferroptosis have emerged as crucial contributors to its pathophysiology. However, the regulatory mechanisms underlying ferroptosis in SCI remain largely unclear. We analyzed peripheral blood transcriptome data (GSE151371) from 10 healthy controls, 10 non-CNS trauma patients, and 38 SCI patients to identify differentially expressed mRNAs (DE-mRNAs) and miRNAs (DE-miRNAs). Ferroptosis-related genes (FRGs) were screened by intersecting DE-mRNAs with a curated list of FRGs. Functional enrichment analyses, regulatory network construction (lncRNA–miRNA–mRNA, TF-miRNA-mRNA), and drug target predictions were conducted. Key findings were validated using the GSE166009 dataset from a rat SCI model and through experimental verification in a TSCI rat model. We identified 38 differentially expressed FRGs (DE-FRGs) in SCI, enriched in lipid metabolism and inflammatory pathways, including IL-17 and TNF signaling. Protein–protein interaction network analysis identified IL-1β as a central hub gene. A miRNA–mRNA network revealed miR-326 as a key regulator of IL-1β. The IL-1β/miR-326 axis was also closely associated with lncRNA-miRNA-mRNA networks, transcription factor regulation, and drug target predictions. Validation in the GSE166009 dataset and a rat SCI model confirmed progressive downregulation of miR-326 and upregulation of IL-1β post-SCI. Dual-luciferase reporter assays demonstrated that miR-326 directly binds the 3′UTR of IL-1β, suppressing its expression. Our study highlights the IL-1β/miR-326 axis as a critical regulator of ferroptosis in SCI and a potential therapeutic target for intervention.

The nematode Caenorhabditis elegans displays many distinct behaviors, making it an ideal system to understand the relationship between genes, cells, and behavioral output. In C. elegans, thermal information is primarily detected by the AFD sensory neurons, with minor input from the AWC neurons. Similarly, ionic solutes such as sodium chloride are detected by the ASE chemosensory neurons. Both sensory neuron pairs synapse primarily onto the AIY interneurons. We show that AIYL/R ventral contact is mediated via the ephrin gene efn-1 in a linear genetic pathway with vab-1. In addition, we show that this activity requires both a VAB-1 kinase-dependent and a kinase independent function. We also show that efn-4 is required for AFD neuron axon extension, and that this strongly correlates with AIY neuron morphology. ASE morphology, however, does not require efn-4 function. In addition, efn-4 is required, in part, for normal synaptic vesicle cluster count in both AFD and ASEL neurons. Finally, we demonstrate that efn-4 is required for normal thermotaxis behavior, and to a lesser degree, salt-dependent chemotaxis, while vab-1 and efn-1 also contribute to normal thermosensory function, albeit to a lesser degree than efn-4. These data illustrate that left-right circuit connectivity, between the left-right thermosensory neuron pair and/or the left-right first layer interneuron pair, may be required for normal thermotactic responses. These data also highlight the importance of EphRs and ephrins in multiple aspects of sensory circuit assembly and function and suggest that efn-4 may coordinate thermosensory circuit assembly. Not applicable.

IntroductionGlioblastoma is the most aggressive primary brain cancer. It is considered an ‘immunologically cold’ tumour where immune infiltrates are polarised to drive immunosuppression—and therefore tumour proliferation. An important driver of neuroinflammation in glioma is the purinergic P2X7 receptor (P2X7R). While much of the complex glioma microenvironment has been characterised, studies expounding the associations between various cytokines/chemokines, immune cell markers, P2X7R expression and glioma stemness are lacking. Here we aimed to characterise the mRNA expression profiles of various tumour markers, and common ‘pro-‘ and ‘anti-tumour’ inflammatory mediators, and correlate this to P2X7R expression in human high-grade glioma samples compared to ‘healthy’ non-tumour post-mortem brain.MethodsHigh grade gliomas were collected from 34 patients undergoing routine tumour resection surgery and compared to 12 ‘healthy’ post-mortem controls. High throughput qPCR was performed on extracted RNA converted to cDNA to examine a custom-made panel of 38 tumour and immune related genes.ResultsMarkers of innate immunity including CD68, S100A9, HLADR, NLPR3, interleukin (IL) 1β, IL-6, TNFα and NF-κB were significantly increased in human derived glioblastoma samples compared to healthy control brain. P2X7R was also upregulated in the glioma microenvironment and its expression was linked to the expression of VEGFB, MMP9, PCNA, IL-4 and IL-8. The level of expression of P2X7R was not associated with overall survival in high grade gliomas.DiscussionCollectively, this study confirms the significant overexpression of P2X7R in human high-grade gliomas as well as highlights the presence of a multidirectional neuroinflammatory milieu in which both tumour-promoting and tumour-suppressive genes are overexpressed.

Depression is a prevalent mental disorder, and prolonged exposure to social defeat is a major contributing factor in the onset of depression. Repeated social defeat stress (RSDS) is a commonly used animal model for depression, significantly impacting on the pathogenesis of depression-related to social disorders. The basolateral amygdala (BLA) and the ventral hippocampus (vHPC) are critical brain regions involved in RSDS-induced social behavioral disorders, but the specific neural oscillations occurring in these regions following social defeat remain unclear. Using simultaneous multi-electrode recordings, we captured local field potentials (LFPs) from BLA and vHPC while the stressed mice underwent a social interaction test. Power spectral analysis and Amplitude transform entropy were respectively applied to assess social defeat-induced alterations in neural oscillatory activity and directional inter-regional communication. Our study demonstrated that repeated social defeat induces social avoidance and depression-like behaviors. Notably, the power spectral analysis within the BLA and vHPC revealed statistically differences in the theta band (4-12Hz) between control and RSDS groups, particularly during the With CD1 phase in the 0-3s stage, when mice entered the social interaction zone, compared to the - 3 -0s stage prior to enter the zone. Moreover, machine learning analysis successfully classified control and RSDS groups based on neural oscillatory activity in the BLA and vHPC. Finally, ketamine treatment was found to reduce social avoidance and depressive-like behaviors, as well as enhance theta oscillation in the BLA and vHPC. These results suggest that social defeat alters theta oscillations in the BLA and vHPC, highlighting potential therapeutic avenues for addressing depression-related social dysfunction.

BackgroundChronic neuroinflammation, driven by M1-polarized microglia, is a core pathological mechanism of Alzheimer’s disease (AD). Elevated expression levels of miR-199a-3p and pro-inflammatory cytokines were detected in the hippocampi of AD transgenic mice and in LPS-stimulated BV2 microglial cells. We hypothesized that miR-199a-3p exacerbates neuroinflammation by promoting M1 microglial polarization in AD progression.ObjectiveTo explore the role of miR-199a-3p in AD-associated neuroinflammation.MethodsAD transgenic (APPswe/PSEN1dE9) mice and LPS-treated BV2 cells were used to assess miR-199a-3p effects in vivo and in vitro. Inflammatory cytokines and markers for microglial cell typing were detected. Transcriptome sequencing was performed on miR-199a-3p-modulated BV2 cells, and the sequencing data were cross-analyzed with public databases to predict miR-199a-3p-mediated pathways.ResultsIntracerebroventricular administration of miR-199a-3p agomir exacerbated amyloid deposition and impaired cognitive function in AD mice, and promoted microglial polarization toward the M1 phenotype. Conversely, treatment with miR-199a-3p antagomir attenuated AD pathology and suppressed M1 polarization. In LPS treated BV2 cells, miR-199a-3p mimics promoted M1 polarization, while inhibitors reversed this effect. Transcriptome analysis revealed that miR-199a-3p downregulated WDR76, subsequently suppressing cell cycle-associated pathways, IL-17 signaling, and FOXO pathways, resulting in an increase in the proportion of M1 type microglia.ConclusionMiR-199a-3p aggravates neuroinflammation of AD by promoting M1-polarization microglia. These findings highlight miR-199a-3p as a potential therapeutic target for AD.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12868-025-00965-5.

AimTo explore the effects of arabinoxylan on the BDNF/TrkB/p-CREB signaling pathway in the prefrontal cortex of post-stroke depressed rats, and to explore its neuronal protective effects through the microbial-gut-brain axis in the regulation of this pathway.MethodsThe rat model of post-stroke depression (PSD) was established by middle cerebral artery occlusion (MCAO) combined with chronic unpredictable mild stimulation (CUMS). They were randomly divided into 5 groups (blank control, post-stroke depression, arabinoxylan, fluoxetine hydrochloride, fluoxetine hydrochloride combined arabinoxylan). The rats were treated differently for 28 days according to their grouping. Body mass, sugar and water consumption experiments and open-field experiments were used to evaluate the behavior of rats. The pathological changes were observed by H&E staining. The expression levels of amine neurotransmitters were detected by ELISA. The expression levels of BDNF mRNA and BDNF, TrkB and p-CREB were detected by RT-PCR and Western blot. The analysis of intestinal metagenomics was conducted by 16 S rDNA sequencing.ResultsCompared with the post-stroke depression group, the body weight, activity and sugar water consumption rate of the arabinoxylan group were increased. The expression levels of 5-HT in the prefrontal cortex, colon and serum levels of 5-HT, DA and NE were increased. The expression levels of BDNF mRNA and BDNF, TrkB and P-CREB in the prefrontal cortex were also upregulated. The number of neurons in the prefrontal cortex increased; Colon mucosal injury and inflammatory cell infiltration decreased, the intestinal microbial diversity increased; The relative abundance of probiotics such as bifidobacterium, Christensenia, Dubosiella New York and ruminococcus increased. The relative abundance of Prevotella NK3B31 group was reduced. The level of 5-HT in the prefrontal cortex was negatively correlated with the abundance of Prevotellaceae NK3B31 group.ConclusionArabinoxylan improved depressive-like behavior in rats and its neuroprotective role was achieved by promoting the growth of intestinal probiotics, improving the intestinal barrier, affecting the BDNF/TrkB/p-CREB signaling pathway, and increasing the expression levels of monoamine neurotransmitters 5-HT, DA and NE.

BackgroundMethyl CpG binding protein 2 (MECP2) is an essential global modulator of transcription and mutations in MECP2 are the most common cause of Rett syndrome, an X-linked neurodevelopmental disorder. Patients diagnosed with Rett syndrome have increased risk for epilepsy as well as problems with anxiety and social communication. Using the zebrafish mecp2Q63X line, this study aimed to increase our understanding of the role of Mecp2 function in regulation of pharmacologically-induced hyperlocomotion, developmental social preference, and adult socialization, anxiety-related behaviour, and baseline cortisol levels. To determine responses of mecp2−/− zebrafish to a stimulating convulsant, general locomotor activity was measured at 5 days post-fertilization (dpf) in sibling mecp2+/+, mecp2+/−, and mecp2−/− fish after treatment with a GABAA receptor antagonist pentylenetetrazol (PTZ) at varying concentrations. Responses to social stimulus were investigated in juvenile (21 dpf) and adult mecp2−/− and mecp2+/+ fish. Anxiety responses to a novel tank and whole-body cortisol levels were also measured in adult mecp2−/− and control mecp2+/+ zebrafish.ResultsThe behavioural tests showed that mecp2−/− zebrafish displayed hypolocomotion at the larval stage, along with increased freezing time and thigmotaxis, and higher whole-body cortisol levels in adulthood. However, the hyper-locomotion response to PTZ at 5 dpf and social preference for visual social stimulus at 21 dpf and in adulthood were not affected by the lack of functional Mecp2.ConclusionsFunctional Mecp2 modulated larval locomotion and behavioural anxiety at different ages and adult cortisol levels, but mecp2 null-mutation did not alter adult locomotion and socialization, and developmental sociability and PTZ-induced hyperlocomotion in zebrafish. Given the variability reported in patients and in rodent Mecp2 knockout models, studies using zebrafish can explore vital elements of MECP2’s role across development and improve our understanding of neural mechanisms underlying neurodevelopmental disorders.

BackgroundTo explore the effect and mechanism of hippocampus on experimental orthodontic pain-induced anxiety.MethodsHerein, we document a novel modeling method whereby the nickel–titanium (Ni–Ti) orthodontic wire was fixed stably in the oral cavity of mice with a ligation technique to induce stable distal movement of maxillary incisors to mimic orthodontic tooth movement. At the experimental endpoint, serum corticosterone assay, Golgi staining and Micro-CT were performed in each group after oral-facial mechanical pain sensitivity assessment and open field test.ResultsThe mechanical pain sensitivity of experimental tooth movement pain (ETMP) mice had an apparent increased elicited following tooth movement. And anxiety-like behavior was developed: reduced the time proportion of center zone and the total moving distance in the open field test and the elevated serum corticosterone levels in ETMP mice relative to control group mice. The Golgi staining in ventral hippocampal CA1 revealed that neural spine density, dendritic length and number of dendrites are reduced markedly in ETMP mice compared with the control group.ConclusionExperimental orthodontic pain drives emotional anxiety through the plasticity changes in decreased neuronal complexity and reduced spine density in ventral hippocampal CA1 in mice.

BackgroundCoping styles are individually coherent sets of behavioural and physiological responses to stress. Coping styles are thought to remain consistent across context and time, and display a certain level of heritability. Here, we examined whether risk taking is a predictor for consistency and heritability of stress coping styles in both larval and adult zebrafish (Danio rerio).ResultsA group emergence test where fish emerge from a familiar housing compartment into a potentially dangerous novel environment, established the level of risk taking of F0 generation adult zebrafish. The degree of risk taking appeared to be consistent over time and context. Then, the F0 risk taking degree was further correlated with various behavioural parameters related to stress coping of the F1 and F2 generations. In larval fish, these parameters were measured during a light dark challenge which elicits an anxiety like response. In adults, they were measured during a single emergence test and a combined open field and mirror biting test, estimating the degree of risk taking and the level of explorativeness and aggressiveness. The results show that (i) parental risk taking behaviour is a good predictor for a large number of larval and adult behavioural parameters, within and between generations; (ii) a number of these parameters are consistent over ontogenetic (larval and adult) stages within the same generation, and (iii) four of these parameters representing risk taking, aggressiveness, and swimming behaviour, were correlated over multiple generations, establishing heritability of coping styles.ConclusionWe conclude that risk taking behaviour is a strong predictor of coping style within and between generations and behavioural parameters associated with risk taking are consistent over time and heritable over generations.