ABSTRACTBackgroundDespite abundant neuroprotective successes in rodents, effective clinical therapies for spinal cord injury (SCI) remain elusive. This translational disconnect stems from a fidelity paradox. The over‐reliance on rodent models that achieve biomechanical mimicry of human trauma but lack fundamental biological equivalence.MethodsWe evaluated how physical simulation masks critical interspecies divergences. Following PRISMA guidelines, we systematically searched PubMed and Web of Science (2000–2024) to assess preclinical model utilization frequencies and synthesized evidence across distinct pathophysiological pillars to evaluate cross‐species biological mismatches.ResultsOur analysis reveals profound spatiotemporal dissonances across three pillars: (i) immunodynamics, where the delayed inflammatory resolution in mice misaligns with human chronobiology; (ii) lesion architecture, distinguishing rodent cystic cavitation from the fibrotic scarring characteristic of human pathology; and (iii) neural circuitry, contrasting indirect rodent corticospinal projections with the direct cortico‐motoneuronal connections essential for human dexterity. To address this, we propose a mechanistic fidelity matching framework. This paradigm shifts from indiscriminate single‐model validation to a problem‐driven matrix, selecting models based on their specific biological fidelity to targeted mechanisms—utilizing mice for scar modulation, rats for cystic repair, and nonhuman primates for fine sensorimotor recovery.ConclusionRestoring translational credibility requires replacing the pursuit of a universal model with a hierarchical, cross‐species validation pipeline anchored in objective, mechanism‐coupled readouts.

Traumatic brain injury (TBI) can trigger secondary oxidative stress and exacerbate neurological dysfunction. This study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) attenuates oxidative stress and improves neurological recovery after TBI in mice. The TBI model was established using a controlled cortical impact (CCI) model. Seventy C57BL/6 mice were divided into the sham group, TBI group, taVNS group, MDHB (pathway agonist, administered alone) group, and ML385 (pathway inhibitor, administered 30 min before each taVNS session) group. Outcomes were assessed by Western blotting, ELISA, immunofluorescence, T2-weighted MRI-based volumetric quantification of edema, and behavioral tests. TBI markedly increased oxidative stress and neurological impairment, as reflected by reduced serum glutathione (GSH) and superoxide dismutase (SOD) levels, increased lesion and edema burden on MRI, and worsened behavioral performance. TaVNS significantly alleviated these changes, increasing GSH and SOD levels, reducing edema burden, and improving mNSS and open-field performance. In addition, taVNS was associated with increased expression of antioxidant-related proteins, including Nrf-2 and HO-1, whereas pharmacological inhibition with ML385 attenuated these beneficial effects. These findings suggest that taVNS may alleviate oxidative stress and improve neurological outcomes after TBI in mice, with possible involvement of the Nrf-2/HO-1 pathway.

Patients with intracerebral hemorrhage (ICH) who require antithrombotic therapy (AT) face competing risks of recurrent bleeding and ischemic events. Optimal timing of AT resumption during hospitalization remains uncertain. We evaluated whether restarting AT in hospitalized patients with acute spontaneous ICH reduces ischemic complications without increasing hemorrhagic risk. We conducted a retrospective cohort study at Peking Union Medical College Hospital (2014-2022) including adults (≥ 18 years) admitted with spontaneous ICH within 6 months of onset. Patients were categorized as: Group 1, no AT indication; Group 2, AT indicated but not treated; Group 3, AT indicated and treated. Primary endpoints were ischemic events (ischemic stroke, transient ischemic attack, myocardial infarction, pulmonary embolism, deep venous thrombosis) and hemorrhagic events (new ICH or hematoma expansion ≥ 12.5 mL or ≥ 33%). Outcomes were assessed from onset to discharge. Among 601 patients (median age 58 years; 40.3% female), 256 (42.6%) were in Group 1, 247 (41.1%) in Group 2, and 98 (16.3%) in Group 3. Median time to AT resumption was 19 days (IQR 8-36). Restarting AT (Group 3) significantly reduced ischemic events (14.3% vs. 28.7%; adjusted HR 0.34, 95% CI 0.18-0.65) without increasing hemorrhagic events (5.1% vs. 6.3%; adjusted HR 0.67, 95% CI 0.20-2.19). Competing-risk models and sensitivity analysis confirmed these findings. In-hospital resumption of AT after acute spontaneous ICH significantly decreased ischemic events without excess hemorrhagic risk, supporting its potential benefit in carefully selected patients.

Sleep disturbances are a potential risk factor for stroke. Our clinical cohort shows that insomnia is associated with a higher 90-day stroke recurrence rate, prompting an investigation into the underlying mechanisms, particularly the role of the gut microbiota. We utilized a rat MCAO model of sleep deprivation (SD) combined with antibiotic (ABX)-induced gut dysbiosis. Neurological deficits were assessed through behavioral tests, and cerebral infarct volume was measured using TTC staining. Structural changes in brain and intestinal tissues were observed by H&E staining, while the expression of blood-brain barrier (BBB)-related proteins was detected by immunofluorescence and Western blot. Gut microbial composition was analyzed by 16S rRNA sequencing, and metabolomic analysis was performed using an untargeted LC-MS approach. In rats with an intact microbiota, SD had a limited effect on MCAO-induced ischemic injury. Strikingly, in ABX-induced dysbiosis, SD-exposed rats subjected to MCAO displayed more severe motor deficits, larger infarct volumes, heightened inflammation, and decreased expression of key intestinal and BBB proteins. Microbiota analysis identified Akkermansia as a potential key mediator, whose abundance was significantly decreased in the ABX + SD + MCAO group and negatively correlated with infarct size. Subsequent metabolomics profiling revealed a distinct dysregulation of Akkermansia-associated metabolites (including PG(14:0/15:0), 3-Methylbutylamine, N-Acetylcytidine, and N-Methylisoleucine). In conclusion, our study proposes a mechanism whereby SD worsens stroke outcomes by depleting Akkermansia and disrupting metabolic homeostasis.

To investigate alterations in basal forebrain (BF) subregional functional connectivity (FC), cerebral glucose metabolism, and their spatial correspondence with atlas-based neurotransmitter distributions in Alzheimer's disease (AD). Forty-two Aβ-PET-positive AD patients and forty-one matched healthy controls (HC) underwent simultaneous PET/MRI. We analyzed resting-state FC of BF subregions (Ch1-3, Ch4) and measured cerebralglucose metabolism using 18F-FDG PET standardized uptake value ratio (SUVR). Spatial correlations with neurotransmitter maps were assessed using the JuSpace toolbox. Compared with HC, AD patients showed decreased FC between the left Ch4 and hippocampus/posterior cingulate gyrus, and increased FC between the right Ch4 and precentral/postcentral gyrus. Additionally, AD patients showed increased FC between the left Ch1-3 and superior temporal gyrus/insula, decreased FC between the right Ch1-3 and the orbitofrontal gyrus, and increased FC between the right Ch1-3 and the left temporal lobe (voxel-level p < 0.001, cluster-level p < 0.05, GRF correction). These FC changes were spatially correlated with serotonergic (5HT1a, 5HT4, SERT) and dopaminergic (D1, D2, DAT) receptor distributions (p < 0.05, FDR corrected). Widespread cerebral hypometabolism in temporoparietal and frontal regions was spatially correlated with serotonin, dopamine, GABA, glutamate, and kappa-opioid systems (p < 0.05, FDR corrected). The FC of BF and cerebral metabolic changes in AD show distinct spatial correspondence with specific neurotransmitter systems, highlighting the crucial involvement of serotonin and dopamine in AD pathophysiology.

ABSTRACTBackgroundEarly brain injury after subarachnoid hemorrhage (SAH) involves oxidative stress and ferroptosis. Sestrin2 (SESN2) regulates redox homeostasis, but its role in SAH‐induced ferroptosis remains unclear.MethodsSAH was induced by internal carotid puncture; HT22 cells were hemin‐treated. We assessed neurological deficits, brain edema, BBB integrity, iron levels, mitochondrial ultrastructure, and ferroptosis and signaling proteins by Western blot and immunofluorescence. SESN2 function was probed using knockdown, recombinant human SESN2 (rh‐SESN2), and pathway inhibitors.Resultsrh‐SESN2 improved neurological outcomes, attenuated iron accumulation, and preserved mitochondrial morphology after SAH. In HT22 cells, rh‐SESN2 increased viability, decreased ROS and MDA, and partially restored SOD activity. rh‐SESN2 upregulated GPX4, SLC7A11, and Nrf2 and its nuclear translocation, whereas SESN2 knockdown exacerbated ferroptosis and reduced these proteins. Mechanistically, SESN2 activated AMPK and upregulated PGC1α, facilitating Nrf2 nuclear translocation and inducing antiferroptotic proteins. Pathway inhibition established an AMPK/PGC1α/Nrf2 hierarchy: AMPK inhibition suppressed PGC1α and Nrf2 activation, PGC1α inhibition reduced Nrf2 translocation, and ML385 abrogated SESN2's protective effects.ConclusionSESN2 activates AMPK, which in turn upregulates PGC1α and promotes Nrf2 nuclear translocation, ultimately inhibiting neuronal ferroptosis after SAH. Targeting this AMPK/PGC1α/Nrf2 axis may provide a novel therapeutic approach for post‐SAH neuroprotection.

The intermediolateral column (IML) serves as a crucial hub for sympathetic information processing between the brain and peripheral organs, with its defining hallmark being the presence of cholinergic neurons expressing choline acetyltransferase (ChAT). Specifically, the IML of the lower thoracic cord plays a pivotal role in regulating abdominal metabolic and digestive viscera. However, little is known about the whole-brain neural connectivity targeting these lower thoracic IML cholinergic neurons, necessitating further investigation. Specific retrograde tracing virus was injected into the lower thoracic IML of ChAT-Cre transgenic mice expressing Cre in the cholinergic neurons. After the virus has fully expressed, brain and spinal cord sections were prepared for whole-brain fluorescence imaging and quantitative analysis. We found that virally labeled neurons were detected in 40 brain regions of ChAT-Cre mice, encompassing the telencephalon, diencephalon, and brainstem. Afferents were predominantly concentrated in 25 brainstem regions, with the pons providing the highest total number of afferents and the medulla offering the highest afferent density across both hemispheres. Although a small subset of regions exhibited strictly unilateral inputs or hemispheric preference, the overall projection pattern remained bilateral. Furthermore, our results revealed extensive projections to the IML from regions classically implicated in sympathetic outflow regulation and homeostatic control, including the paraventricular hypothalamic nucleus (PVN), lateral hypothalamic area (LH), and rostroventrolateral reticular nucleus (RVLM). In addition, inputs were also observed from motor-related regions, such as primary and secondary motor cortices (M1, M2), red nucleus (RN), and gigantocellular reticular nucleus (Gi), suggesting a potential anatomical basis for the central coupling of somatic motor and sympathetic functions. Our study provides a comprehensive whole-brain anatomical map of inputs to lower thoracic IML cholinergic neurons. This extensive supraspinal network, integrating classical sympathetic and homeostatic centers with motor-related regions, suggests a potential anatomical basis for the central coordination of somatic motor and autonomic functions.

The purpose of this study was to explore the molecular mechanism of circRNA mediated colonic hypersensitivity in rats with diabetes. Intraperitoneal injection of streptozocin female rats was used to induce Type 1 Diabetes Mellitus. A combination of molecular biology and behavioral approaches was used to investigate the role of circRbfox1 in the pathogenesis of colonic hypersensitivity in diabetic rats. A new circular RNA-Rbfox1, derived from the host gene encoding RNA-Binding Protein Fox1, as a mechanism of visceral pain is identified. We confirmed that circRbfox1 remarkably upregulated in T13-L2 dorsal root ganglions in rats with diabetes, and could interact with the RNA-binding protein HuC to promote its transition from the cytosol into the nucleus to promote the translation level of RBFOX1. In addition, the increased expression of Rbfox1 could further promote colonic hypersensitivity in diabetic rats by regulating the expression of Cav1.3. We conclude that circRbfox1 serves as pain regulator in diabetic colonic hypersensitivity and provides a potential therapeutic target in clinic.

Teriflunomide has been proven to be effective in the therapy of relapsing-remitting multiple sclerosis (RMS). In an approach to better elucidate the mode of action of teriflunomide in the central nervous system (CNS), we aimed here to clarify the role of teriflunomide on glial cells using an exvivo demyelination model. Organotypic cerebellar slice cultures (OSC) were cultivated from 10-day-old mice and left to fully myelinate for another 7 days. Demyelination was induced by lysolecithin (LPC) and was studied by immunohistochemistry against myelin proteins and electron microscopy. Glial cell responses were investigated by immunohistochemistry. Intra-glia interactions were studied using primary rodent glial cell cultures. Teriflunomide treatment did not affect developmental myelination but attenuated myelin degradation induced by LPC, as assessed by myelin basic protein and myelin oligodendrocyte glycoprotein immunoreactivity. During demyelination, teriflunomide treatment was associated with reduced microglial cell density and proliferation. Partial depletion of microglia using the CSF-1R inhibitor BLZ945 resulted in a similar preservation of myelin, supporting a functional association between microglial abundance and the extent of myelin loss in this model. Quantitative ultrastructural analysis further supported preserved myelin structures in teriflunomide-treated slices. Spontaneous remyelination was improved and enhanced numbers of oligodendrocytes were detected following teriflunomide treatment in OSC. However, direct cytoprotective/pro-proliferative effects of teriflunomide on oligodendroglia were not observed in primary glial cultures. There were also no indirect effects of teriflunomide-treated microglia on oligodendrocyte progenitor cells invitro. Teriflunomide exerts beneficial effects on myelin preservation and remyelination in an exvivo demyelination model, potentially through modulation of glial cell dynamics rather than direct effects on oligodendroglial cells.

Traumatic brain injury (TBI) is a leading global cause of disability and mortality, with blood-brain barrier (BBB) disruption exacerbating secondary injury. Transglutaminase 2 (TGM2), a multifunctional enzyme implicated in neuroinflammation and extracellular matrix remodeling, remains underexplored in TBI-related BBB dysfunction. This study elucidates the role of TGM2 in BBB disruption following TBI and explores its therapeutic potential in mitigating BBB damage. The controlled cortical impact (CCI) and oxygen-glucose deprivation (OGD) models were used to establish invivo and invitro TBI models in mice. The experimental approaches comprised RNA sequencing, Western blot analysis, RT-qPCR, immunofluorescence staining, and behavioral assessments. TGM2 expression peaked at 48 h after TBI, predominantly in brain endothelial cells, correlating with BBB disruption (reduced tight junction proteins, increased edema). TGM2 knockdown may attenuate MMP-9 via the IL-17 pathway, restoring BBB integrity. Invivo, TGM2 inhibition reduced Evans blue leakage, upregulated CLAUDIN-5/ZO-1, and improved motor coordination, balance, and spatial memory. TGM2 is a key molecule affecting the BBB after TBI. Inhibition of TGM2 can alleviate the blood-brain barrier and neurological deficits after TBI, acting through the IL-17-MMP-9 axis.