Brain Research Bulletin[JOURNAL]
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200 papers
N6-methyladenosine Demethylase ALKBH5 Mediates Remote Ischemic Postconditioning in Cerebral Ischemia-Reperfusion Injury by Regulating KLF4.
Wang A, Wu W, Mei Y … +5 more , Ying W, Zhou M, Liu L, Li C, Miao W
Brain Res Bull · 2026 Jul · PMID 42402316 · Publisher ↗
This study aimed to investigate the role of the m6A demethylase ALKBH5 in RIPostC against CI/R injury and its underlying regulatory mechanism. A rat model of CI/R was established using the MCAO method. Subsequently, RIPo...
This study aimed to investigate the role of the m6A demethylase ALKBH5 in RIPostC against CI/R injury and its underlying regulatory mechanism. A rat model of CI/R was established using the MCAO method. Subsequently, RIPostC was performed to evaluate its therapeutic potential against CI/R injury. The effects of overexpressing ALKBH5 and KLF4 on CI/R injury were also examined in the rat model. A cellular model of CI/R was established by inducing OGD/R in PC12 cells. The effects of ALKBH5 and KLF4 on cellular function in the CI/R model were investigated, and the specific regulatory role of ALKBH5 in the mA modification of KLF4 was elucidated. The mRNA expression of ALKBH5 and KLF4 in acute ischemic stroke patients and healthy individuals was measured by RT-qPCR. The results demonstrated that ALKBH5 and KLF4 expression was decreased in acute ischemic stroke patients, as well as in CI/R rats and OGD/R-induced cells. RIPostC treatment alleviated MCAO-induced neurological deficits, reduced cerebral infarct volume, apoptosis, and inflammatory cytokines levels. Furthermore, RIPostC upregulated the expression of ALKBH5 and KLF4 in CI/R rats. Overexpression of ALKBH5 and KLF4 further enhanced the therapeutic efficacy of RIPostC in CI/R rats. Overexpression of ALKBH5 and KLF4 alleviated OGD/R-induced cellular injury. Mechanistically, overexpression of ALKBH5 upregulated KLF4 expression by promoting m6A demethylation of KLF4 mRNA. In conclusion, overexpression of ALKBH5 upregulates KLF4 by promoting mA demethylation modification, thereby attenuating CI/R injury.
Expression of concern: "Effect of perioperative preemptive analgesia on hippocampal GABAA receptor α1/α5 balance in aged mild cognitive impairment rats" [Brain Res. Bull. 237 (2026) 111811].
Brain Res Bull · 2026 Apr · PMID 42389804 · Publisher ↗
Abstract loading — click title to view on PubMed.
Ubiquitination in ischemic stroke: Molecular mechanisms and therapeutic implications.
Zhang K, Ruan X, Chen Z … +4 more , Wang S, Hu B, Wen Z, Wang H
Brain Res Bull · 2026 Jul · PMID 42386007 · Publisher ↗
Ischemic stroke is an acute cerebrovascular syndrome caused by a precipitous reduction or interruption of cerebral blood flow. Its pathophysiology involves the sequential activation of energy failure, excitotoxicity, oxi...
Ischemic stroke is an acute cerebrovascular syndrome caused by a precipitous reduction or interruption of cerebral blood flow. Its pathophysiology involves the sequential activation of energy failure, excitotoxicity, oxidative stress, neuroinflammation, and multiple cell death programs. As a pivotal post-translational modification, ubiquitination deeply participates in post-ischemic remodeling of proteostasis by controlling the stability, subcellular localization, and signaling activity of substrate proteins. Accumulating evidence indicates that the ubiquitin-proteasome system (UPS) and deubiquitinase networks undergo pronounced time- and cell type-dependent changes after ischemic stroke and exert bidirectional effects on cell death, neuroinflammation, mitochondrial quality control, synaptic remodeling, and blood-brain barrier homeostasis. On the one hand, specific E3 ubiquitin ligases or deubiquitinases can restrain inflammatory amplification, facilitate the clearance of damaged proteins, and preserve mitochondrial homeostasis. On the other hand, aberrant or imbalanced ubiquitination can exacerbate oxidative injury, mitochondrial dysfunction, and neuronal loss. Although targeting ubiquitination pathways has shown therapeutic promise, substantial heterogeneity across ubiquitin chain types, cell populations, and disease stages continues to constrain clinical translation. This review therefore summarizes the global response, molecular mechanisms, and interventional prospects of the ubiquitination network after ischemic stroke, with the aim of providing a theoretical basis for precision therapies targeting the UPS/DUB axis.
Corrigendum to "Peripheral to central: Exploring the neural, endocrine, and immune pathways of the gut-brain axis in postoperative neurocognitive dysfunction" [Brain Res. Bull. 242 (2026) 111975].
Cao R, Shi Z, Ou W … +1 more , Liu Z
Brain Res Bull · 2026 Jun · PMID 42373424 · Publisher ↗
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GLUT1-driven glycolytic reprogramming in microglia promotes neuroinflammation and cognitive deficits in sepsis-associated encephalopathy.
Guo H, Li H, Han H … +5 more , Wei Y, Liu S, Han K, Zhai H, Dong S
Brain Res Bull · 2026 Jun · PMID 42372832 · Publisher ↗
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a severe neurological complication driven by microglial neuroinflammation. Proinflammatory microglial activation requires glycolytic reprogramming, but whether GLUT1...
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a severe neurological complication driven by microglial neuroinflammation. Proinflammatory microglial activation requires glycolytic reprogramming, but whether GLUT1 governs this process in SAE remains unclear. METHODS: In vitro, LPS-stimulated BV2 microglia were transfected with siRNA targeting GLUT1 or GLUT3. Glucose uptake (2-NBDG), glycolytic flux (ECAR, lactate), mitochondrial respiration (OCR), glycolytic enzyme expression (HK2, PFKFB3, PKM2, LDHA), and inflammatory cytokine release were assessed. In vivo, SAE was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Hippocampal GLUT1 knockdown was achieved via stereotactic lentivirus injection. Cognitive function, neuronal damage, neuroinflammation, cerebral lactate/ATP levels, and glycolytic protein expression were evaluated. RESULTS: LPS significantly upregulated GLUT1, but not GLUT3, in BV2 cells. GLUT1 knockdown markedly suppressed LPS-enhanced glucose uptake, ECAR, lactate production, and expression of HK2, PFKFB3, PKM2, and LDHA, while restoring OCR and reducing TNF-α, IL-1β, and IL-6 secretion. GLUT3 knockdown showed no such effects. In SAE mice, hippocampal GLUT1 expression was increased. Hippocampal GLUT1 knockdown ameliorated cognitive deficits, attenuated hippocampal neuronal loss and Nissl body damage, reduced cerebral inflammatory cytokines and lactate, restored ATP content, and abrogated CLP-induced upregulation of glycolytic enzymes. CONCLUSIONS: GLUT1 is a critical metabolic checkpoint driving microglial glycolytic reprogramming and proinflammatory activation in SAE. Targeted GLUT1 knockdown in microglia alleviates neuroinflammation and cognitive impairment in experimental SAE models. These findings provide a proof-of-concept that metabolic checkpoint targeting may counteract microglial pro-inflammatory activation.
Spinal astrocytes hardly proliferate following peripheral nerve injury: Evidence from adult Aldh1l1-GFP reporter mice.
Deng YT, Liu QY, Zheng XJ … +3 more , Bai XH, Zeng JT, Jiang BC
Brain Res Bull · 2026 Jun · PMID 42372679 · Publisher ↗
Peripheral nerve injury (PNI) induces neuroinflammatory responses in the spinal cord that contribute to neuropathic pain. While microglial proliferation is a well-established feature of this process, whether spinal astro...
Peripheral nerve injury (PNI) induces neuroinflammatory responses in the spinal cord that contribute to neuropathic pain. While microglial proliferation is a well-established feature of this process, whether spinal astrocytes undergo proliferation after PNI seems to be controversial. In this study, we examined astrocytic proliferative responses using Aldh1l1-GFP transgenic mice subjected to spinal nerve ligation (SNL), combined with immunohistochemical and transcriptomic analyses. SNL elicited a temporally organized glial reaction, characterized by early microglial reactivity followed by delayed astrocytic reactivity marked by increased GFAP expression. Despite pronounced astrocytic reactivity, the number of Aldh1l1-GFP⁺ astrocytes in the spinal dorsal horn remained unchanged across all examined time points, and only negligible colocalization with proliferation markers (Ki67 and EdU) was detected. Consistently, transcriptomic analyses revealed extensive astrocyte-associated transcriptional reprogramming without activation of cell-cycle gene programs after PNI. Minimally proliferative astrocytic responses were observed in additional cranial nerve injury model, partial infraorbital nerve transection (pIONT), in which proliferative responses in medullary dorsal horn were also restricted to microglia. Together, these findings demonstrate that spinal or medullary astrocytes respond to PNI with minimal proliferation (rare colocalization with proliferation markers) and primarily through reactive remodeling rather than cell division, providing direct evidence addressing previous inconsistencies and highlighting astrocytic functional plasticity as a key mechanism contributing to neuropathic pain.
Shared neural mechanisms of trait mindfulness and hypnotic susceptibility: A scoping review toward a unifying predictive coding framework.
Chen Q, Zhang Y, Liu C … +3 more , Fu Y, Gan Q, Chen Z
Brain Res Bull · 2026 Jun · PMID 42364853 · Publisher ↗
BACKGROUND: This scoping review systematically compares the neural mechanisms underlying trait mindfulness and hypnosis susceptibility, focusing on three key dimensions: brain region activation, electroencephalographic (...
BACKGROUND: This scoping review systematically compares the neural mechanisms underlying trait mindfulness and hypnosis susceptibility, focusing on three key dimensions: brain region activation, electroencephalographic (EEG) signals, and core brain networks. The aim is to elucidate potential shared mechanisms involved in conscious state modulation. METHODS: Through a comprehensive review of existing brain imaging and EEG studies, we found that both phenomena involve the prefrontal cortex and anterior cingulate cortex, enhanced theta and alpha EEG rhythms, and are closely related to the dynamic interaction between the salience network and the central executive network. RESULTS: These findings suggest their potential role in attentional regulation. Guided by the theory of predictive coding for interoception, we propose an integrative framework: trait mindfulness and hypnosis susceptibility jointly influence cognitive processes and alter self-conscious states through differential regulation. Specifically, trait mindfulness enhances perceptual inference and metacognitive awareness, whereas hypnosis susceptibility facilitates the acceptance of high-precision prior cues (suggestions) and promotes active inference. CONCLUSIONS: This framework provides a unified perspective for understanding the foundation of the two constructs and identifies directions for future research and clinical translation (e.g., anxiety interventions).
Cerebellar gray matter volume alterations and metabolic associations stratified by disease duration in patients with type 2 diabetes.
Yue X, Dai Z, Diao Z … +2 more , Tan X, Qiu S
Brain Res Bull · 2026 Jun · PMID 42364298 · Publisher ↗
AIMS: To investigate cerebellar alterations and their associations with metabolic profiles across different disease durations in type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional study included 302 healthy c...
AIMS: To investigate cerebellar alterations and their associations with metabolic profiles across different disease durations in type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional study included 302 healthy controls and 513 T2DM patients. T2DM patients were stratified into three groups based on disease duration, which defined as T2DM-D1 (<5 years), T2DM-D2 (5-9 years), and T2DM-D3 (≥10 years). Cerebellar segmentation was performed using Spatially Unbiased Infratentorial toolbox. Generalized linear models and partial correlation analyses were used to assess cerebellar volume differences and metabolic associations in different duration stages. RESULTS: T2DM patients exhibited significant cerebellar atrophy (Cohen's d = -0.418 to -0.199). Duration-stratified analyses revealed distinct subgroup differences: the T2DM-D1 group had posterior-predominant atrophy (Cohen's d = -0.339 to -0.282), the T2DM-D2 group showed limited involvement, with only the left lobule X affected (Cohen's d = -0.436), and the T2DM-D3 group exhibited more widespread alterations, including lobules VIIIa, VIIb, X, IX, Crus I, and vermis IX (Cohen's d = -0.741 to -0.399). Cerebellar alterations were primarily associated with insulin and C-peptide levels in T2DM-D1, whereas they were more closely related to glycemic, renal, and lipid-related markers in T2DM-D3. CONCLUSIONS: This study demonstrates that cerebellar alterations in T2DM vary with disease duration, accompanied by distinct metabolic profiles, underscoring the importance of duration-based stratification for individualized assessment and management.
Research progress of depression and pain comorbidity: Animal model, mechanism, treatment strategy.
Li Q, Ren L, Tu K … +6 more , Zhang Z, Yang X, Li M, Jiang L, Wang S, Zhou J
Brain Res Bull · 2026 Jun · PMID 42349664 · Publisher ↗
Pain and depression comorbidity refers to a clinical condition in which patients experience both pain and depressive disorders. This condition is characterized by a high prevalence and complex underlying mechanisms and p...
Pain and depression comorbidity refers to a clinical condition in which patients experience both pain and depressive disorders. This condition is characterized by a high prevalence and complex underlying mechanisms and profoundly affects patients' quality of life. However, challenges such as therapeutic complexity and poor prognosis remain in clinical practice. This review systematically summarizes research progress in this field, including the development of animal models, potential pathogenic mechanisms, and therapeutic strategies. The animal models discussed include complete Freund's adjuvant (CFA) models, reserpine models, nerve injury models, chronic stress models, and combined models, each of which has distinct advantages and limitations. Evidence suggests that pain and depression comorbidity is associated with multiple pathological mechanisms, including hypothalamic-pituitary-adrenal (HPA) axis dysfunction, neuroinflammatory activation, and neurotransmitter imbalance. Current clinical treatment primarily adopts an integrated approach combining pharmacological interventions, psychotherapy, and physical therapy. This review aims to deepen the understanding of the mechanisms underlying pain and depression comorbidity and provide a foundation for developing novel therapeutic strategies and clinical diagnostic approaches, thereby improving patients' quality of life and reducing the disease burden.
Hypnosis reduces decoding accuracy of visual and auditory representations.
Zhang M, Li Y, Ma L … +2 more , Wang K, Li X
Brain Res Bull · 2026 Jun · PMID 42341850 · Publisher ↗
This study used event-related potentials (ERPs), time-frequency analysis, and multivariate pattern analysis (MVPA) to investigate how hypnosis modulates visual and auditory processing. Twenty-two highly hypnotizable part...
This study used event-related potentials (ERPs), time-frequency analysis, and multivariate pattern analysis (MVPA) to investigate how hypnosis modulates visual and auditory processing. Twenty-two highly hypnotizable participants performed an independent oddball task. Under the hypnotic suggestion of "seeing without perceiving, hearing without listening," behavioral results showed that hypnosis reduced target detection accuracy and prolonged reaction times in both modalities, while false alarm rates remained low. ERP analysis revealed no significant difference in the N100 component between hypnosis and wakefulness, but hypnosis attenuated the late cognitive evaluation reflected by the P300 component. MVPA further showed that hypnosis delayed the onset of neural decoding to 160 ms in the visual pathway and to 120 ms in the auditory pathway from a baseline of 80 ms, and also reduced the temporal stability of neural representations. Time-frequency analysis of the visual task indicated that in the wakeful state, target stimuli elicited stronger delta-band (1-4 Hz) power than distractors, whereas hypnosis significantly diminished this neural representational specificity. These findings suggest that when individuals internalize hypnotic suggestions as personal goals, top-down regulatory mechanisms may alter neural temporal dynamics, reduce representational specificity, and lead to more homogeneous neural coding patterns, thereby decreasing perceptual efficiency while retaining weak decodability. This study provides neurobiological evidence for the neural mechanisms underlying perceptual dissociation during hypnosis.
Microglial ferroptosis mediated neuroinflammation in central nervous system diseases.
Ren SX, Jia FJ, Zhu J … +3 more , Liu JR, Guo HD, Cui GH
Brain Res Bull · 2026 Jun · PMID 42341849 · Publisher ↗
Microglial ferroptosis has become an important pathological mechanism in studies of central nervous system (CNS) diseases. Rather than being viewed only as an endpoint of cell death, ferroptosis in microglia is increasin...
Microglial ferroptosis has become an important pathological mechanism in studies of central nervous system (CNS) diseases. Rather than being viewed only as an endpoint of cell death, ferroptosis in microglia is increasingly recognized as a process that links iron dyshomeostasis, lipid peroxidation, oxidative stress, and immune-inflammatory activation, thereby contributing to the sustained amplification of neuroinflammation. In this review, we summarize the molecular mechanisms by which microglial ferroptosis mediates neuroinflammatory responses, with a focus on iron homeostasis disruption, lipid peroxidation and ROS amplification, collapse of the GPX4-dependent antioxidant defense, mitochondrial ROS generation, and inflammasome activation. We further classify related CNS diseases into three categories according to disease course and pathological features: chronic neurodegenerative and demyelinating diseases, acute CNS injuries, and neuropsychiatric or systemic inflammation-related brain dysfunction. Within this framework, we compare the pathological significance of microglial ferroptosis across different disease contexts. We also discuss potential therapeutic strategies targeting iron homeostasis, lipid peroxidation, antioxidant defenses, inflammatory amplification networks, and microglia-specific delivery systems. Finally, we address current challenges in the field, including insufficient cell-type specificity, inconsistent detection criteria, disease-stage heterogeneity, and barriers to clinical translation. This review provides an integrated perspective on the mechanisms by which microglial ferroptosis drives neuroinflammation and highlights its potential relevance for precision intervention in CNS diseases.
BACH1 inhibition confers neuroprotection after subarachnoid hemorrhage through activation of the Nrf2 signaling pathway.
Zhang H, Zhang HR, Wang KW … +4 more , Wang WH, Pang C, Chen X, Zhang XS
Brain Res Bull · 2026 Jun · PMID 42341848 · Publisher ↗
Subarachnoid hemorrhage (SAH) remains one of the most severe forms of stroke, yet effective therapeutic options remain limited. The BTB domain and CNC homolog 1 (BACH1), a transcription factor widely distributed across m...
Subarachnoid hemorrhage (SAH) remains one of the most severe forms of stroke, yet effective therapeutic options remain limited. The BTB domain and CNC homolog 1 (BACH1), a transcription factor widely distributed across mammalian tissues, has been implicated in regulating diverse cellular functions. Nevertheless, its role in early brain injury after SAH remains incompletely understood. In this study, we found that BACH1 expression rose rapidly and peaked at 24 h after SAH. Both neurons and microglia exhibited detectable BACH1 expression. Silencing BACH1 with siRNA markedly alleviated neuroinflammation and oxidative stress, and improved neurological performance. Additionally, BACH1 suppression shifted microglial phenotypes by diminishing the M1 response and enhancing M2 polarization. Further analysis revealed that inhibiting BACH1 activated the Nrf2-dependent pathway, whereas Nrf2 depletion with ML385 diminished the protective effects associated with BACH1 knockdown. Collectively, these results identify BACH1 as a promising candidate for alleviating brain damage associated with SAH.
Edaravone attenuates ACSL4-dependent ferroptosis in spinal motor neurons following cardiac arrest in rats.
Lee J, Lee SH, Kim R … +5 more , Sabuj MSS, Tae HJ, Thi Mai H, Han SC, Park BY
Brain Res Bull · 2026 Jun · PMID 42341847 · Publisher ↗
The contribution of acute spinal motor neuron injury following cardiac arrest (CA) remains poorly understood. This study aimed to investigate the role of ferroptosis in CA-induced spinal cord injury and to evaluate the n...
The contribution of acute spinal motor neuron injury following cardiac arrest (CA) remains poorly understood. This study aimed to investigate the role of ferroptosis in CA-induced spinal cord injury and to evaluate the neuroprotective effects of edaravone. Asphyxial CA was induced in rats for 5 min, followed by resuscitation. Edaravone was administered immediately after the return of spontaneous circulation (ROSC). At 24 h post-ROSC, The CA group exhibited significant hindlimb motor deficits and reduced survival rates. Histological analysis revealed selective injury of choline acetyltransferase (ChAT)-positive motor neurons in the lumbar spinal cord, accompanied by mitochondrial shrinkage and membrane rupture, which are characteristic of ferroptosis. Immunofluorescence demonstrated a selective upregulation of the pro-ferroptotic enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) specifically in ChAT-positive motor neurons, whereas glutathione peroxidase 4 (GPX4) expression remained relatively preserved. Edaravone treatment significantly improved neurological outcomes and survival, attenuated lipid peroxidation (evidenced by decreased malondialdehyde and preserved glutathione levels), and effectively suppressed ACSL4 upregulation in the motor neurons. Furthermore, edaravone mitigated neuroinflammation by reducing astrogliosis and microglial activation. These findings provide the first evidence that ACSL4-mediated ferroptosis is a key driver of acute spinal motor neuron injury following CA. Edaravone exerts potent neuroprotection by targeting this pathway, suggesting its therapeutic potential for ameliorating spinal cord injury in patients with CA.
Altered effective connectivity in internet gaming disorder and its predictive value for clinical severity: A spectral DCM study.
Guo Y, Lu G, Li W … +11 more , Wang X, Liu Y, Zhou S, Ma L, Mei B, Zhang M, Wei Y, Han S, Lang Y, Zhang Y, Wang W
Brain Res Bull · 2026 Jun · PMID 42341846 · Publisher ↗
BACKGROUND: To explore the functionally disordered regions and the directed effective-connectivity relationships among them in Internet Gaming Disorder (IGD), we adopted a meta-analysis-based Dynamic Causal Modeling appr...
BACKGROUND: To explore the functionally disordered regions and the directed effective-connectivity relationships among them in Internet Gaming Disorder (IGD), we adopted a meta-analysis-based Dynamic Causal Modeling approach. METHODS: We first performed a meta-analysis of existing rs-fMRI literature using Anisotropic Effect Size Signature Differential Mapping (AES-SDM) to localize the consistent regions with functional changes, which were then defined as regions of interest (ROIs). Next, we collected resting-state fMRI data and IGD-related scale scores from 54 IGD patients and 46 healthy controls, extracted the neuronal time series (BOLD time series) and input them into spectral Dynamic Causal Modeling (spDCM), and characterized between-group changes in effective connectivity (EC) between the ROIs through Parametric Empirical Bayes (PEB) analysis. RESULTS: In the IGD group, SFGdor_R showed reduced inhibitory effective connectivity with IFGopercular_L, IFGorb_L, and INS_R, and IFGorb_L also exhibited attenuated self-inhibition; in addition, an exploratory internally validated prediction analysis suggested that the IFGorb_L self-connection was associated with IAT severity. CONCLUSIONS: These findings indicate altered frontal effective-connectivity patterns consistent with reduced top-down regulatory signaling, rather than definitive evidence of a causal biological mechanism. The internally validated prediction of IAT severity was exploratory, explained a modest proportion of variance, and requires confirmation in larger longitudinal studies with external validation.
Cortical EEG network analysis reveals stage-specific rich-club reorganization across the patients with iRBD and PD.
Jiang X, Xu X, Feng Z … +6 more , Wang S, Cai J, Yu Y, Sun Y, Hu Y, Sun Y
Brain Res Bull · 2026 Jun · PMID 42336162 · Publisher ↗
Idiopathic rapid eye movement sleep behavior disorder (iRBD) has been recognized as a prodromal stage of Parkinson's disease (PD) - a well-known neurodegenerative brain disorder that is characterized by dysconnectivity....
Idiopathic rapid eye movement sleep behavior disorder (iRBD) has been recognized as a prodromal stage of Parkinson's disease (PD) - a well-known neurodegenerative brain disorder that is characterized by dysconnectivity. Elucidating how brain network topology evolves across the healthy controls (HCs)-iRBD-PD cohorts is crucial for clarifying disease-stage-related neurophysiological alterations. Using EEG source-space connectivity, we aimed to reveal the stage-specific spatio-spectral alterations of rich-club organization (the network's backbone architecture) across these three cohorts. Resting-state high-density EEG data was recorded from 104 participants (HCs/iRBD/PD = 32/33/39). Functional brain networks were estimated via source reconstructed and quantitatively compared across groups. A robust rich-club architecture was identified in all groups, with hubs primarily residing in parietal and temporal areas and exhibiting leftward dominance in the δ, θ, and β bands. Statistical comparisons revealed a significant graded enhancement of rich-club metrics (specifically local connection strength, global efficiency within feeder subnetwork, rich-club-feeder and feeder-local internetworks), predominantly in the θ band, across the three groups. This graded hyperconnectivity likely underscores a disease-stage-dependent reorganization, manifesting as a complex interplay between early compensatory responses and maladaptive pathological synchronization. These findings highlight EEG-based rich-club metrics as potential non-invasive biomarkers for characterizing the PD continuum and provide nascent insights into the neurophysiological mechanisms underlying PD-related disorders.
Lamivudine ameliorates neuropathology in 5×FAD mice via coordinated inhibition of the cGAS-STING pathway with enhancement of mitophagy.
Zhang Y, Zhang X, Huang J … +1 more , Sun Z
Brain Res Bull · 2026 Jun · PMID 42336161 · Publisher ↗
Alzheimer's disease is a neurodegenerative disorder for which there is currently no effective treatment available. Epidemiological and clinical evidence suggests that lamivudine, a nucleoside reverse transcriptase inhibi...
Alzheimer's disease is a neurodegenerative disorder for which there is currently no effective treatment available. Epidemiological and clinical evidence suggests that lamivudine, a nucleoside reverse transcriptase inhibitor, is associated with a reduced risk of Alzheimer's disease and shows potential in alleviating neuroinflammation. This study therefore aims to employ AD mouse models to further investigate the molecular mechanisms by which lamivudine ameliorates AD-related phenotypes. In this study, we showed that lamivudine administration inhibited cGAS-STING activation and attenuated mitochondrial damage in the 5 ×FAD mouse model, as supported by improved mitochondrial morphology and enhanced mitophagy. These changes were associated with improved spatial memory, alongside reduced neuronal apoptosis and synaptic loss. Our findings underscore the neuroprotective potential of lamivudine in AD via coordinated preservation of mitochondrial integrity and suppression of innate immune signaling, suggesting its promise for clinical translation in neurodegenerative disorders.
YTHDF1-modified neural stem cells confer neuroprotection and promote functional recovery following traumatic brain injury.
Zhang X, Wang J, Lu Y … +7 more , Xu F, Cheng X, Qin J, Tian M, Jin G, Zhang L, Li W
Brain Res Bull · 2026 Jun · PMID 42336160 · Publisher ↗
Traumatic brain injury (TBI) is a significant contributor to global morbidity and mortality, with limited effective treatment options available. Neural stem cells (NSCs) have shown great potential in the treatment of TBI...
Traumatic brain injury (TBI) is a significant contributor to global morbidity and mortality, with limited effective treatment options available. Neural stem cells (NSCs) have shown great potential in the treatment of TBI. However, the relatively low differentiation rate of neurons largely hinders the therapeutic efficacy of brain tissue repair. Here, we found that following TBI, the expression level of YTHDF1 in the hippocampus significantly increased and then decreased. Previous reports have also indicated that YTHDF1 mRNA is preferentially expressed in the mouse hippocampus, a key region involved in spatial learning and memory. Subsequently, we overexpressed or knocked down YTHDF1 in NSCs, and the results demonstrated that YTHDF1 promoted NSC proliferation and neuronal differentiation. In vitro, neuronal injury was induced by HO, and co-cultured with YTHDF1-modified NSCs to assess neuronal cell viability, apoptosis, and oxidative stress biomarkers, including the activities of superoxide dismutase (SOD) and catalase (CAT). YTHDF1-modified NSCs significantly reduced neuronal apoptosis and lowered oxidative stress levels. The expression of YTHDF1 in the hippocampus of TBI mice could rescue sensory, motor, and cognitive deficits, promoting neuronal survival. Mechanistically, YTHDF1 may be transcriptionally regulated by MYCN, and exert neuroprotective effects through the PI3K/AKT signaling pathway.
Association of APOE rs405509 (-219 T/G) with multidimensional cognitive function, brain structure, and resting-state networks in Chinese community-dwelling older adults.
Wang Z, Ding J, Hu X … +7 more , Bai J, Li J, Pang J, Ren L, Dong M, Wang L, Sun J
Brain Res Bull · 2026 Jun · PMID 42336159 · Publisher ↗
BACKGROUND: The effects of the APOE rs405509 (-219 T/G) polymorphism on cognition, lipid profiles, gray matter volume (GMV), and resting-state networks (RSNs) in older Chinese adults remain unclear. METHODS: A total of 1...
BACKGROUND: The effects of the APOE rs405509 (-219 T/G) polymorphism on cognition, lipid profiles, gray matter volume (GMV), and resting-state networks (RSNs) in older Chinese adults remain unclear. METHODS: A total of 123 community-dwelling elderly individuals were divided into G allele carriers (n = 68) and TT homozygotes (n = 55). Participants underwent neuropsychological assessments and lipid detection; 111 received MRI. Multivariate linear regression analyzed genotype-cognition associations, with stratified analyses by demographics and APOE ε4 status. Structural images were processed using CAT12 for GMV, and independent component analysis identified RSNs. RESULTS: In the full sample, G allele carriers showed worse performance in the Auditory Verbal Learning Test (AVLT), Rey-Osterrieth Complex Figure (ROCF) copy, and Boston Naming Test (BNT), with deficits remaining stable across stratified subgroups. However, in the neuroimaging subsample (n = 111), deficits remained significant only for AVLT and BNT, likely due to reduced statistical power. No significant group differences were found in lipid profiles or CAT12-derived GMV. Conversely, significant group differences emerged in resting state functional connectivity (rsFC) within auditory, language, and visual networks, where altered rsFC of auditory network positive correlated with cognitive performance. CONCLUSION: The APOE rs405509 G allele is associated with cognitive decline, particularly in memory and naming. These deficits appear independent of gross GMV alterations but may be mediated by disrupted functional network integration, suggesting functional changes might precede structural atrophy.
Projectomic profiles of calbindin D28K-expressing neurons in the mediodorsal thalamic nucleus of mouse.
Zhao TY, Zhu H, Zhang YN … +7 more , Ren X, Ye XN, Li F, Lei LJ, Zhang MM, Li YQ, Zhang FX
Brain Res Bull · 2026 Jun · PMID 42320642 · Publisher ↗
Expression of calbindin D28K (CB) and parvalbumin (PV) distinguishes matrix and core type thalamic neurons, respectively, in primates. Whether the nice correspondence of intracellular calcium binding proteins and matrix/...
Expression of calbindin D28K (CB) and parvalbumin (PV) distinguishes matrix and core type thalamic neurons, respectively, in primates. Whether the nice correspondence of intracellular calcium binding proteins and matrix/core neuron types translates to mouse remains unknown. Sixty reconstructed 3D mediodorsal thalamic nuclear neurons (MD neurons), defined by calb1, the gene encoding CB in mouse MD, were mapped onto Allen Mouse Brain Common Coordinate Framework (CCFv3). Most MD neurons (54/60) were isocortex-projecting ones, possessing collateral connections with caudate putamen (CP). Collectively, MD neuron ensemble linked 93 anatomically-defined brain structures/regions with their axons; and of these 93 axon-connected structures/regions, the single MD neurons had projection areas (receiving ≥ 2 axon terminals) ranging from 3 to 34 in number. Distinct projectomic profiles defined roughly 8 neuron subgroups, which differed from each other in composition of axon targets involving cortical and subcortical regions. Isocortical areas in prefrontal and sensorimotor cortices such as agranular insular cortex (AI), secondary motor cortex (MOs) and orbital cortex (ORB) etc., as well as structures of striatopallidal and olfactory systems such as CP, nucleus accumbens (ACB) and main olfactory bulb (MOB), among others, constituted the main axonal projection targets. Intriguingly, some proximal axon branches from over a dozen MD neurons (14/60) were seen to be spatially confined to MD, most frequently within dendritic territories of their source neurons, suggesting intra-MD innervation. For thalamocortical connectivity, most neurons (49/54, i.e., about 91%) had widespread, tangentially distributed axons terminating in layers 1-3 (L1-3) of multiple cortical areas. Thus, these neurons were of thalamic matrix type, per core-matrix-intralaminar classifying framework. Our morphometric data support the role of MD neurons for coordinated signal processing in networks integrating broad cortical areas, as well as subcortical structures, to fulfil emotion/cognition-related executive behaviors.
Lipocalin-2-mediated oligodendrocyte pyroptosis contributes to post-stroke secondary white matter injury.
Liu M, Huang Z, Hou C … +8 more , Xie Y, Li R, Wu M, Zhao Y, Li Y, Zhu W, Liu X, Ye R
Brain Res Bull · 2026 Jun · PMID 42314862 · Publisher ↗
Secondary white matter injury occurs in regions remote from the primary infarct after ischemic stroke, contributing to long-term neurological deficits. However, the mechanisms underlying oligodendrocyte loss in secondary...
Secondary white matter injury occurs in regions remote from the primary infarct after ischemic stroke, contributing to long-term neurological deficits. However, the mechanisms underlying oligodendrocyte loss in secondary white matter injury remain poorly understood. Using a distal middle cerebral artery occlusion (dMCAO) model in mice, we demonstrated that focal cortical ischemia induced significant oligodendrocyte pyroptosis in the contralateral corpus callosum. This pathological process was accompanied by increased interleukin-1β, interleukin-18, and canonical pyroptosis markers, including GSDMD, ASC, and caspase-1. Neutralization of LCN2 reduced pyroptotic signaling, preserved myelin integrity, and improved cognitive performance. Likewise, Lcn2 knockout mice exhibited attenuated oligodendrocyte pyroptosis and secondary white matter injury, whereas re-expression of LCN2 in astrocytes could neutralize the benefits of LCN2 ablation. These findings collectively suggest that LCN2 contributes to oligodendrocyte pyroptosis in secondary white matter injury and may represent a potential therapeutic target for ischemic stroke.
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