Mol Brain [JOURNAL]
Sun
200 papers
Genetically predicted CXCL16 expression is associated with Parkinson's disease risk and peripheral immune cell dysregulation: a two-sample mendelian randomization study.
Li Z, Yang R, Feng H … +2 more , Sun M, Liu H
Mol Brain · 2026 Jun · PMID 42381015 · Full text
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. PANoptosis, an integrated form of programmed cell death involving apoptosis, pyroptosis, and necr...
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. PANoptosis, an integrated form of programmed cell death involving apoptosis, pyroptosis, and necroptosis, has been implicated in neuroinflammation-related neurodegeneration. However, the roles of PANoptosis-related genes in PD remain unclear. METHODS: We performed two-sample Mendelian randomization (MR) using cis-eQTL instruments from the eQTLGen Consortium for 30 PANoptosis-related genes, with PD GWAS data from Nalls et al. 2019 as the outcome. Instrumental variables were selected using a hierarchical strategy, with genome-wide significant cis-eQTLs as primary instruments and a relaxed threshold applied only for genes with fewer than three independent SNPs. Sensitivity analyses included MR-Egger, weighted median, MR-PRESSO, MR-RAPS, and leave-one-out analyses. SMR/HEIDI testing and two-step MR mediation using 731 peripheral immune traits were also performed. RESULTS: Genetically predicted higher CXCL16 expression was associated with increased PD risk (OR = 1.115, 95% CI 1.060-1.173, p = 2.4 × 10), while higher FADD expression was associated with reduced PD risk (OR = 0.861, 95% CI 0.790-0.939, p = 7.1 × 10). CASP1 and IFI27 were nominally significant and considered exploratory. Sensitivity analyses were directionally consistent, although MR-Egger estimates were imprecise. SMR/HEIDI supported CXCL16. Exploratory mediation analysis identified 63/66 candidate immune mediators after FDR correction. CONCLUSION: These findings provide MR-based genetic evidence linking CXCL16 expression to PD risk, with exploratory mediation through peripheral immune phenotypes. The CXCL16-immune cell-PD axis warrants further experimental validation.
Endovascular stem cell therapy reconfigures post-stroke ER dynamics via GRP78/Atlastin/CHOP axis.
Kumari A, Yadav J, Godse P … +10 more , Karmarkar G, Dubey A, More A, Saha C, Ghosh B, Datta A, Barik A, Borah A, Yavagal DR, Bhattacharya P
Mol Brain · 2026 Jun · PMID 42351224 · Full text
The endoplasmic reticulum (ER) resident chaperon proteins require calcium for post-translational modifications and maintaining ER integrity. Post-stroke dysregulation of ER associated calcium homeostasis leads to altered...
The endoplasmic reticulum (ER) resident chaperon proteins require calcium for post-translational modifications and maintaining ER integrity. Post-stroke dysregulation of ER associated calcium homeostasis leads to altered ER dynamics and neurodegeneration. Previously, we have observed that post-stroke intra-arterial mesenchymal stem cells (IA-MSCs) administration renders neuroprotection and alleviates ER stress. Subsequently, the current study aims to investigate the role of IA-MSCs in modulating the post-stroke calcium homeostasis towards regulating ER dynamics. Male SD rats were administered with 1*10 IA-MSCs at 6 h following ischemic stroke. Behaviour and motor impairment were evaluated at day 1, 7, and 14. Biochemical, histopathological, protein, and gene expression studies were also performed using cortical brain tissues. IA-MSCs administration following ischemic injury led to reduced infarct size, oxidative stress, and improved functional outcomes. It also modulated the protein and gene expressions of atlastin, reticulon, climp63 responsible for changes in the ER morphology and dynamics as evident from molecular and histological studies. Additionally, a significant decrease in the level of GRP78 and calreticulin following IA-MSCs administration, suggesting the role of IA-MSCs in maintaining calcium homeostasis. Further, we have observed that IA-MSCs administration alleviated the ER-stress induced apoptosis as evident from the reduced gene and protein expression of CHOP. Thus, the study emphasizes the therapeutic potential of IA-MSCs in ischemic stroke towards regulating the calcium-mediated ER dynamics with its future possibility as one of the adjunctive therapies for ischemic stroke.
OptoHR fusion protein mimics β-arrestin-mediated membrane endocytosis of histamine H receptor in vitro.
Deng S, Zhou Z, Chen Z … +2 more , Zheng Y, Zhou J
Mol Brain · 2026 Jun · PMID 42323615 · Full text
OptoHR is an artificial fusion protein that combines the photosensitive elements of rhodopsin with the signaling domain of the histamine H receptor (HR), enabling light-controlled activation of downstream HR pathways. Al...
OptoHR is an artificial fusion protein that combines the photosensitive elements of rhodopsin with the signaling domain of the histamine H receptor (HR), enabling light-controlled activation of downstream HR pathways. Although our previous study demonstrated that OptoHR mimics the acute effects of HR activation on neuronal activity, whether this tool can also recapitulate the long-term receptor desensitization and internalization processes associated with prolonged HR activation remains unclear. In this study, primary cortical neurons and HeLa cells were employed to investigate the alterations in subcellular localization of OptoHR upon sustained photoactivation, with histamine-stimulated wild-type (WT) HR serving as a control. Furthermore, the role of β-arrestin in this process was explored. Time-lapse fluorescence imaging revealed that the number of puncta progressively increased over time following laser stimulation. Subsequent co-staining experiments with endosome marker EEA1 showed that 75.5% of light‑induced puncta were EEA1‑positive. Notably, the increase in OptoHR-positive vesicles within neuronal cells was attenuated by the β-arrestin inhibitor barbadin, a pattern consistent with the internalization observed in histamine-stimulated WT HR. Collectively, our findings demonstrate that OptoHR recruits β-arrestin signaling upon sustained optical stimulation, thereby recapitulating HR desensitization dynamics. This establishes OptoHR as a useful tool for dissecting the spatiotemporally specific functions of HR, including both its acute signaling and long-term β-arrestin-related mechanisms.
Generating models for isoform-specific PKM-KIBRA interactions with BIFC, stabilization and AlphaFold 3.
Amoah E, Dunn TW, Ferguson L … +4 more , Betriu Diaz K, O'Donnell C, Kremerskoten J, Sossin WS
Mol Brain · 2026 Jun · PMID 42321941 · Full text
The truncated constitutive active form of protein kinase C (PKC) called protein kinase M (PKM) plays a role in long-term memory maintenance in vertebrate and invertebrate models. Previously we have shown that the Aplysia...
The truncated constitutive active form of protein kinase C (PKC) called protein kinase M (PKM) plays a role in long-term memory maintenance in vertebrate and invertebrate models. Previously we have shown that the Aplysia Kidney/Brain protein (KIBRA) stabilizes the atypical PKM Apl III, but not the classical PKM Apl I in Aplysia neurons. Expression of Aplysia KIBRA with changes in the proposed atypical PKM binding site does not stabilize PKM Apl III and erases forms of plasticity supported by PKM Apl III. Here, we have examined biomolecular fluorescence complementation (BIFC) between KIBRA variants and PKM Apl III in Aplysia neurons. These KIBRA variants include: the KIBRA with changes in the proposed atypical binding site noted above; a splicing variant that stabilizes PKM Apl I, but not PKM Apl III; and several mutations identified in mammalian WW and C2 domain containing protein 3 (WWC3, a member of the chordate-specific expansion of the KIBRA family) associated with cancer or neurodevelopmental disorders. Surprisingly, we find that some KIBRA variants show BIFC with PKM Apl III but do not stabilize PKM Apl III. We used models of protein-protein interactions (AlphaFold 3) to gain insights into the discrepancy between BIFC and stabilization of PKMs by KIBRA and KIBRA variants and suggest a model where stabilization is linked to stable inhibition of PKMs by KIBRA.
Therapeutic potential of AdipoRon in cognitive, depressive, and anxiety disorders: a systematic review and meta-analysis.
Gheibi FS, Hosseini L, Kalejahi P … +3 more , Dastgiri S, Shafiee-Kandjani AR, Noorazar SG
Mol Brain · 2026 Jun · PMID 42321855 · Full text
Rising cases of cognitive disorders, depression, and anxiety underscore the need for new treatments, given the limited effectiveness and side effects of current options. AdipoRon targets adiponectin receptors and shows p...
Rising cases of cognitive disorders, depression, and anxiety underscore the need for new treatments, given the limited effectiveness and side effects of current options. AdipoRon targets adiponectin receptors and shows promise for protecting the brain, reducing inflammation, and supporting metabolism. This review examines preclinical data to determine whether AdipoRon consistently improves mood and cognitive function and to identify the underlying neurobiological pathways. We conducted a comprehensive literature search using PubMed, Embase, Web of Science, and Scopus, with no time limit, up to August 30, 2025. The quality of the selected studies was evaluated using the Collaborative Approach to Meta-Analysis and Review of Animal Studies (CAMARADES) checklists and the SYRCLE risk of bias tool. The studies found that AdipoRon treatment significantly reduced immobility in the forced swim test and had a significant anxiolytic effect in the open field test, especially in chronic unpredictable mild stress models. It also improved recognition memory in the novel object recognition test in models of Alzheimer's and Parkinson's diseases. Additionally, AdipoRon increased the expression of synaptic proteins, such as synaptophysin and PSD-95, in rodent models of these diseases. It also modulated the production of inflammatory cytokines. This review establishes AdipoRon's capacity to resolve depressive, anxious, and cognitive deficits in rodent models. Because the meta-analyses were based on a limited number of studies and substantial heterogeneity was observed across studies, the findings should be interpreted with caution. However, further well-designed preclinical and clinical investigations are essential to confirm these findings.
PAK1 expression protects cellular and behavioral defects in animal models of Parkinson' s disease.
Kim JE, Lee K, Kim HJ … +2 more , Oh WJ, Kim HK
Mol Brain · 2026 Jun · PMID 42277926 · Full text
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Although various therapeutics have been developed, no disease-modifying treatment has been established to date. Recent studies h...
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Although various therapeutics have been developed, no disease-modifying treatment has been established to date. Recent studies highlight critical roles of p21-activated protein kinases (PAKs) in the pathogenesis of PD. To investigate the potential of PAK1 as a therapeutic target for PD, we examined the effects of a constitutively active form of PAK1 (PAK1-T423E; PAK1-CA) in animal models. An animal model of PD, recapitulating α-synucleinopathy was established by injecting human α-synuclein preformed fibrils into the biceps femoris of M83 A53T homozygous mice. PAK1-CA expression significantly ameliorated behavioral deficits and prevented the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Moreover, PAK1-CA expression increased the survival rate, although it was not significant in this model. In contrast, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxin model, PAK1-CA expression significantly improved survival rates compared to the GFP-expressing control group. These findings suggest a potential role for constitutively active PAK1 in contributing to the neuroprotection of dopaminergic neurons, which may imply its utility as a candidate for gene therapy.
Diabetes reprograms brain and systemic immune landscapes to impair repair after injury.
Lee KA, Kim SY, Lee JS … +5 more , Yang H, An J, Park SM, Lee EJ, Joe EH
Mol Brain · 2026 Jun · PMID 42265567 · Full text
Diabetes is a major risk factor for poor outcomes following brain injury, yet the underlying mechanisms remain incompletely understood. Using stereotaxic ATP injection into the striatum combined with 9.4T MRI, we found t...
Diabetes is a major risk factor for poor outcomes following brain injury, yet the underlying mechanisms remain incompletely understood. Using stereotaxic ATP injection into the striatum combined with 9.4T MRI, we found that diabetic mice exhibited larger initial lesions and delayed recovery compared to controls, even after matching for initial lesion size. Transcriptomic profiling of the intact diabetic brain revealed extensive gene expression changes before injury, with prominent downregulation of excitatory synaptic transmission and cytoskeletal organization pathways. RNA-seq of peripheral blood mononuclear cells (PBMCs) showed that diabetes altered systemic immune response, mitochondrial metabolism, and cell structure-related genes after injury. Infiltrating monocytes in diabetic brains exhibited dispersed distribution, and transcriptional remodeling characterized by upregulation of transporters and channels and downregulation of mitochondrial and prostaglandin biosynthesis genes. Furthermore, diabetes attenuated astrocyte activation, impairing monocyte distribution. These results reveal that diabetes induces pre-injury transcriptional reprogramming in both the brain and immune system, leading to heightened injury severity and impaired repair responses.
Leveraging single-cell and spatial omics for brain tumour insights to improve therapeutic strategies.
Roy S, Nassor M, Zahin F … +4 more , Chaudhry S, Odei KPK, Nkrumah-Boateng PA, Wireko AA
Mol Brain · 2026 Jun · PMID 42231441 · Full text
Single-cell and spatial omics (SPOs) technologies have advanced how healthcare physicians characterise brain tumours by enabling detailed understanding of their cellular architecture, functional states, and microenvironm...
Single-cell and spatial omics (SPOs) technologies have advanced how healthcare physicians characterise brain tumours by enabling detailed understanding of their cellular architecture, functional states, and microenvironmental dynamics. These approaches provide high-resolution detection of tumour heterogeneity and allow precise analysis of the brain tumour microenvironment. Their application has also led to the discovery of novel biomarkers used for early brain tumour detection, prognosis, and improved tumour stratification. Furthermore, integrative multi-omic analyses have revealed new therapeutic targets, clarified mechanisms of drug resistance, and uncovered molecular pathways underpinning treatment failure. By bridging cellular-level insights with spatial context, SPOs hold significant promise for advancing personalised diagnostics, predicting therapeutic response, and guiding the development of targeted interventions for brain tumours. Despite these advances, several limitations constrain the full translational potential of SPOs, including high experimental costs, substantial computational demands, lack of standardised protocols, and challenges in data integration and reproducibility. Addressing these barriers through scalable bioinformatic pipelines, consensus experimental frameworks, and cost-effective platforms remains critical for broadening accessibility and enabling clinical adoption.
The CDK4/6 inhibitor abemaciclib attenuates cognitive impairment and neuroinflammation via DYRK1A in human tau transgenic mice.
Lee HJ, Hoe HS
Mol Brain · 2026 Jun · PMID 42226198 · Full text
We recently demonstrated that abemaciclib treatment modulates cognitive function, Alzheimer's disease (AD) pathology, and neuroinflammatory responses in wild-type mice treated with lipopolysaccharide and in 5xFAD mice. I...
We recently demonstrated that abemaciclib treatment modulates cognitive function, Alzheimer's disease (AD) pathology, and neuroinflammatory responses in wild-type mice treated with lipopolysaccharide and in 5xFAD mice. In this study, we investigated the influence of abemaciclib treatment on neuroinflammation and cognitive function in 6- or 9-month-old PS19 mice, a P301S mutant tauopathy model. We found that abemaciclib administration suppressed microglial activation in 6-month-old PS19 mice, whereas astrocytic activation was partially attenuated in the entorhinal cortex but not in the hippocampus. In addition, abemaciclib treatment improved short-term and recognition memory and the dendritic spine formation in 6- and 9-month-old PS19 mice. More importantly, abemaciclib administration enhanced short-term and recognition memory in a DYRK1A-dependent manner in 6-month-old PS19 mice. Collectively, our results suggest that abemaciclib treatment alleviates neuroinflammatory responses and cognitive impairment through DYRK1A in 6- or 9-month-old human tau transgenic PS19 mice, highlighting how this multi-kinase-targeting drug could be leveraged for the treatment of neurodegenerative diseases.
Organoids as next-generation models for investigating intracranial tumours.
Roy S, Zahin F, Nkrumah-Boateng PA … +5 more , Chaudhry S, Nassor M, Kwarteng MFA, Owusu-Boampong AB, Wireko AA
Mol Brain · 2026 May · PMID 42218467 · Full text
Tumour organoids have emerged as important tools in brain tumour research, addressing long-standing limitations of conventional two-dimensional cultures, xenograft models, and genetically engineered mouse models. By pres...
Tumour organoids have emerged as important tools in brain tumour research, addressing long-standing limitations of conventional two-dimensional cultures, xenograft models, and genetically engineered mouse models. By preserving patient-specific genetic alterations, cellular diversity, spatial architecture, and key microenvironmental features, organoid systems enable more faithful modelling of tumour biology across a broad range of intracranial tumours, including gliomas, meningiomas, medulloblastomas, pituitary tumours, and craniopharyngiomas. Patient-derived organoids, genetically engineered models, co-culture systems, and bioprinted platforms have collectively advanced understanding of tumour initiation, invasion, heterogeneity, and therapeutic resistance, while offering clinically relevant systems for drug screening and personalised therapy prediction. Importantly, organoid models facilitate mechanistic interrogation of tumour-microenvironment interactions that are difficult to capture in other systems, including neural-tumour crosstalk, vascular niche formation, and immune modulation. Their compatibility with high-throughput screening and integration with emerging technologies, such as single-cell and spatial omics, CRISPR-based genome editing, microfluidics, and artificial intelligence, has further expanded their utility for functional genomics, biomarker discovery, and predictive modelling of treatment response. The development of large-scale organoid biobanks that represent diverse tumour subtypes and patient populations also provides critical infrastructure for reproducible research and collaborative precision oncology efforts. While challenges remain, including variability in culture protocols, incomplete immune and vascular representation, and barriers related to cost and technical complexity, ongoing methodological innovations are progressively enhancing the physiological fidelity and translational relevance of organoid systems. Overall, tumour organoids represent a promising interface between experimental research and clinical application in neuro-oncology, with significant potential to accelerate therapeutic discovery, refine patient stratification, and ultimately improve outcomes for individuals with brain tumours.
Blocking estrogen receptors restores surface mGluR5 but not downstream signaling in female APP/PS1 Mice.
Ibrahim KS, Albaker A, Abd-Elrahman KS … +1 more , Ferguson SSG
Mol Brain · 2026 May · PMID 42216035 · Full text
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disproportionately affects women. Deposition of β-amyloid (Aβ), a hallmark of AD pathology, disrupts metabotropic glutamate receptor-5 (mGluR5) re...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disproportionately affects women. Deposition of β-amyloid (Aβ), a hallmark of AD pathology, disrupts metabotropic glutamate receptor-5 (mGluR5) regulation of autophagy and accelerates disease progression in male AD mouse models. Yet, mGluR5 contribution to Aβ pathology is not observed in female AD mice, suggesting a distinct sex-selective profile. Given that estrogen receptors (ERs) form functional complexes with mGluR5 selectively in females, we assessed the role of ER activity in mGluR5 expression and downstream signaling in APPswe/PS1ΔE9 (APP/PS1) mice. We report here that mGluR5 cell surface expression is elevated in male but reduced in female APP/PS1 cortex relative to sex-matched wildtype controls, with total receptor expression remaining unchanged in both sexes. Treatment with the ER blocker, ICI 182,780, restored mGluR5 cell surface expression in female APP/PS1 mice but failed to rescue GSK3β and ULK1-regulated autophagy signaling. These findings indicate that male and female mGluR5 are embedded within intrinsically distinct signaling interactomes that are independent of ER regulation.
Npas4 regulates synaptic development in the patch/striosome compartment and early affective vocalization in neonatal mice.
Lee YH, Kuo HY, Chen SY … +3 more , Chang YN, Gerfen CR, Liu FC
Mol Brain · 2026 May · PMID 42216033 · Full text
Early vocal communication, such as isolation-induced ultrasonic vocalization (USV) in neonatal rodents, is critical for infant survival and represents a primary readout of early affective states. The patch/striosome comp...
Early vocal communication, such as isolation-induced ultrasonic vocalization (USV) in neonatal rodents, is critical for infant survival and represents a primary readout of early affective states. The patch/striosome compartment in the striatum has been proposed to serve as a limbic-motor interface integrating emotion and motivation. Developmentally, this compartment undergoes early maturation, during which activity-dependent transcription factors might enable the functional assembly of limbic-striosomal circuits to regulate infant vocal-motor behavior. Npas4, an activity-dependent early-response transcription factor, controls the developmental balance of excitatory and inhibitory synaptic activity. Here, we investigated how patch/ striosome compartment-expressing Npas4 shapes early synaptic development and neonatal vocalization. We found that Npas4 transcripts were transiently enriched in patch/striosomes at postnatal days (P) 4 and P8, before adopting a homogenous striatal distribution by P14. To investigate its biological function, we generated a patch/striosome-specific Npas4 conditional knockout. Anatomically, Npas4 deletion disrupted patch/striosomal synaptic balance, evidenced by a significant reduction in excitatory (Vglut1) and an increase in inhibitory (Vgat) presynaptic terminals. Behaviorally, acoustic and Markov-chain syntactical analyses of isolation-induced USVs revealed a hyper-vocal phenotype at P8, characterized by a significant increase in total USV call numbers and augmented temporal clustering of vocal bouts and sequences. Furthermore, acoustic analysis demonstrated a shift toward more complex syllable types. While the structure of global transition networks was preserved, Npas4 knockout mice exhibited an elevated sequence entropy rate, indicating greater moment-to-moment structural variability. Our study suggests that Npas4 shapes the development of limbic-striosomal circuits to provide top-down gating of early affective vocalization in neonates.
Environmental enrichment is associated with enhanced novel object recognition performance and an increased proportion of smooth endoplasmic reticulum-containing spines in the dentate gyrus of Septin3 mice.
Ageta-Ishihara N, Fuse N, Suzuki A … +2 more , Fukazawa Y, Kinoshita M
Mol Brain · 2026 May · PMID 42204717 · Full text
Septin-3 is a neuron-enriched member of the septin family, a group of GTP-binding cytoskeletal proteins. We previously reported that Septin-3 supports late-phase long-term potentiation (L-LTP)-induced entry of smooth end...
Septin-3 is a neuron-enriched member of the septin family, a group of GTP-binding cytoskeletal proteins. We previously reported that Septin-3 supports late-phase long-term potentiation (L-LTP)-induced entry of smooth endoplasmic reticulum (sER) into dentate gyrus (DG) spines, and that Septin3 mice show reduced numbers of sER-containing DG spines and reduced performance in 24-h novel object recognition. Environmental enrichment (EE) enhances experience-dependent plasticity, raising the possibility that EE could modulate cognitive performance and spine sER phenotypes in Septin3 mice. Here, we tested whether 4-week EE exposure enhances novel object recognition performance in Septin3 mice and whether such behavioral changes are accompanied by changes in the proportion of sER-containing DG spines. Male Septin3 mice were housed in standard housing (SH) or EE for 4 weeks and then subjected to novel object recognition. Septin3 mice exposed to EE showed significantly better performance than SH-housed Septin3 mice in the 24-h test session. Using serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstructions of the DG in Septin3 mice immediately after the novel object recognition test following 4 weeks of SH or EE housing, we found that EE increased synapse density and elevated the proportion of spines containing sER, whereas spine volume and postsynaptic density (PSD) area were not detectably altered. Together, these results show that EE enhances 24-h novel object recognition performance and is associated with an increased proportion of sER-containing DG spines in Septin3 mice following the novel object recognition test.
Sevoflurane ameliorates cerebral ischemia-reperfusion injury by modulating mitochondrial dynamics and attenuating apoptosis via Shh-YAP1 signaling pathway.
Peng L, Yang M, Liu J … +5 more , Yin T, Li J, Sun S, Zhu H, Wang S
Mol Brain · 2026 May · PMID 42169018 · Full text
Ischemia-reperfusion injury (IRI) is a critical issue in the prevention and treatment of ischemic stroke. Inhalational anesthetics have been proven to have neuroprotective effects and sevoflurane is currently the most co...
Ischemia-reperfusion injury (IRI) is a critical issue in the prevention and treatment of ischemic stroke. Inhalational anesthetics have been proven to have neuroprotective effects and sevoflurane is currently the most commonly used inhaled anesthetic in the clinic. However, the effects and underlying mechanism of sevoflurane on cerebral IRI have not been fully elucidated. In this study, oxygen-glucose deprivation model was established in primary mouse cortical neurons and HT22 cells, while the middle cerebral artery occlusion model was established in mice. Using laser speckle imaging, TTC staining, HE staining, Nissl staining, flow cytometry, calcium imaging and neurologic deficit scoring, we found that sevoflurane post-conditioning (SPC) significantly increased cerebral blood flow, reduced the infarct volume, alleviated neuronal pathological damage, promoted the survival of cortical neurons, reduced cell apoptosis, enhanced calcium responses and decreased the neurologic deficit scores after IRI. The results of RNA sequencing, Western blot, co-immunoprecipitation, TUNEL staining, immunofluorescence, transmission electron microscopy imaging, MPTP measurement, MMP detection, and ATP production measurement showed that the sonic hedgehog (Shh) signaling pathway crosstalk with Hippo-YAP signaling pathway, and the Shh-YAP1 pathway regulated mitochondrial dynamics and mitochondrial ultrastructure and function. In addition, SPC affected the phosphorylation and SUMOylation of dynamin-related protein 1 (Drp1), and there was an interaction between the phosphorylation and SUMOylation of Drp1. In conclusion, this study revealed that SPC might affect the phosphorylation and SUMOylation of Drp1 through the Shh-YAP1 signaling pathway, regulating mitochondrial dynamics, reducing cell apoptosis and ameliorating IRI. These findings offer new insights into the therapeutic strategies for ischemic stroke.
Tbx1 heterozygosity in the oligodendrocyte lineage shifts myelinated axon composition in the mouse fimbria without behavioral impairments.
Wells AM, Tanifuji T, Takano T … +6 more , Endo A, Kang G, Esparza M, Shi Q, Bhat MA, Hiroi N
Mol Brain · 2026 May · PMID 42163352 · Full text
Constitutive heterozygosity of Tbx1, a T-box transcription factor gene located within the 22q11.2 deletion region, results in behavioral deficits and altered composition of myelinated axons in the fimbria, together with...
Constitutive heterozygosity of Tbx1, a T-box transcription factor gene located within the 22q11.2 deletion region, results in behavioral deficits and altered composition of myelinated axons in the fimbria, together with reduced levels of an oligodendrocyte precursor cell (OPC) marker, in mice. However, the cellular origins of these effects and the extent to which axonal changes causally contribute to behavioral impairments remain unclear. We hypothesized that Tbx1 deficiency specifically within the oligodendrocyte lineage contributes to myelin and behavioral phenotypes. To test this hypothesis, we first demonstrated through in vitro siRNA knockdown that Tbx1 regulates both OPCs and mature oligodendrocytes. Subsequently, we assessed the impact of Tbx1 heterozygosity initiated in OPCs on behavioral and myelin phenotypes in male conditional PdgfrαCre;Tbx1 mice. These mice exhibited Cre-mediated recombination in Pdgfrα-expressing brain regions and in the OPC progeny within the fimbria. At one month of age, the mutants displayed a higher rate of spontaneous alternation at the longest inter-trial interval in the T-maze compared to their wild-type littermates-an effect that was dissipated at two months. No significant phenotypic abnormalities were observed in conditional PdgfrαCre;Tbx1 mice regarding neonatal ultrasonic vocalizations, social interaction, novel object approach, anxiety-like behavior (elevated plus maze), or open-field locomotion and thigmotaxis. Electron microscopic analysis revealed a compositional shift in myelinated axons within the fimbria of adult male mutants, characterized by an increased number of myelinated axons in the 300-800 nm diameter range and a decreased number in the ~ 1,200 nm and ~ 1,400 nm ranges, with myelin thickness remaining unchanged across diameters. These findings indicate that Tbx1 heterozygosity in the oligodendrocyte lineage leads to a selective shift towards smaller myelinated axons in the fimbria and a transiently higher level of capacity for working memory and cognitive flexibility. However, it does not replicate the full spectrum of myelination abnormalities or the broader cognitive and social deficits observed in constitutive Tbx1 heterozygotes, suggesting that Tbx1 deficiency in non-oligodendrocyte lineage cells may lead to altered myelination and neurodevelopmental behavioral impairments.
REST deficiency and neurogenic-to-gliogenic shift in down syndrome human cerebral organoids.
Huang T, Lim CT, Li W … +5 more , Fakurazi S, Mason JO, Cheah PS, Li Y, Ling KH
Mol Brain · 2026 May · PMID 42143345 · Full text
Down syndrome (DS) features impaired cortical neurogenesis and excess gliogenesis, yet the temporal regulatory events driving this imbalance remain unclear. Here, we combine multi-timepoint transcriptomic analyses from p...
Down syndrome (DS) features impaired cortical neurogenesis and excess gliogenesis, yet the temporal regulatory events driving this imbalance remain unclear. Here, we combine multi-timepoint transcriptomic analyses from publicly available datasets, network modelling, and machine-learning prioritization, with validation in isogenic human iPSC-derived cerebral organoids, to identify a discrete pathogenic window at 90 days in vitro (DIV 90). Across five developmental stages, REST target genes were preferentially dysregulated in DS organoids. WGCNA revealed a DS-associated module at DIV-90 that strongly overlapped with REST targets, and two orthogonal machine-learning approaches converged on six REST-regulated hub genes-CSTB, MCM3AP, PFKL, POFUT2, PRMT2, and RWDD2B. In trisomic organoids, REST mRNA and nuclear protein were markedly reduced at DIV-90, accompanied by diminished DCX expression and activation of NFIA and STAT3, suggesting a neurogenic-to-gliogenic fate transition. These findings suggest REST dysfunction as a potential temporal regulator of lineage imbalance in DS and highlight REST-linked networks as potential targets for early developmental intervention.
Modulation of BK-like potassium currents by ketamine in rat cochlear outer hair cells.
Yang X, Lu Y, Zhang X … +4 more , Xu Y, Lin J, Ji F, Zhao Q
Mol Brain · 2026 May · PMID 42116094 · Full text
Ketamine is widely used as an anesthetic agent, yet its cellular effects on the auditory system, particularly on cochlear outer hair cells (OHCs), remain incompletely understood. In this study, we investigated the electr...
Ketamine is widely used as an anesthetic agent, yet its cellular effects on the auditory system, particularly on cochlear outer hair cells (OHCs), remain incompletely understood. In this study, we investigated the electrophysiological effects of ketamine on isolated OHCs from young Sprague Dawley rats using whole-cell patch-clamp techniques. OHCs were acutely dissociated and exposed to ketamine at varying concentrations to evaluate its impact on membrane currents. Ketamine produced a dose- and voltage-dependent reduction in outward membrane currents, particularly at membrane potentials more positive than -36 mV. Pharmacological blockade with iberiotoxin and ion substitution experiments using intracellular Cs support that the ketamine-sensitive current is predominantly mediated by BK-like Ca-activated K channels. Ketamine had minimal effects on resting membrane potential and on voltage-activated K currents at hyperpolarized potentials, indicating selective modulation of depolarization-activated conductances. Acetylcholine (ACh)-evoked outward currents recorded at a depolarized holding potential (+ 3 mV) were not significantly altered by ketamine. Under these conditions, the measured current primarily reflects secondary Ca-activated K channel activity rather than direct α9α10 nicotinic receptor-mediated currents. Therefore, the present experimental design does not allow determination of whether ketamine directly affects α9α10 receptor function. These findings demonstrate that ketamine modulates BK-like potassium currents in OHCs and may influence cochlear electrophysiological function. However, the precise mechanism-whether through direct channel interaction or indirect modulation via calcium signaling-remains to be determined.
Oligomer logic of memory molecules.
Rudy JW
Mol Brain · 2026 May · PMID 42104413 · Full text
It has been 40 years since Francis Crick [1] noted the problem molecular turnover poses for maintaining memories and offered a general solution. The solution requires that the critical molecules must be replaced without...
It has been 40 years since Francis Crick [1] noted the problem molecular turnover poses for maintaining memories and offered a general solution. The solution requires that the critical molecules must be replaced without altering the overall structure of the complex. It is timely then that Todd Sacktor's group [2] has identified critical intermolecular interactions that satisfy Crick's requirement. Sacktor's early work identified the continuously active kinase, protein kinase Mzeta (PKMzeta) as a critical molecule for maintaining localized postsynaptic AMPA receptors that support long-term potentiation (LTP) and memory. More recent work revealed that PKMzeta forms heterodimers with the scaffolding protein KIBRA (KIbra BRAin) and preventing dimerization erased both LTP and memory. Even so, dimers degrade too fast to support long-lasting memories. Based on biophysical modeling, Sacktor's group with Harel Shouval reasoned that if KIBRA-PKMzeta heterodimers interact to form oligomers (such as hexamers), they can survive molecular turnover because as a dimer degrades it can be replaced by another. AlphaFold 3 predicted a site where the small molecule inhibitor, zeta-stat, would bind and disrupt oligomer formation. If so, then infusing zeta-stat into the hippocampus should erase long-term memory. This predicted outcome was observed. Thus, Crick's solution has been achieved. Oligomers formed from KIBRA-PKMzeta dimers allow degraded individual molecules to be replaced one at a time while maintaining their overall structure. This permits a continuous presence of PKMzeta where it interacts with AMPA receptors (through GluA2 subunits) and other molecules to ensure long-term memories endure.
VPS13B maintains lysosomal homeostasis through regulation of TFEB.
Lee SK, Park S, Yeom MY … +1 more , Lee JA
Mol Brain · 2026 May · PMID 42104376 · Full text
Cohen syndrome (CS) is a rare autosomal recessive neurodevelopmental disorder characterized by intellectual disability, microcephaly, retinal dystrophy, and neutropenia. We previously demonstrated that VPS13B mediates ph...
Cohen syndrome (CS) is a rare autosomal recessive neurodevelopmental disorder characterized by intellectual disability, microcephaly, retinal dystrophy, and neutropenia. We previously demonstrated that VPS13B mediates phosphatidylinositol 4-phosphate (PI4P) transport to promote mitochondrial fission. Here, we identify VPS13B as a regulator of lysosomal homeostasis. VPS13B knockout (KO) HeLa cells exhibited aberrant lysosomal distribution and reduction in LAMP1-positive lysosomes. Bulk RNA sequencing revealed coordinated downregulation of lysosome-related genes, including genes required for acidification and lysosome biogenesis, which was confirmed by quantitative RT-PCR. Consistent with these transcriptional changes, VPS13B KO significantly reduced the abundance of LysoTracker-positive acidic compartments. Induced neurons derived from CS patient iPSCs recapitulated the loss of acidic lysosomal compartments, supporting disease relevance. Mechanistically, VPS13B KO altered TFEB mRNA levels and modestly increased the basal nuclear-to-cytoplasmic (N/C) ratio of endogenous TFEB, but blunted its further increase upon Torin1 treatment. Together, these findings identify VPS13B as a regulator of lysosomal homeostasis and provide insight into how VPS13B deficiency may contribute to Cohen syndrome pathology.
An alternative inhibitory avoidance task for studying hippocampus-dependent spatial aversive memory in mice.
Wang H, Nomoto M, Murayama E … +2 more , Yamada-Nomoto K, Inokuchi K
Mol Brain · 2026 May · PMID 42071238 · Full text
In natural environments, animals must navigate to goals while avoiding potential danger, making adaptive route choice crucial for survival. However, behavioral tasks for quantitatively evaluating avoidance through route...
In natural environments, animals must navigate to goals while avoiding potential danger, making adaptive route choice crucial for survival. However, behavioral tasks for quantitatively evaluating avoidance through route choice during spatial navigation remain limited in mice, and the neural mechanisms underlying experience-dependent updating of route choice remain incompletely understood. Here, we established an air puff-based alternative inhibitory avoidance (AIA) task in mice to examine how aversive experience modifies a previously learned route preference. Water-restricted mice were first trained for 3 consecutive days to prefer a short path for obtaining water reward. They were then trained to avoid this preferred short path by receiving an air puff at its center when they passed through it. Mice that received only 3 air puffs showed lower avoidance behavior at the 6-h memory test. In contrast, mice that continued to receive air puffs until they rarely selected the short path during training showed significantly stronger avoidance at the 6-h test, and this avoidance was also observed at the 24-h test. We next examined whether hippocampal activity is required for retrieval of aversive memory in the AIA task. Chemogenetic suppression of hippocampal activity 30 min before the 6-h test impaired retrieval of aversive memory. Together, these results indicate that the AIA task provides a useful behavioral paradigm for assessing experience-dependent changes in route choice based on aversive events in mice, and that retrieval of this spatial aversive memory depends on hippocampal activity.
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