Neurobiology of Disease最新文献

{"title":"Network-wide morphometric organization deficits and transcriptomic correlates in Parkinson's disease with freezing of gait: A morphometric inverse divergence study","authors":"Xiuhang Ruan ,&nbsp;Xiaofei Huang ,&nbsp;Mengfan Wang ,&nbsp;Qian Zhou ,&nbsp;Riyu Guo ,&nbsp;Ting Wang ,&nbsp;Shuwen Bu ,&nbsp;Mengyan Li ,&nbsp;Xinhua Wei","doi":"10.1016/j.nbd.2025.107230","DOIUrl":"10.1016/j.nbd.2025.107230","url":null,"abstract":"<div><h3>Background</h3><div>Freezing of gait (FOG) in Parkinson's disease is an episodic locomotor arrest during rapid sensorimotor transitions (e.g., turning, gait initiation). Its macroscale cortical architecture and transcriptomic context remain unclear.</div></div><div><h3>Methods</h3><div>We constructed individual Morphometric Inverse Divergence (MIND) networks from T1-weighted MRI and derived regional weighted degree (WD). Regions were assigned to Yeo 7 functional systems and network-level WD was compared across PD with FOG (FOG), PD without FOG (nFOG), and healthy controls (HC) using ANCOVA. To assess discriminative value, logistic regression and ROC analyses were performed using network-level WD metrics and clinical covariates. Clinical relevance was tested within FOG using exploratory correlations with UPDRS-III and FOGQ. To relate WD alterations to cortical transcriptomics, partial least squares (PLS) regression linked the FOG vs nFOG WD t-map to the Allen Human Brain Atlas; significance was evaluated by surface-based spin permutations and gene-weight stability by bootstrap. Enrichment analyses were performed on PLS-significant genes.</div></div><div><h3>Results</h3><div>FOG showed widespread WD reductions in visual, somatomotor, dorsal/ventral attention, frontoparietal, and default-mode networks relative to nFOG and/or HC, whereas nFOG exhibited higher WD than HC in several networks. Logistic modeling demonstrated that WD in the somatomotor and frontoparietal networks significantly discriminated FOG from nFOG, and the combined model achieved the highest classification performance. Within FOG, exploratory correlations were observed between WD and UPDRS-III, whereas no associations were found with FOGQ. PLS identified a first component (PLS1) whose weighted gene-expression pattern aligned with the FOG vs nFOG WD map. Gene Ontology of the pooled PLS1-significant set highlighted synaptic signaling and neuronal projection/axon guidance along with cellular homeostatic programs (RNA/DNA metabolism, chromatin/cell-cycle regulation, membrane trafficking, stress responses). Cell-type analyses showed enrichment of positively weighted genes in excitatory and inhibitory neurons and oligodendrocytes, and of negatively weighted genes in excitatory and inhibitory neurons.</div></div><div><h3>Conclusions</h3><div>FOG is characterized by widespread reductions in morphometric network organization that co-vary with spatially patterned cortical gene expression. These multi-scale findings link macroscale network vulnerability to molecular context and nominate testable targets for mechanism-informed and therapeutic studies in PD-related gait freezing.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107230"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytes differentiated from patient iPSCs model the rare leukodystrophy MLC and uncover disease-linked maturation defects and Kir4.1 channel dysfunction","authors":"Angela Lanciotti ,&nbsp;Maria Stefania Brignone ,&nbsp;Chiara De Nuccio ,&nbsp;Sara Sposito ,&nbsp;Elena Sofia Caprini ,&nbsp;Marcello Belfiore ,&nbsp;Francesco Nicita ,&nbsp;Caterina Veroni ,&nbsp;Chiara Meloni ,&nbsp;Rosalba Carrozzo ,&nbsp;Teresa Rizza ,&nbsp;Chiara Aiello ,&nbsp;Jacopo Sartorelli ,&nbsp;Enrico Bertini ,&nbsp;Sergio Visentin ,&nbsp;Elena Ambrosini","doi":"10.1016/j.nbd.2025.107218","DOIUrl":"10.1016/j.nbd.2025.107218","url":null,"abstract":"<div><div>Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy caused by astrocyte dysfunction. Mutations in the <em>MLC1</em> gene, which encodes the astrocyte-specific membrane protein MLC1 represent the main cause. MLC is characterized by myelin vacuolation, subcortical cysts, and brain edema. Clinically, patients show motor impairments such as ataxia and spasticity, and epilepsy. Currently, the function of MLC1 and the molecular mechanisms underlying MLC remain poorly understood, limiting therapeutic development. This is especially relevant since symptom reversibility has been observed in some patients.</div><div>To date, functional studies have mainly relied on mouse models, which do not fully reproduce human pathology. To develop a more relevant disease model, we generated astrocytes from induced pluripotent stem cells (iPSCs) derived from fibroblasts of three healthy donors and three MLC patients.</div><div>Using molecular, biochemical, electrophysiological, and imaging approaches, we found that MLC astrocytes show impaired volume regulation, cytoplasmic vacuolation, and altered EGF receptor expression, consistent with prior MLC models. Notably, we also revealed endosomal alterations, increased proliferation, and abnormal expression of the critical astrocyte maturation markers EAAT1, GFAP, Cx43, AQP4, and Kir4.1, the latter causing impaired potassium currents in patient-derived cells.</div><div>These results provide the first evidence that MLC1 mutations alter astrocyte maturation and potassium homeostasis, potentially contributing to disease pathogenesis.</div><div>Our patient-specific iPSC-derived model offers novel insights into the molecular basis of MLC and highlights the role of MLC1 in astrocyte development. This platform represents a valuable tool for preclinical drug screening and supports the development of personalized therapeutic strategies for this rare leukodystrophy.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107218"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cortical and subcortical gray matter alterations link cerebral small vessel disease burden to motor slowing: A cross-sectional and longitudinal study","authors":"Pengcheng Liang ,&nbsp;Tao Chen ,&nbsp;Yena Che ,&nbsp;Nan Zhang ,&nbsp;Xinyue Zhang ,&nbsp;Na Wang ,&nbsp;Yuanyuan Wang ,&nbsp;Yiwen Chen ,&nbsp;Zhenyu Cheng ,&nbsp;Changhu Liang ,&nbsp;Lingfei Guo ,&nbsp;Meng Li","doi":"10.1016/j.nbd.2025.107220","DOIUrl":"10.1016/j.nbd.2025.107220","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral small vessel disease (CSVD) causes cortical atrophy and motor decline, but the specific cortical regions involved and their mediating role remain unclear. We aimed to determine whether regional cortical thickness mediates the association between CSVD severity and motor function.</div></div><div><h3>Methods and materials</h3><div><em>We</em> recruited 354 participants with CSVD (mean age 57.2 ± 11.4 years), of whom 55 had 16-month follow-up. Participants underwent 3.0 T MRI with 3D T1-weighted MPRAGE (1 mm³ isotropic) and motor testing (TUG and 3-m walk test). Cortical thickness was quantified using FreeSurfer v6.0 with longitudinal processing for follow-up scans. General linear models tested cross-sectional associations, linear mixed-effects models examined longitudinal effects, and mediation analysis assessed indirect effects.</div></div><div><h3>Results</h3><div>Significant negative associations were observed between cortical thickness and CSVD severity in the right insula, left rostral anterior cingulate cortex, and left lateral occipital cortex. Additionally, significant associations were found between cortical thickness at multiple time points in the right insula (β = 0.594, <em>P</em> = 0.024) and TUG test scores. The thickness of the right insular cortex mediated the relationship between CSVD severity and TUG performance (mean [SE] indirect effect, 0.085 [0.045]; 95 % CI, 0.015–0.197).</div></div><div><h3>Conclusions</h3><div>CSVD severity was associated with cortical thinning in specific cortical regions, and right insular cortical thickness levels were related to motor performance and partially mediated the association between CSVD severity and mobility impairment.</div></div><div><h3>Ethics approval and consent to participate</h3><div>All study procedures were approved by the Ethical Committee of the Institutional Review Board (IRB) of the Shandong Institute of Medical Imaging (2019–002). The study was conducted in accordance with the Declaration of Helsinki. All participants signed an informed consent form before the commencement of the study.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107220"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice","authors":"Tanveer Singh ,&nbsp;Emma Bridgeman ,&nbsp;Annie J. Baker ,&nbsp;Hayden A. Noblet ,&nbsp;Kang Yi Yang ,&nbsp;Sehong Kang ,&nbsp;Ki H. Lim ,&nbsp;Sarah S. Lee ,&nbsp;Nicolette M. Amundsen ,&nbsp;Yongjae Lee ,&nbsp;Paul R. Selvin ,&nbsp;Hyunjoon Kong ,&nbsp;Hee Jung Chung","doi":"10.1016/j.nbd.2025.107246","DOIUrl":"10.1016/j.nbd.2025.107246","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the leading cause of dementia, characterized by the deposition of amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Seizures have also emerged as a prevalent clinical feature of AD and are associated with <em>APOE4</em>, the major genetic risk factor of AD. However, the mechanism by which <em>APOE4</em> induces seizures and neuronal hyperexcitability is incompletely understood. We discovered that human <em>APOE4</em> targeted replacement mice showed increased seizure severity and seizure-induced death at 5.5–7 but not 2–3 months of age compared to <em>APOE3</em> mice using the kainic acid model of status epilepticus which preferentially arises from the hippocampus. While Tau burden alone did not alter seizure susceptibility in mice, <em>APOE4</em> together with Tau burden enhanced seizure severity in female mice. Notably, <em>APOE4</em> was associated with decreased hippocampal levels of sodium/potassium-ATPase, ATP-generating glycolytic enzymes, including phosphoglycerate kinase 1 (PGK1) and pyruvate kinase M, and ATP. While inhibition of Na⁺/K⁺- ATPase increased hippocampal neuronal activity, pharmacologically stimulating PGK1 with terazosin increased hippocampal ATP levels and decreased seizure severity in <em>APOE4</em> but not <em>APOE3</em> mice. Lastly, co-application of lactate dehydrogenase inhibitor sodium oxamate to prevent the conversion of pyruvate to lactate further enhanced hippocampal ATP levels and suppressed seizure severity in <em>APOE4</em> mice. Together, these findings suggest that reductions in hippocampal expression of sodium/potassium-ATPase and glycolytic enzymes may underlie <em>APOE4</em>-associated hippocampal hyperexcitability, revealing a novel mechanistic insight. Our results also demonstrate potent anti-seizure effects of terazosin, supporting the possibility of repurposing this anti-hypertension drug to mitigate seizure comorbidity in AD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107246"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The DNA methylation enzymatic machinery in substance use disorders: A systematic review","authors":"Margot Diringer ,&nbsp;Mathieu Bruggeman ,&nbsp;Pierre-Eric Lutz","doi":"10.1016/j.nbd.2025.107241","DOIUrl":"10.1016/j.nbd.2025.107241","url":null,"abstract":"<div><div>Substance use disorders (SUD) are chronic affections defined by similar symptoms across a variety of psychoactive drugs, including alcohol, cocaine, opioids, or methamphetamine. Epigenetic mechanisms such as DNA methylation represent key candidates to help explain the long-lasting effect of these drugs, as well as inter-individual variation in vulnerability. Here, we systematically reviewed current knowledge on the role of DNA methylation and the related enzymatic machinery in rodent models of SUD. Using a prospectively registered methodology, 99 articles were prioritized. A first set of studies manipulated the expression or activity of methylation or demethylation pathways. Depending on the brain region or drug considered, SUD-related behavioral and molecular manifestations were bidirectionally modulated, suggesting both pathogenic and protective roles for drug-induced methylomic plasticity. A second set of articles focused on candidate genes. Although significant heterogeneity across experimental models, brain regions or gene targets resulted in an absence of replicated findings, available data nevertheless support the notion that drugs of abuse trigger DNA methylation changes at discrete loci. Third, recent genome-wide studies have started to demonstrate that these drugs recruit widespread reprogramming. Strikingly, most adaptations occur outside promoter regions, highlighting an important challenge toward their functional interpretation. Finally, studies of drug exposure during gestation or adolescence suggest long-lasting consequences, with the potential for early intervention.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107241"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Context-specific expression quantitative trait loci dynamics uncover genetic pleiotropy in schizophrenia","authors":"Linyan Ye ,&nbsp;Zongrui Shen ,&nbsp;Qi Yang ,&nbsp;Xiaohui Wu ,&nbsp;Junping Ye ,&nbsp;Zhongwei Li ,&nbsp;Fu Xiong ,&nbsp;Siyao Che ,&nbsp;Cunyou Zhao ,&nbsp;Zhongju Wang","doi":"10.1016/j.nbd.2025.107236","DOIUrl":"10.1016/j.nbd.2025.107236","url":null,"abstract":"<div><div>Schizophrenia (SCZ) is a highly heritable psychiatric disorder, yet the mechanisms linking genetic risk to pathogenesis remain unclear. This study employs context-specific expression quantitative trait loci (eQTL) analysis using the BrainSeq Phase 1 dataset to dissect schizophrenia-associated regulatory dynamics. We identified widespread loss and gain of regulatory associations in schizophrenia group versus controls, alongside consistent eQTLs. A notable target gene switching phenomenon emerged, where specific SNPs regulated distinct genes across disease states, indicative of genetic pleiotropy mediated by competition for shared regulatory elements. Pleiotropic SNPs exhibited stronger schizophrenia associations, localized farther from target genes, and were enriched in repressive chromatin domains marked by H3K27me3. Transcription factor binding site analysis implicated EZH2, a polycomb repressive complex component, in mediating these regulatory shifts. Integration of schizophrenia-specific eQTLs with GWAS data via Mendelian Randomization prioritized risk genes like <em>ANKRD45</em>, which showed disease-context regulation and links to behavioral deficits. Overexpression of <em>ANKRD45</em> inhibited neuronal differentiation, whereas knockdown promoted it. This study presents context-specific eQTL dynamics as a crucial factor in the genetic landscape of schizophrenia, enhancing our understanding of non-coding risk variants and their role in disease susceptibility, and emphasizing the importance of utilizing context-specific eQTL data in elucidating the mechanisms of mental illness.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107236"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocyte-specific deletion of ceruloplasmin exacerbates oxidative stress and demyelination in the spinal cord in a murine model of multiple sclerosis","authors":"Karishma G. Kedari,&nbsp;Zachary Smith,&nbsp;Veronica T. Cheli,&nbsp;Jazmin G. Corral,&nbsp;Congying Wang,&nbsp;Pablo M. Paez","doi":"10.1016/j.nbd.2025.107249","DOIUrl":"10.1016/j.nbd.2025.107249","url":null,"abstract":"<div><div>Astrocytic iron metabolism is essential for maintaining central nervous system (CNS) homeostasis, particularly in the context of neurodegenerative and demyelinating disorders such as multiple sclerosis (MS). Disruption of this regulatory system can result in iron accumulation, heightened neuroinflammation, and demyelination, ultimately accelerating disease progression. Ceruloplasmin (Cp), a copper-containing ferroxidase enzyme highly expressed by astrocytes, plays a pivotal role in facilitating iron efflux and detoxification. However, the precise contribution of astrocytic Cp in demyelinating conditions is currently unknown. To investigate the role of astrocytic iron efflux and Cp in MS pathogenesis, we generated conditional knockout mice lacking Cp specifically in astrocytes (cKO) and induced experimental autoimmune encephalomyelitis (EAE), a widely accepted model of MS. cKO mice exhibited significantly worsened clinical outcomes, including earlier disease onset, increased peak severity, and higher cumulative disease scores during both acute and chronic phases. Histological analyses revealed enhanced microglial activation and lymphocyte infiltration in the spinal cord. These mice also showed elevated demyelination, oxidative stress, lipid peroxidation, and iron accumulation, particularly in spinal cord white matter regions. Similar pathological changes were observed in the cKO brain, with pronounced microglia activation, and immune cell infiltration particularly in the cerebellum. Collectively, these findings highlight a protective role for astrocytic Cp in mitigating neuroinflammation, oxidative damage, and demyelination during EAE. Elucidating the mechanisms by which astrocytic iron regulation influences MS progression may offer novel therapeutic targets focused on glial iron metabolism.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107249"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"4-Aminopyridine induced hyperpolarizing oscillations in pediatric human epileptic tissue are network-driven potassium currents that are abolished by activation of KCNQ2–5 (Kv7.2-Kv7.5) channels","authors":"J. Keenan Kushner ,&nbsp;Paige B. Hoffman ,&nbsp;Christine R. Brzezinski ,&nbsp;Brent R. O'Neill ,&nbsp;Todd C. Hankinson ,&nbsp;Charles C. Wilkinson ,&nbsp;Michael H. Handler ,&nbsp;Charles A. Hoeffer ,&nbsp;Allyson L. Alexander","doi":"10.1016/j.nbd.2025.107252","DOIUrl":"10.1016/j.nbd.2025.107252","url":null,"abstract":"<div><div>Epilepsy is one of the most common neurological disorders worldwide. Despite the availability of many anti-seizure medicines (ASMs), about 30 % of patients with epilepsy develop drug-resistant epilepsy. Unfortunately, the mechanisms of ictogenesis in patients with drug-resistant epilepsy remain to be elucidated. Here, we used 4-aminopyridine (4-AP) to study interictal-like oscillations in human epileptic neocortex. 4-AP is a voltage-gated potassium channel blocker commonly used to induce seizure-like activity in ex vivo brain slices. We observed that 4-AP induced neuronal bursting and robust slow, hyperpolarizing oscillations (HypOs) in layer 2/3 (L2/3) pyramidal neurons (PNs). Using paired recordings, we demonstrate that neuronal bursting and HypOs are synchronized between neighboring L2/3 PNs. We also determined that 4-AP-induced HypOs are potassium currents that were not mediated by GABA_A/_B receptors, NMDA receptors or AMPA receptors, or NKCC1 and KCC2 channels. Instead, HypOs are dependent on network activity and are impacted by gap junction blockade. Interestingly, HypOs were eliminated by activation, but not inactivation, of KCNQ2–5 (Kv7.2-Kv7.5) channels and were reduced via intercellular calcium chelation suggesting a role for calcium in KCNQ channel activation. Our results indicate 4-AP-induced HypOs are due to GABAergic interneuron synchronization, which leads to local extracellular potassium fluctuations without the need for GABA neurotransmission. Moreover, KCNQ2–5 channel activation can help stabilize potassium fluctuations, resulting in cessation of interictal-like events.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107252"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rewiring the OCD brain: Insights beyond cortico-striatal networks","authors":"Feyba Jijimon ,&nbsp;Sonam Fathima Mehak ,&nbsp;Zameel Mohammed ,&nbsp;Samir Kumar Praharaj ,&nbsp;Gireesh Gangadharan","doi":"10.1016/j.nbd.2025.107216","DOIUrl":"10.1016/j.nbd.2025.107216","url":null,"abstract":"<div><div>Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric condition marked by recurrent obsessions and compulsions. Over the years, research has primarily focused on the cortico-striato-thalamo-cortical (CSTC) circuit and its neurochemical disruptions as an ideal circuit system for the development of treatment strategies. However, <!--> <!-->recent findings from neuroimaging studies and rodent research have highlighted the involvement of additional brain regions and network-level dysfunctions that are functionally linked to the CSTC loop. These findings suggest that the sole emphasis on the CSTC circuit is insufficient to address the clinical heterogeneity of the disorder. A broader perspective would therefore better capture the disorder's clinical heterogeneity and diverse cognitive and emotional deficits. Here, we review growing evidence for the role of extra-CSTC brain regions and associated neurotransmitter interactions in OCD, outlining potential pathways for novel therapeutic strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107216"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optic nerve glymphatic system: Physiological characterization, ischemia-induced changes, and neuroprotection in ischemic optic neuropathy","authors":"Yuning Zhang ,&nbsp;Zidong Chen ,&nbsp;Yufan Jiang,&nbsp;Qiaona Ye,&nbsp;Jicheng Lin,&nbsp;Xinyi Zhang,&nbsp;Deling Li,&nbsp;Qinyuan Hu,&nbsp;Yixiao Fu,&nbsp;Liling Liu,&nbsp;Yangfan Yang,&nbsp;Minbin Yu","doi":"10.1016/j.nbd.2025.107214","DOIUrl":"10.1016/j.nbd.2025.107214","url":null,"abstract":"<div><div>The glymphatic system facilitates cerebrospinal fluid (CSF) circulation and metabolic waste clearance in the central nervous system. Its alterations and neuroprotective potentials in cerebral disorders also have been confirmed. However, its role in the optic nerve and involvement in optic neuropathy remain unclear. Here, we utilized the methodology combining fluorescent tracer injection with tissue clearing to visualize and quantify bidirectional glymphatic flow in the optic nerve in mice. Under physiological conditions, low-molecular-weight CSF tracers entered the optic nerve, while intraocular tracers were efficiently cleared via glymphatic pathway—both processes could be temporarily suppressed by using TGN-020. Acute ischemia induced by unilateral common carotid artery occlusion (UCCAO) enhanced CSF accumulation in the optic nerve and impaired intraocular solute clearance. Administration of TGN-020 30 min before ischemia induction reduced CSF accumulation during the ischemic phase and preserved retinal and optic nerve structure and function after ischemia. These findings further reveal a widespread, highly active glymphatic system in the optic nerve. Ischemia-induced dynamic changes of glymphatic function may contribute to optic nerve injury, while usage of TGN-020 during acute ischemia holds certain therapeutic potential in ischemic optic neuropathy.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107214"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}