Neurobiology of Disease最新文献

{"title":"Brain extracellular matrix implications in multiple neurological disorders revealed through a meta-analysis of transcriptional changes","authors":"Hagit Sadis ,&nbsp;Wote Amelo Rike ,&nbsp;David Peles ,&nbsp;Yara Hussein ,&nbsp;Tchelet Stern ,&nbsp;Irit Sagi ,&nbsp;Shani Stern","doi":"10.1016/j.nbd.2026.107263","DOIUrl":"10.1016/j.nbd.2026.107263","url":null,"abstract":"<div><div>Neurological disorders comprise a wide range of illnesses that may affect the central and peripheral nervous systems. Despite their diverse etiologies, many of these disorders present overlapping symptoms. In this study, we sought to generate hypotheses about shared biological mechanisms across neurodegenerative, neuropsychiatric, and neurodevelopmental disorders by analyzing gene expression data and identifying the most consistently dysregulated genes within and between these groups. To provide additional validation, we referenced Genome-Wide Association Studies (GWAS) data, which supported many of the transcriptomic analyses. Our exploratory analysis identified 31 differentially expressed genes shared across these neurological conditions, compared to healthy controls. These genes were significantly enriched in brain extracellular matrix (ECM) pathways, and dysregulation of ECM genes was evident separately in each of the three disorder categories. Notably, <em>SST</em> (Somatostatin), involved in modulating cortical circuits and cognitive function, was the most frequently reported dysregulated gene shared among the three categories of disorders. Furthermore, we observed consistent patterns suggesting that <em>GFAP</em> (glial fibrillary acidic protein), a key intermediate filament in mature astrocytes and a well-known marker of reactive astrocytes, and <em>IFITM3</em> (interferon-induced transmembrane protein 3), a crucial component of the first-line antiviral defense, were on average the most frequently reported genes among the studied disorders. Our study's core findings indicated that shared molecular features may exist across neurological disorders, emphasizing significant differences in the ECM of the central nervous system (CNS) between health and disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107263"},"PeriodicalIF":5.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934493","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":"A fresh view of the zona incerta: From circuit complexity to disease pathogenesis","authors":"You Wu ,&nbsp;Chen Chen ,&nbsp;Ningcan Ma ,&nbsp;Yiwen Zhang ,&nbsp;Jialin Si ,&nbsp;Xiaolin Zhang ,&nbsp;Shengxi Wu ,&nbsp;Yang Bai ,&nbsp;Jing Huang","doi":"10.1016/j.nbd.2026.107261","DOIUrl":"10.1016/j.nbd.2026.107261","url":null,"abstract":"<div><div>The zona incerta (ZI) is a diencephalic nucleus that houses neurochemically diverse neuronal populations. It serves as a critical integrative hub because of its bidirectional connectivity with multiple central nervous system regions. Emerging evidence highlights its essential roles in sensorimotor integration, affective processing, and behavioral regulation, thus positioning ZI neuromodulation as a key focus in systems neuroscience. Despite progress in characterizing its cytoarchitecture, molecular profiles, and network connectivity, a systematic understanding of the functional topography of ZI is yet to be achieved. This review utilizes current knowledge across three domains: 1) multimodal sensory processing, 2) emotional valence encoding, and 3) behavioral regulation and proposes an integrative framework to advance translational investigations of ZI-mediated neurophysiological mechanisms.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107261"},"PeriodicalIF":5.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917485","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":"Compensatory circuits in resting-state networks of epilepsy patients with left-sided hippocampus sclerosis","authors":"Silke Kreitz ,&nbsp;Angelika Mennecke ,&nbsp;Andreas Hess ,&nbsp;Sebastian Brandner ,&nbsp;Caroline Reindl ,&nbsp;Hajo Hamer ,&nbsp;Michael Schwarz ,&nbsp;Julie Rösch ,&nbsp;Arnd Dörfler","doi":"10.1016/j.nbd.2026.107264","DOIUrl":"10.1016/j.nbd.2026.107264","url":null,"abstract":"<div><div>Left-sided temporal lobe epilepsy (LTLE) causes bihemispheric dysfunctions in large networks and poor cognitive performance. To address possible compensatory mechanism in the resting-state we investigated the functional alteration in LTLE patients with histologically proven sclerosis in the left hippocampal CA1-field compared to healthy controls.</div><div>Eight drug resistant LTLE-patients and eight sex and age matched healthy controls were included in the study. The patients' hemispherical language and verbal memory function was determined by intracarotid amytal testing. Additional cognitive abilities and depression-like symptoms were collected using standard questionnaires. 7 T-fMRI of the resting-state and graph-theoretical whole-brain analysis including hippocampal subfields enabled sensitive detection of highly specific resting-state modulations without predefinition of regions of interest. Graph-theoretical network parameter were correlated with patients' cognitive performance and depression-like symptoms.</div><div>Functional connectivity of the hippocampus of LTLE patients was reduced interhemispheric and to the cortex. However, the whole-brain functional connectivity was strengthened, indicating a compensating mechanism for the above mentioned reduced hippocampus connectivity. The network's small-world index did not differ between groups. Graph-theoretical node-parameter were lateralized to the left hemisphere, reflecting interhemispheric neuroplasticity. A network component mediated by the left globus pallidus, the right inferior temporal gyrus and the left anterior corona radiata reinforced the functional connectivity between the impaired hippocampus and the bilateral cortex. The graph-theoretical resilience of the globus pallidus was correlated with improved depression-like symptoms. Therefore, we hypothesize, that the observed compensatory circuit reflects an allostatic adaptation of the brain to balance energy and disease-induced environmental stress rather than to improve cognitive impairments.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107264"},"PeriodicalIF":5.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917839","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":"Chemogenetic activation of hippocampal area CA2 promotes acute and chronic seizures in a mouse model of epilepsy","authors":"John J. LaFrancois ,&nbsp;Meghan Kennedy ,&nbsp;Monarchsinh Rathod ,&nbsp;Bina Santoro ,&nbsp;Christos Panagiotis Lisgaras ,&nbsp;Steven A. Siegelbaum ,&nbsp;Helen E. Scharfman","doi":"10.1016/j.nbd.2025.107256","DOIUrl":"10.1016/j.nbd.2025.107256","url":null,"abstract":"<div><div>Pyramidal cells (PCs) of hippocampal area CA2 exhibit increased excitability in temporal lobe epilepsy (TLE) and in mouse models of TLE. In epileptic mice, selective inhibition of CA2 PCs reduces chronic seizures. Here we asked if activating CA2 PCs increases seizures. Mice expressing Cre recombinase in CA2 PCs (<em>Amigo2</em>-Cre mice) were injected with the convulsant pilocarpine to induce a period of severe seizures (<em>status epilepticus</em>, SE), which leads to chronic seizures after 3–4 weeks (epilepsy). Epileptic mice were injected with a Cre-dependent adeno-associated virus (AAV) to express an excitatory designer receptor exclusively activated by designer drug (eDREADD; hM3Dq) in dorsal CA2 bilaterally and implanted with subdural EEG electrodes. After recovery, mice were recorded continuously using video and EEG for 6 weeks, 3 weeks with drinking water containing the eDREADD activator clozapine-N-oxide (CNO) and 3 weeks without CNO. CA2 activation with CNO caused a significant increase in seizure frequency and duration. Seizures occurred in clusters (many seizures per day over several consecutive days) and mice given water with CNO had a greater maximum number of seizures per day during a cluster compared to water without CNO. CNO had no significant effect in control mice. In naïve <em>Amigo2-</em>Cre mice expressing hM3Dq, pre-treatment with CNO before pilocarpine administration shortened the latency to SE and increased EEG power at the start of SE. Taken together with prior findings, the results suggest that CA2 is a control point for regulating seizures in the pilocarpine mouse model of TLE.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107256"},"PeriodicalIF":5.6,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906369","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":"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":"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":"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 multiple mechanisms of NR4A2 in neurological disorders and advances in targeted therapy research","authors":"Kexin Duan ,&nbsp;Caiyun Yang ,&nbsp;Da Gao ,&nbsp;Mengzhu Li ,&nbsp;Mengxuan Chen ,&nbsp;Haiyan Li ,&nbsp;Weicong Zeng ,&nbsp;Lijun Zhao ,&nbsp;Meiling Zhu","doi":"10.1016/j.nbd.2025.107229","DOIUrl":"10.1016/j.nbd.2025.107229","url":null,"abstract":"<div><div>Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) is a transcription factor widely distributed in the central nervous system, playing a crucial regulatory role in various physiological and pathological processes, including dopaminergic neuronal differentiation, synaptic plasticity, neuroinflammation, immune responses, and addictive behaviors. Previous studies have primarily focused on exploring the relationship between NR4A2 and Parkinson's disease, with less attention given to the potential association between NR4A2 and other neurological disorders. In this context, this paper systematically reviews the current research on NR4A2 in Parkinson's disease, Alzheimer's disease, multiple sclerosis, psychiatric disorders, neurodevelopmental disorders (NDD), addictive behaviors, and stroke, revealing its multifaceted mechanisms in neurological disorders and elucidate its common and specific roles across different conditions. Furthermore, it also highlights cutting-edge strategies such as NR4A2 agonists, indirect NR4A2 regulators, and NR4A2-based cell replacement therapy or gene therapy, providing a comprehensive discussion of the progress and breakthroughs in NR4A2-targeted therapeutic approaches.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107229"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794204","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":"Transcriptomic and neurotransmitter correlates of structure and function spatial variations patterns in spinocerebellar Ataxia","authors":"Manxi Xu ,&nbsp;Yuanhao Li ,&nbsp;Jixin Luan ,&nbsp;Aocai Yang ,&nbsp;Li Zhu ,&nbsp;Ni Shu ,&nbsp;Gaoxiang Ouyang ,&nbsp;Yunjing Xue ,&nbsp;Linwei Zhang ,&nbsp;Guolin Ma","doi":"10.1016/j.nbd.2025.107228","DOIUrl":"10.1016/j.nbd.2025.107228","url":null,"abstract":"<div><h3>Background</h3><div>Spinocerebellar ataxia (SCA) is characterized by cortical structural and functional impairments, but the underlying biological mechanisms remain poorly understood.</div></div><div><h3>Methods</h3><div>We applied T1-weighted magnetic resonance imaging (MRI) and resting-state functional MRI (fMRI) to investigate cortical alterations in 49 SCA patients and 48 matched controls. Cortical thickness and amplitude of low-frequency fluctuations (ALFF) were quantified and compared with spatial maps of 19 neurotransmitter systems. Gene expression patterns were examined using partial least squares regression, followed by gene ontology analysis to identify associated biological processes.</div></div><div><h3>Results</h3><div>Both cortical thickness and ALFF emerged as sensitive biomarkers of cortical impairment in SCA. Thickness alterations were strongly associated with disruptions in cholinergic, serotonergic, and glutamatergic systems. ALFF alterations were linked to toxin-response and detoxification processes, with relevant gene expression enriched in astrocytes.</div></div><div><h3>Conclusion</h3><div>Our convergent imaging–transcriptomic analysis integrates direct molecular vulnerability and CTC-based transsynaptic degeneration, yielding a unified systems-level view of SCA. These findings go beyond correlation by prioritizing molecular pathways and non-neuronal cellular targets and enabling network-informed prediction of additional vulnerable regions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107228"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800560","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}