Neurobiology of Disease最新文献

{"title":"Stathmin 1 regulates epileptic seizures by influencing GABAA R-mediated inhibitory synaptic activity","authors":"Min Yang ,&nbsp;Yida Hu ,&nbsp;Junhong Wu ,&nbsp;Hui Zhang,&nbsp;Juan Li,&nbsp;Xuefeng Wang,&nbsp;Xin Xu","doi":"10.1016/j.nbd.2026.107310","DOIUrl":"10.1016/j.nbd.2026.107310","url":null,"abstract":"<div><div>Epilepsy is a common neurological disease, and approximately 30% of patients with epilepsy do not respond adequately to antiseizure medications. STMN1 (Stathmin 1) is a potent regulator of microtubule stability, and previous research has shown that STMN1 expression is increased in epileptic brain. However, the effect of STMN1 on epileptic seizures remains unclear. Our study found that STMN1 expression was associated with GABA_A receptor (GABA_AR), inhibitory GABAergic neurons and the inhibitory postsynaptic scaffold protein gephyrin. STMN1 downregulation decreased the susceptibility to epileptic seizures in a kainic acid–induced model and pentylenetetrazole-induced kindling model of epilepsy, whereas the overexpression of STMN1 showed opposite effects. More specifically, whole-cell patch-clamp recordings indicate that STMN1 regulated inhibitory synaptic transmission, potentially due to STMN1-mediated postsynaptic GABA_AR transport. These results provides the demonstration that STMN1 plays a critical role in the regulation of epileptic seizures, suggesting a molecular mechanism for new therapeutic strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107310"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166017","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":"Differences in white matter detected by ex vivo 9.4 T MRI are associated with axonal changes in the R6/1 model of Huntington's disease","authors":"C. Casella ,&nbsp;B. Kelly ,&nbsp;A. Murillo ,&nbsp;I. Mills-Smith ,&nbsp;G.D. Parker ,&nbsp;C. Von Ruhland ,&nbsp;Y.A. Syed ,&nbsp;V. Dion ,&nbsp;C. Metzler-Baddeley ,&nbsp;A.E. Rosser ,&nbsp;D.K. Jones ,&nbsp;M.J. Lelos","doi":"10.1016/j.nbd.2026.107318","DOIUrl":"10.1016/j.nbd.2026.107318","url":null,"abstract":"<div><div>White matter volume loss has been reported as one of the first indicators in Huntington's disease (HD) patients, but the cellular basis of this deficit remains to be elucidated. To address this, we assessed white matter microstructure in the transgenic R6/1 mouse model of HD with ex vivo MRI. Specifically, a tractometry approach was employed to inspect region-specific differences across the corpus callosum (CC), while voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were used to identify brain-wise white matter macro- and microstructure abnormalities. Alterations in the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) and in the intra-axonal signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) suggested regional decreases in myelin content and widespread increases in axonal density in this mouse model of HD. A cohort of sex/age-matched mice was assessed on cognitive and simple motor tasks to demonstrate that functional impairments were coincident with imaging deficits. Finally, the neurobiological basis of the MRI phenotype was assessed with histological and electron microscopy analyses in a cohort of sex/age-matched mice, revealing disruptions in axonal morphology (i.e. less complex, thinner axons) and organization (i.e. more densely packed axons) in this mouse model of HD. Furthermore, our results indicate that, at least early in disease progression, R6/1 mice present a reduction in the expression or content of myelin-associated proteins without significant alterations in the structure of myelin sheaths. Crucially, our findings highlight the potential of FR, an in vivo estimate of axon density, as a novel MRI biomarker of HD-associated changes in white matter microstructure.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107318"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195270","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 HCF-1:OGT axis regulates neuronal proliferation and differentiation","authors":"Ayushma ,&nbsp;Priyanka Prakash Srivastava ,&nbsp;Shruti Kaushal ,&nbsp;Jaspreet K. Dhanjal ,&nbsp;Vaibhav Kapuria ,&nbsp;Shilpi Minocha","doi":"10.1016/j.nbd.2026.107308","DOIUrl":"10.1016/j.nbd.2026.107308","url":null,"abstract":"<div><div>Neuronal differentiation requires precise coordination of progenitor proliferation, lineage commitment, and chromatin regulation to establish functional brain architecture. Host Cell Factor-1 (HCF-1), an X-linked transcriptional co-regulator linked to human intellectual disability, is essential for early development, yet its lineage-specific roles during mammalian neurogenesis remain incompletely defined. Here, we investigate the function of the HCF-1–OGT axis during neuronal differentiation and forebrain development.</div><div>Early embryonic loss of HCF-1 resulted in developmental arrest due to gastrulation defects, while conditional deletion in Nkx2.1-derived neuronal lineages caused pronounced cortical disorganization, reduced GABAergic interneuron survival, and severe defects in forebrain commissures, including the corpus callosum and anterior commissure. These abnormalities were not observed following glial-restricted deletion, indicating a neuron-specific requirement for HCF-1. Neuronal ablation alone did not phenocopy these defects; however, combined neuronal ablation and HCF-1 loss exacerbated cortical and commissural abnormalities, revealing increased neuronal vulnerability.</div><div>Transcriptomic profiling following HCF-1 depletion identified widespread dysregulation of gene networks associated with neuronal differentiation, synaptic organization, chromatin regulation, and axon guidance. Consistently, HCF-1 directly occupied promoters of key neuronal genes, including Elavl3 and NeuroD1, and its loss reduced activating chromatin marks at these loci. In vitro, depletion of HCF-1 or inhibition of OGT impaired neuronal proliferation, differentiation, and neurite outgrowth. Glycoproteomic analysis further revealed disruption of OGT-dependent protein networks involved in neuronal structure and maturation.</div><div>Together, these findings identify HCF-1 as a central regulator of neuronal differentiation and forebrain organization and provide mechanistic insight into how disruption of the HCF-1–OGT axis contributes to neurodevelopmental disorders.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107308"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132535","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":"Activating the vlPAG-LC neural pathway alleviates neuropathic pain and comorbid anxiety-like behaviors through distinct projections","authors":"Liang Zhang ,&nbsp;Fei Li ,&nbsp;Han-Xue Sun ,&nbsp;Hui Li ,&nbsp;Fen-Sheng Huang ,&nbsp;Jun-Bin Yin ,&nbsp;Yun-Qing Li","doi":"10.1016/j.nbd.2026.107298","DOIUrl":"10.1016/j.nbd.2026.107298","url":null,"abstract":"<div><div>The ventrolateral periaqueductal gray (vlPAG) functions as a critical hub in the descending pain modulatory system. The vlPAG receives and processes upstream pain information, which is involved in descending pain modulation through projecting downstream to rostroventral medulla (RVM) or locus coeruleus (LC). Although the modulatory roles of the upstream pathways and the vlPAG-RVM connection in neuropathic pain have been extensively studied, but the involvement of the vlPAG-LC neural pathway in regulating neuropathic pain and related comorbidity requires further investigation. In the present study, the excitability of the vlPAG-LC pathway was found to be increased in spared nerve injury (SNI) mice. Activating of the vlPAG-LC pathway using chemogenetic approach produced antinociceptive and anxiolytic effects in SNI mice. Intrathecal administration of α2-adrenergic receptor antagonist reversed analgesic effect of the vlPAG-LC pathway in SNI mice. However, the anxiolytic effect of this neural pathway was unaffected. A previously unrecognized vlPAG-LC-anterior cingulate cortex (ACC) tertiary pathway was identified in the current work. The excitability of ACC increased in SNI mice, whereas decreased following activation of the vlPAG-LC pathway. Activation of the ACC pyramidal neurons blocked the vlPAG-LC pathway-mediated anxiolytic effect but not analgesic effect in SNI mice. Furthermore, the anxiolytic effect of the vlPAG-LC pathway in SNI mice was altered after activation of the LC-ACC pathway or microinjection of norepinephrine into ACC. The present results underscored spinal dorsal horn and ACC as the potential downstream targets for analgesic and anxiolytic effects of the vlPAG-LC neural pathway in SNI mice, respectively.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107298"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132588","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 role of the kynurenine pathway in the pathophysiology of autism-like phenotype induced by maternal inflammation in male mice","authors":"Danielle Santana-Coelho ,&nbsp;Rafael dos Santos de Bessa ,&nbsp;Rodrigo Neves Romcy-Pereira ,&nbsp;Miguel A. de la Flor ,&nbsp;Jason C. O'Connor","doi":"10.1016/j.nbd.2026.107282","DOIUrl":"10.1016/j.nbd.2026.107282","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that may include deficits in communication, social challenges, and repetitive/stereotyped behavior. The etiology of ASD is not well defined, but both genetic and environmental risk factors have been identified. In animal models, prenatal maternal immune activation precipitates the development of a behavioral phenotype resembling ASD, but the mechanisms by which this occurs are not fully understood. Inflammation can upregulate the kynurenine pathway metabolism through the enzyme indoleamine 2,3-dioxygenase-1 (IDO). Increased levels of kynurenines during development can have deleterious consequences leading to behavioral deficits in adulthood. We sought to determine whether the kynurenine pathway plays a pathogenic role in the development of an ASD-like phenotype using a well-characterized mouse model of maternal immune activation (MIA). Multiparous IDO null (IDO−/−) or C57BL/6 J wild-type dams were administered the viral mimetic polynosinic:polycytidylic acid (Poly IC) at gestational day 12.5. A similar immune response to Poly IC occurred in the maternal plasma and placenta of both genotypes, while kynurenine metabolism was only increased in the fetal tissue of WT mice exposed to Poly IC challenge. Interestingly, <em>N</em>-methyl-<span>d</span>-aspartate (NMDA) receptor subunit expression was reduced in the fetal brains of male WT, but not IDO−/−, after MIA with Poly IC. Here, we used machine-learning as an advanced method to evaluate ultrasonic vocalizations. Offspring exposed to prenatal MIA exhibited fewer and less complex ultrasonic vocalizations along with diminished social preference; however, MIA-induced repetitive/stereotyped behaviors were only present in WT mice. Taken together, our data indicate that fetal IDO1-dependent kynurenine metabolism mediates distinct components of the MIA-induced ASD-like phenotype in male mice, which may be related to alterations in the expression of NMDAR subunits during neurodevelopment.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107282"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041479","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":"Corrigendum to “Molecular mechanism of PANoptosis and programmed cell death in neurological diseases” [Neurobiology of Disease Volume 209 (2025) 106907]","authors":"Ketian Hou ,&nbsp;Wenhan Pan ,&nbsp;Lianhui Liu ,&nbsp;Qianqian Yu ,&nbsp;Jiahao Ou ,&nbsp;Yueqi Li ,&nbsp;Xi Yang ,&nbsp;Zhenlang Lin ,&nbsp;Junhui Yuan ,&nbsp;Mingchu Fang","doi":"10.1016/j.nbd.2026.107302","DOIUrl":"10.1016/j.nbd.2026.107302","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107302"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227632","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":"GDF-11, GDF-15, Jag-1, and leptin in neuronal-derived extracellular vesicles as aging-related biomarkers to identify individuals at risk of Alzheimer's dementia: A pilot study","authors":"Simona Lanzillotta ,&nbsp;Virginia Boccardi ,&nbsp;Barbara Zulli ,&nbsp;Alessandro Napoli ,&nbsp;Gabriele Paolozzi ,&nbsp;Roberta Angelini ,&nbsp;Barbara Ruzicka ,&nbsp;Federica Fratini ,&nbsp;Anna Giulia Guazzarini ,&nbsp;Michela Scamosci ,&nbsp;Patrizia Bastiani ,&nbsp;Martina Alunno ,&nbsp;Eric Westman ,&nbsp;Fabio Di Domenico ,&nbsp;Marzia Perluigi ,&nbsp;Antonella Tramutola ,&nbsp;Roberta Cecchetti ,&nbsp;Tommaso Mazza ,&nbsp;D. Allan Butterfield ,&nbsp;Patrizia Mecocci ,&nbsp;Eugenio Barone","doi":"10.1016/j.nbd.2026.107291","DOIUrl":"10.1016/j.nbd.2026.107291","url":null,"abstract":"<div><div>Aging is the strongest risk factor for Alzheimer's disease (AD). Identifying reliable biomarkers of brain aging helps to predict functional decline and dementia onset. Evaluations of aging-related biomarkers in plasma and neuronal-derived extracellular vesicles (nEVs) from cognitively healthy and AD subjects, alongside post-mortem IPL brain samples from control (Ctr), pre-clinical AD (PCAD), mild cognitive impairment (MCI) and AD cases were performed. Cognitive tests, functional assessments, and MRI data were also included. Biomarkers in nEVs more accurately reflected brain pathology than those measured in plasma and showed stronger associations with cognitive and functional decline. Sex-specific patterns also emerged: GDF-15 was higher in nEVs from females with AD, whereas IL-6, IL-18 and Jag-1 were higher in nEVs from males with AD. A minimal nEV-derived panel including lower GDF-11 and higher GDF-15, Jag-1 and Leptin (after correction for age and sex) discriminated AD from Ctr and was associated with MRI-determined cortical atrophy in regions vulnerable to AD. These markers captured aging-related molecular trajectories that were disrupted in AD, and key associations observed in nEVs were confirmed in post-mortem brain tissue. Our results suggests that nEV-derived biomarkers capture early, brain-specific and sex-modulated aging signatures, providing superior sensitivity compared to plasma. Their convergence with post-mortem findings underscores their biological validity and translational potential. These results highlight the value of nEVs for stratifying individuals at higher risk of AD and support their integration into precision medicine approaches for dementia prevention.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107291"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080756","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":"Post adversity changes in nigro-striatal dopamine: A mechanism for anxiety induced exacerbated innate repetitive behaviors","authors":"Lior Givon ,&nbsp;Lee Amado ,&nbsp;Shahaf Edut ,&nbsp;Oded Klavir","doi":"10.1016/j.nbd.2026.107294","DOIUrl":"10.1016/j.nbd.2026.107294","url":null,"abstract":"<div><div>Anxiety exacerbates symptoms in various psychiatric disorders. In conditions such as obsessive-compulsive disorder (OCD) or Tourette syndrome, anxiety intensifies stereotypic and repetitive behaviors. Rodent self-grooming, a structured, repetitive innate behavior, serves as an effective rodent platform for studying these behaviors in neuropsychiatric research. Anxiety is also linked to altered functioning of the dopamine (DA) system, particularly within the substantia-nigra pars compacta (SNc), the main DA source to the dorsal striatum through the nigro-striatal pathway. Striatal modulation by DA signal also plays a complex role in repetitive behaviors and OCD-like symptoms, suggesting this system as linking anxiety to the induced exacerbation of repetitive behavior. In the present study, we observed several long-term effects of anxiety-inducing foot shock on grooming behavior. Recording single unit neuronal activity in the SNc revealed distinct response patterns related to grooming behavior with changes in the magnitude and timing following the shock treatment. Notably, DA neurons of different nigro-striatal pathways demonstrated different changes in different response pattern type units. DA neurons projecting to the dorsolateral striatum (DLS) showed increase, while those targeting the dorsomedial striatum (DMS) exhibited decrease in transient activity - suggesting a shift in cortico-striatal circuitry of behavioral control. These neural changes were correlated with the observed behavioral alterations following adversity. Furthermore, targeted stimulation of SNc DA neurons projecting to the DLS rescued the anxiety-induced behavioral effects, highlighting the critical role of the nigro-striatal pathway to the DLS in mediating the interaction between anxiety and repetitive behaviors, thus offering future direction for mitigation of relevant psychiatric symptoms.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107294"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119699","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":"Multi-omics dissection of Parkinson’s patients in subgroups associated with motor and cognitive severity","authors":"Efi Athieniti,&nbsp;Sotiroula Afxenti,&nbsp;George Minadakis,&nbsp;George M. Spyrou","doi":"10.1016/j.nbd.2026.107288","DOIUrl":"10.1016/j.nbd.2026.107288","url":null,"abstract":"<div><div>Heterogeneity in the severity of Parkinson’s disease (PD) inhibits the effective interpretation of clinical trial outcomes. Multi-omics analysis may help explain the pathological mechanisms underlying disease progression and reveal biomarkers of clinical severity. We performed Multi-Omics Factor Analysis (MOFA) on whole blood RNA, miRNA and cerebrospinal fluid (CSF) and blood plasma proteomics from the Parkinson’s Progression Marker Initiative (PPMI), to identify molecular factors correlated with motor (MDS-UPDRS3) and cognitive (Semantic Fluency Test, SFT) function. Three molecular factors significantly correlated with the MDS-UPDRS3 score and two with SFT, which remained significant after adjusting for age, sex, and medication dose. We used the identified factors to stratify patients into subgroups with distinct motor and cognitive severity. The severe motor clusters showed deregulation of cytotoxic natural killer cell mechanisms in peripheral blood, and changes to proteins associated with the endoplasmic reticulum and dense core vesicle in CSF. The severe cognitive clusters showed changes in the complement system and synaptic dysfunction. Our analysis capitalizes on multi-omics data integration to enrich our understanding of the mechanisms driving motor and cognitive decline in PD, to support precision medicine.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107288"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119646","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":"Cholinergic neurotransmission underlying visual hallucinations in Parkinson's disease: Integration of multimodal evidence and translational approaches","authors":"Jinshuo Liu ,&nbsp;Dezhu Yu ,&nbsp;Yu Liu ,&nbsp;Yuxuan Yong ,&nbsp;Zihao Wang ,&nbsp;Peidong Fan ,&nbsp;Xinling Yang","doi":"10.1016/j.nbd.2026.107316","DOIUrl":"10.1016/j.nbd.2026.107316","url":null,"abstract":"<div><div>Visual hallucinations (VH) represent a prevalent and clinically significant non-motor manifestation in Parkinson’s disease (PD), often leading to accelerated cognitive decline, increased caregiver burden, and reduced quality of life. Despite their impact, the neurobiological basis of VH remains poorly defined, and effective treatments are limited. This review systematically synthesizes evidence from neuropathology, multimodal neuroimaging (PET, DTI, fMRI), neurophysiology, and computational modeling to establish a coherent mechanism of VH rooted in cholinergic system failure. We demonstrate that selective degeneration of cholinergic circuits—notably the basal forebrain-cortical and brainstem-basal forebrain pathways—induces VH through multiple convergent pathways: disruption of thalamocortical sensory gating, breakdown in predictive coding, and maladaptive functional connectivity, particularly hypercoupling between the default mode network (DMN) and visual cortex. Imaging studies further delineate a posterior-anterior gradient of cholinergic denervation, quantified by AChE-PET as reduced k₃ values in occipito-temporal regions, while dynamic interactions with dopaminergic fluctuations amplify perceptual noise and computational imbalance. Beyond conventional cholinesterase inhibitors, novel interventions are emerging. These include α7-nAChR agonists, M4 receptor-positive allosteric modulators, and occipital tDCS. They represent circuit-specific strategies with the potential to restore cholinergic modulation and normalize network dynamics<strong>.</strong> This review integrates multimodal insights into a translational framework<strong>,</strong> thereby clarifying the cholinergic etiology of PD-VH and outlines a personalized therapeutic roadmap. We also urge future research to bridge molecular mechanisms with clinical innovation in hallucination management.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107316"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165979","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}