Neurobiology of Disease最新文献

{"title":"Role of Tropomodulins in brain physiology and pathology","authors":"Chuan Hong ,&nbsp;Xiaopeng Liu ,&nbsp;Zhou Zhou ,&nbsp;Yuan Xing ,&nbsp;Zixuan Cao ,&nbsp;Yan-Zhong Chang ,&nbsp;Guofen Gao","doi":"10.1016/j.nbd.2025.107006","DOIUrl":"10.1016/j.nbd.2025.107006","url":null,"abstract":"<div><div>Actin dynamics are crucial for the morphogenesis and function of neurons in the brain. Tropomodulins (Tmods) belong to a family of actin-binding proteins that cap the pointed-end of actin filaments. There are four Tmod isoforms, and three of which, Tmod1, Tmod2 and Tmod3, are expressed in the brain, with Tmod2 exhibiting neuronal specific expression. By regulating actin filament dynamics, Tmods participate in neurite outgrowth, dendritic spine formation, and synaptic morphology, thereby contributing to structural and functional neural plasticity. Dysregulation of Tmods has been demonstrated in several neurodegenerative and neuropsychiatric diseases, such as Alzheimer's disease, epilepsy, Down syndrome, and addictive behaviors. Currently, compared to cancer and cardiovascular diseases, the roles and mechanisms of altered Tmod expression in neurological diseases remain poorly understood. In this article, we provided an overview on the physiological roles and crucial functions of Tmods in the brain, summarized the recent advances in alterations of Tmods in neurodegenerative and neuropsychiatric diseases, and discussed their implications and potential contributions to disease pathology and treatment. This review may expedite future studies to delineate the roles and molecular mechanisms of Tmods in brain physiology and pathology, ultimately promoting the development of novel diagnostic and therapeutic strategies for related neurological diseases.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107006"},"PeriodicalIF":5.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144297830","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":"Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensity","authors":"Carlos M. Díaz-Domínguez ,&nbsp;Hasier Eraña ,&nbsp;Francesca Peccati ,&nbsp;Enric Vidal ,&nbsp;Jorge M. Charco ,&nbsp;Cristina Sampedro-Torres-Quevedo ,&nbsp;Miguel A. Pérez-Castro ,&nbsp;Nuria L. Lorenzo ,&nbsp;Samanta Giler ,&nbsp;Glenn C. Telling ,&nbsp;Mariví Geijo ,&nbsp;Jesús R. Requena ,&nbsp;Gonzalo Jiménez-Osés ,&nbsp;Joaquín Castilla","doi":"10.1016/j.nbd.2025.107005","DOIUrl":"10.1016/j.nbd.2025.107005","url":null,"abstract":"<div><div>Protein misfolding is central to numerous neurodegenerative disorders, collectively known as proteinopathies, which include Alzheimer's disease, Parkinson's disease, and prion diseases, among others. In many cases, specific polymorphisms of the proteins associated with these diseases influence their misfolding. However, the precise ways in which these polymorphisms affect protein integrity and how they contribute to misfolding propensity remain unclear. In the case of prion diseases, they are caused by prions or PrP^Sc, the misfolded isoforms of the cellular prion protein (PrP^C). Chronic Wasting Disease (CWD) is a prion disease that affects cervids and can exhibit lymphotropic properties, making it the most widespread proteinopathy. For that reason, cervid PrPs and their polymorphisms have been extensively studied. To better understand the role of these polymorphisms, we analyzed 45 cervid PrP variants to assess their effects on flexibility, stability, and spontaneous misfolding propensity.</div><div>The cervid variants were expressed as recombinant PrP in <em>E. coli</em> and were analyzed for thermal stability using circular dichroism. Additionally, the rec-PrPs served as substrates for Protein Misfolding Shaking Amplification (PMSA), enabling assessment of each variant's spontaneous misfolding propensity. This process led to the formation of <em>bona fide</em> prions, as confirmed by inoculation of one of the resulting conformers into transgenic mice expressing bank vole PrP. In parallel, molecular dynamics simulations were conducted to analyze the structural flexibility of the variants. While differences in protein flexibility were observed, no correlation was detected among flexibility, thermal stability, and the observed variable spontaneous misfolding propensity, suggesting that these properties are independent parameters.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107005"},"PeriodicalIF":5.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302571","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":"PD-1 deficiency disrupts in vivo neural activity in mouse Hippocampus and cortex","authors":"Minghui Hu ,&nbsp;Cui Lv ,&nbsp;Jianping Zhu ,&nbsp;Hao Zhang ,&nbsp;Xinyu Wang ,&nbsp;Luyan You ,&nbsp;Jinlu Xie ,&nbsp;Wei Liu ,&nbsp;Xiaocen Wei ,&nbsp;Kai Chen ,&nbsp;Zifa Li ,&nbsp;Sheng Wei ,&nbsp;Xiwen Geng","doi":"10.1016/j.nbd.2025.107002","DOIUrl":"10.1016/j.nbd.2025.107002","url":null,"abstract":"<div><div>Programmed cell death 1 (PD-1), encoded by the <em>Pdcd1</em> gene, was identified as a target in cancer immunotherapy but may result in the overactivation of T cell function and emotional changes such as anxiety. The dynamic changes in neuronal activity related to the anxious status caused by <em>Pdcd1</em>^{<em>−/−</em>} remain unclear. In this study, we addressed these physiological issues by simultaneously recording neuronal activity (spikes) and local field potentials (LFPs) in the medial prefrontal cortex (mPFC) and hippocampal CA3 region using <em>in vivo</em> multi-channel electrodes. Our results demonstrate that PD-1 deficiency induces anxiety-like behaviours and extensive neuronal firing disorders in the mPFC and CA3 regions of mice. The key finding was that in pyramidal neuron and interneurons in the CA3 region, the <em>in vivo</em> firing and spike-LFP encoding was disordered in the opposite direction by <em>Pdcd1</em>^{<em>−/−</em>}. These changes leaded to abnormal oscillations in mPFC and CA3 and disturbed mPFC neuronal firing. Targeting the activation of excitatory neurons in CA3 regions could rescue anxiety-like behaviours in <em>Pdcd1</em>^{<em>‐/</em>}‐ mice. This study provides physiological insights into the dynamic cooperation mechanisms between the mPFC and CA3 circuits in anxiety-like behaviours caused by <em>Pdcd1</em>^{<em>−/−</em>} and other mental disorders associated with autoimmune problems.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107002"},"PeriodicalIF":5.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294143","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":"Impaired plasma membrane calcium ATPase activity and mitochondrial dysfunction contribute to calcium dysregulation in Fabry disease-related painful neuropathy","authors":"Francesco Formaggio ,&nbsp;Asia Pizzi ,&nbsp;Cecilia Delprete ,&nbsp;Davide Pasqualini ,&nbsp;Isabella Mataloni ,&nbsp;Roberto Rimondini ,&nbsp;Ludovica Campolongo ,&nbsp;Vincenzo Donadio ,&nbsp;Anna Maria Ghelli ,&nbsp;Rocco Liguori ,&nbsp;Marco Caprini","doi":"10.1016/j.nbd.2025.107000","DOIUrl":"10.1016/j.nbd.2025.107000","url":null,"abstract":"<div><div>Neuropathic pain is a hallmark symptom in Fabry disease (FD), a hereditary X-linked lysosomal storage disorder caused by a reduced activity of α-galactosidase A (α-Gal A). The α-Gal A deficiency results in the progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in the body fluids and lysosomes of various cell types, including sensory ganglia. The FD neuropathy affects the small thinly myelinated Aδ fibers and unmyelinated C fibers leading to the loss of intra-epidermal neuronal terminations, along with altered thermal and mechanical perception. Lipid accumulation, such as Gb3 and lyso-Gb3, is implicated in various cellular dysfunctions, including the alteration of ionic currents. It has been shown that administration of Gb3 to human umbilical vein endothelial cells leads to the downregulation of the calcium (Ca²⁺)-activated K⁺ channel K_Ca3.1, whereas lyso-Gb3 evokes cytosolic Ca²⁺ transients and an enhancement of voltage-activated Ca²⁺ currents in murine dorsal root ganglia. Therefore, we examined the mechanism underlying Ca²⁺ regulation in primary afferent neurons from the α-Gal A (−/0) mouse model. The obtained results suggest that other transport proteins participate in Ca²⁺ homeostasis in FD and their dysfunction may be directly involved in nociception. In this context, plasma-membrane Ca²⁺ ATPases exhibited reduced activity in FD, leading to an increased resting [Ca²⁺]_i in sensory neurons. The reduced activity was associated with a decrease of cytosolic pH which weakened the PMCA-dependent calcium extrusion. We finally evaluated the contribution of mitochondria to the Ca²⁺ signalling and we observed impairment of the mitochondrial buffer capacity, as well as dysfunctional mitochondria and enhanced autophagy/mitophagy. These findings provide a basis for future insights into the alterations of calcium signalling underlying the onset of neuropathic symptoms in FD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107000"},"PeriodicalIF":5.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294142","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":"Glymphatic dysfunction is related to motor disability fully mediated by gray matter degeneration in early-stage Parkinson's disease","authors":"Zihao Zhu ,&nbsp;Xiaojie Duanmu ,&nbsp;Cheng Zhou ,&nbsp;Jiaqi Wen ,&nbsp;Jianmei Qin ,&nbsp;Qianshi Zheng ,&nbsp;Weijin Yuan ,&nbsp;Tao Guo ,&nbsp;Haoting Wu ,&nbsp;Chenqing Wu ,&nbsp;Jingwen Chen ,&nbsp;Jingjing Wu ,&nbsp;Yingni Jin ,&nbsp;Nan Lu ,&nbsp;Lu Wang ,&nbsp;Bingting Zhu ,&nbsp;Yuelin Fang ,&nbsp;Lifang Wang ,&nbsp;Ziyi Zhu ,&nbsp;Yaping Yan ,&nbsp;Xiaojun Xu","doi":"10.1016/j.nbd.2025.107001","DOIUrl":"10.1016/j.nbd.2025.107001","url":null,"abstract":"<div><h3>Background</h3><div>Glymphatic dysfunction plays a critical role in Parkinson's disease (PD), but its impact on neurodegeneration and clinical symptoms in the early-stage remains unclear. This study investigates the relationship between glymphatic dysfunction, gray matter (GM) degeneration, and clinical deterioration in early-stage PD.</div></div><div><h3>Methods</h3><div>A total of 249 early-stage PD patients and 114 healthy controls (HC) underwent T1-weighted and DTI scans, along with clinical assessments. Among them, 83 patients and 32 HC were longitudinally re-visited. The diffusion tensor imaging along the perivascular space (DTI-ALPS) index was used to estimate glymphatic function. Linear mixed model was performed to identify longitudinal GM degeneration and clinical deterioration; partial correlation analysis was applied to explore GM degeneration associated with glymphatic dysfunction; while mediation analysis was conducted to investigate the mediation role of GM degeneration in the relationship between glymphatic dysfunction and clinical deterioration.</div></div><div><h3>Results</h3><div>Significantly lower DTI-ALPS index was observed in PD patients, which correlated with reduced cortical thickness in the bilateral posterior cingulate and left lingual gyrus at baseline, and faster atrophy in the left rostral anterior cingulate during follow-up. The relationship between DTI-ALPS index and baseline motor disability was fully mediated by the degeneration of the left posterior cingulate.</div></div><div><h3>Conclusion</h3><div>Glymphatic dysfunction in early-stage PD correlates with GM degeneration and motor decline. Left posterior cingulate degeneration fully mediates the impact of glymphatic dysfunction on motor disability. These findings deepen the understanding of the clinical relevance of glymphatic dysfunction and provide further insights into the regulatory mechanisms underlying PD-related neurodegenerative circuits.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107001"},"PeriodicalIF":5.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144280694","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":"Frequency-coded spatiotemporal control of telencephalic ictal oscillations and inter-cortical coherence by thalamus","authors":"Ping Chou ,&nbsp;Yi-Chen Lai ,&nbsp;Yen-Hsin Zheng ,&nbsp;Ya-Chin Yang ,&nbsp;Chung-Chin Kuo","doi":"10.1016/j.nbd.2025.106993","DOIUrl":"10.1016/j.nbd.2025.106993","url":null,"abstract":"<div><div>Many epileptic seizures (hereafter abbreviated as seizures) are characterized by overly synchronized oscillating activities in the thalamocortical system. Despite dense reciprocal innervation between cortex and thalamus, the exact role of thalamus in ictogenesis (e.g. as a passive associate, lenient modulator, or indispensable controller) has been unsettled. We found that either electrical or chemical ictogenic stimulation of basolateral amygdala (BLA) induces augmentation of δ-frequency local field potential (LFP) oscillations in situ. In contrast, the thalamic mediodorsal nucleus (MD), which is reciprocally connected with BLA, responds with mixed θ-α and δ oscillations at first. MD may then be entrained more and more into the latter, leading to augmented δ oscillations as well as δ coherence in the thalamocortical system and maximal behavioral seizures. Inhibition of MD with topical tetrodotoxin dissipates the coherent δ augmentation and decreases multi-unit spikes in BLA and other telencephalic areas, suggesting critical involvement of MD in the inter-cortical communication and focal ictogenesis. Systemic application of proconvulsant pentylenentetrazol could induce interchanging periods of δ and θ-α augmentation in MD, at which periods concomitant electrical stimulation of BLA would be much more and less likely to induce seizures, respectively. The mechanism underlying thalamic δ entrainment in telencephalic ictogenesis and “θ-α antagonism” may involve local GABA-glutamate interactions and the requirement of cortical glutamatergic input for the generation of thalamic burst discharges (“relay bursts\"). Thalamus thus assumes a critical control of the temporal pace and spatial scale of telencephalic oscillations, with a specific but well adaptable order of frequency and amplitude modulation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106993"},"PeriodicalIF":5.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285773","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":"Dynamic alterations of SEEG characteristics during peri-ictal period and localization of seizure onset zone","authors":"Lidao Xu ,&nbsp;Yongxin Yang ,&nbsp;Qinghua Tan ,&nbsp;Hongping Tan ,&nbsp;Yifan Wang ,&nbsp;Zeliang Hou ,&nbsp;Jingxian Shen ,&nbsp;Rihui Li ,&nbsp;Yuxi Luo ,&nbsp;Lizhang Zeng ,&nbsp;Qiang Guo ,&nbsp;Xuchu Weng ,&nbsp;Jiuxing Liang","doi":"10.1016/j.nbd.2025.106998","DOIUrl":"10.1016/j.nbd.2025.106998","url":null,"abstract":"<div><h3>Background</h3><div>The evolution in peri-ictal period (from pre-ictal to ictal phase) of seizures contains abundant epileptogenic information, which aids in exploring the mechanism of seizures and localizing the epileptogenic zone (EZ). This study aims to investigate the regulatory mechanisms of seizure and localize EZ by analyzing the dynamic alterations of diverse characteristics during peri-ictal period based on SEEG.</div></div><div><h3>Methods</h3><div>A total of 61 patients with refractory focal epilepsy were included, and each patient underwent SEEG electrodes implantation. The data in the peri-ictal period were selected, and the dynamic alterations of phase-amplitude coupling (MI), connectivity strength (wPLI, DTF), and sample entropy were calculated in each sliding window. Finally, machine learning models were utilized to predict the seizure onset zone (SOZ) and undergo performance evaluation.</div></div><div><h3>Results</h3><div>The MI and inflow intensity of SOZ in each frequency band were significantly higher (<em>p</em> &lt; 0.001) than those of nSOZ, and exhibited an initial increase followed by a decrease after onset. The outflow intensity and sample entropy (except delta band) of SOZ were significantly lower (<em>p</em> &lt; 0.001) than those of nSOZ, which rose first and then fell after onset. The features of the propagation zone lay between those of the SOZ and non-involved zone. Integrating these features with machine learning models effectively localized SOZ, among which XGBoost model had the best performance, its AUC, accuracy, specificity, and sensitivity, and were 0.905, 87.0 %, 87.9 %, and 79.5 % respectively.</div></div><div><h3>Conclusions</h3><div>This study explored the dynamic evolution during the peri-ictal period from multiple perspectives. There were strong control effects both inside and outside the SOZ before seizure onset but decreased later, confirming the existence of regulatory mechanism of seizures. Further subdivision revealed a hierarchical organization of the regulatory model. Combined with machine learning models, multiple features accurately localized the SOZ, providing a new sight for clinical treatment and serving as a reference model.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106998"},"PeriodicalIF":5.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144255163","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":"TIMP1 inhibits Rac1-mediated ROS production to ameliorate blood–spinal cord barrier disruption in amyotrophic lateral sclerosis","authors":"Jingshu Tang,&nbsp;Yuying Kang,&nbsp;Qiuyu Chen,&nbsp;Baodan Zhang,&nbsp;Nianying Shang,&nbsp;Jiaqi Lan,&nbsp;Lei Wu,&nbsp;Ying Peng","doi":"10.1016/j.nbd.2025.106987","DOIUrl":"10.1016/j.nbd.2025.106987","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration of motor neurons, for which therapeutic strategies and pharmacological interventions remain limited. Disruption of the blood–spinal cord barrier (BSCB) has been identified as a significant factor that may exacerbate motor neuron damage. Tissue inhibitor of metalloproteinase-1 (TIMP1), a molecule known for its dual roles in inhibiting matrix metalloproteinase (MMP) activity and exerting cytokine-like effects via receptor interactions, has been demonstrated to ameliorate endothelial barrier damage in various diseases. Here, we explored the potential of TIMP1 to restore BSCB integrity as a strategy to slow the ALS progression. Specifically, the expression of TIMP1 or its mutant variant AlaTIMP1, which lacks MMP-inhibitory activity, in spinal cord microvascular endothelial cells (SCMECs) prior to disease onset significantly reduces BSCB leakage in mice with ALS, thereby alleviating motor function deficits and delaying disease progression. Additionally, TIMP1 expression restores the expression of junctional complexes in SCMECs, as demonstrated in both in vivo and in vitro ALS models. Mechanistic studies revealed that TIMP1 suppresses ALS injury-induced integrin β1 activation independent of MMP inhibition, blocking downstream Rac1 translocation to the membrane to form a complex with NOX2. The inhibition of NOX2 activity reduces ROS-induced cytoskeletal remodeling, consequently stabilizing overall junctional alignment and preserving the BSCB integrity. Overall, our findings elucidate an MMP-independent mechanism through which TIMP1 regulates BSCB integrity in ALS context, suggesting that TIMP1 could serve as a novel tool for the treatment of ALS, particularly for prophylactic treatment in patients with familial ALS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106987"},"PeriodicalIF":5.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144280693","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":"Modulation of miR-145 in a mouse model of multiple sclerosis: A promising approach to attenuate inflammation and degeneration","authors":"Monique Marylin Alves de Almeida ,&nbsp;Samantha F. Kornfeld ,&nbsp;Yves De Repentigny ,&nbsp;Majd Al-Aarg ,&nbsp;Ibrahim Ghani ,&nbsp;Sarah E. Cummings ,&nbsp;Emma R. Sutton ,&nbsp;Rebecca Yaworski ,&nbsp;Kelsea S. McKay ,&nbsp;Sabrina Gagnon ,&nbsp;Ariane Beauvais ,&nbsp;Rashmi Kothary","doi":"10.1016/j.nbd.2025.106999","DOIUrl":"10.1016/j.nbd.2025.106999","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is a progressive inflammatory disease of the central nervous system (CNS) marked by myelin loss, which impairs nerve function. Current therapies fail to halt disease progression or prevent myelin and axonal degeneration. In this study, we explored the impact of miR-145 loss in a murine model of experimental autoimmune encephalomyelitis (EAE), which mimics MS pathology. Loss of miR-145 reduced clinical severity and significantly decreased immune cell infiltration in the lumbar spinal cord during both the onset and chronic stages of the disease. Additionally, miR-145 loss altered the expression of key inflammatory genes and modulated astrocytic activity throughout EAE. Of significant interest, acute treatment with an antisense oligonucleotide (ASO) targeting miR-145 decreased miR-145 levels and led to reduced disease severity, decreased immune cell infiltration, and an increase in regulatory T cells in EAE mice. Moreover, miR-145 deficiency mitigated axon and myelin degeneration. Our findings suggest that ASOs targeting miR-145 may offer a promising therapeutic strategy, addressing both inflammatory and degenerative components of MS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106999"},"PeriodicalIF":5.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279787","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":"Early and widespread cerebellar engagement during hippocampal seizures and interictal discharges","authors":"M.L. Streng ,&nbsp;B.W. Kottke ,&nbsp;E.M. Wasserman ,&nbsp;L. Zecker ,&nbsp;L. Luong ,&nbsp;S. Kodandaramaiah ,&nbsp;T.J. Ebner ,&nbsp;E. Krook-Magnuson","doi":"10.1016/j.nbd.2025.106991","DOIUrl":"10.1016/j.nbd.2025.106991","url":null,"abstract":"<div><div>Despite research illustrating the cerebellum may be a critical circuit element in processes beyond motor control, and growing evidence for a role of the cerebellum in a range of neurological disorders, including the epilepsies, remarkably little is known about cerebellar changes during seizures. We therefore implemented a novel method for repeated widefield calcium imaging of the cerebellum in awake, chronically epileptic mice. We found widespread changes in cerebellar Purkinje cell activity during temporal lobe seizures. Changes were noted in the anterior and posterior cerebellum (lobules IV-VII), along the midline (vermis), and both ipsilaterally and contralaterally (in the simplex and Crus I) to the seizure focus. This was true for both overtly behavioral seizures <em>and</em> for hippocampal seizures that remained electrographic only – arguing against cerebellar modulation simply reflecting motor components. Moreover, even brief interictal spikes produced widespread alterations in cerebellar activity. Perhaps most remarkably, changes in the cerebellum also occurred <em>prior</em> to any noticeable change in the hippocampal electrographic recordings. Together these results underscore the relevance of the cerebellum with respect to seizure networks, warranting a more consistent consideration of the cerebellum in epilepsy.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106991"},"PeriodicalIF":5.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264012","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}