Progress in Neurobiology最新文献

{"title":"NEIL3 shapes hippocampal network dynamics and fear memory through modulation of PV⁺ interneurons.","authors":"Marion Silvana Fernandez-Berrocal, Dagny Sanden Døskeland, Vidar Langseth Saasen, Anna Maria Bugaj, Nicolas Kunath, Mina Heggedal, Mouzuna Munir, Robert Christoffer Marthinsen, Milan Dekovic Ekeli, Katja Scheffler, Magnar Bjørås, Jing Ye","doi":"10.1016/j.pneurobio.2025.102832","DOIUrl":"10.1016/j.pneurobio.2025.102832","url":null,"abstract":"<p><p>The dynamic balance between excitatory and inhibitory (E/I) signaling is critical for hippocampal network function and memory processing. Here, we uncover a novel role for the DNA glycosylase Endonuclease VIII-like 3 (NEIL3) in maintaining this E/I balance through its impact on parvalbumin-positive (PV⁺) GABAergic interneurons. NEIL3 deficiency leads to a selective reduction in PV⁺ interneurons and impaired perineuronal net (PNN) integrity, likely contributing to further PV⁺ neuron dysfunction. These changes result in altered hippocampal oscillatory dynamics, including increased beta and low gamma power, and reduced high gamma and ripple activity. These network alterations are accompanied by distinct effects on fear memory, as demonstrated using contextual and trace fear conditioning paradigms. NEIL3-deficient mice exhibited enhanced extinction of contextual fear memory but impaired extinction of trace fear memory. These findings suggest that the integrity of inhibitory networks plays differential roles in the spatial versus temporal aspects of fear memory extinction. Transcriptomic analysis further reveals dysregulation of genes involved in glutamatergic and GABAergic signaling. Among these, Gabra2 showed a marked downregulation, potentially driven by changes in promoter DNA methylation. This work identifies NEIL3 as an important regulator of the hippocampal inhibitory network, linking PV⁺ interneuron integrity and oscillatory coordination to distinct memory outcomes, and offers potential mechanistic insight into processes that may contribute to cognitive deficits in disorders characterized by E/I imbalance.</p>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":" ","pages":"102832"},"PeriodicalIF":6.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182219","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 shifts in Microtus ochrogaster neurogenic niches reveal psychiatric-risk pathways engaged by pair-bond formation","authors":"D. Ávila-González ,&nbsp;J. Lugo-Baca ,&nbsp;F. Camacho-Barrios ,&nbsp;A.E. Castro ,&nbsp;D.M. Arzate ,&nbsp;R. Paredes-Guerrero ,&nbsp;N.F. Díaz ,&nbsp;W. Portillo","doi":"10.1016/j.pneurobio.2025.102831","DOIUrl":"10.1016/j.pneurobio.2025.102831","url":null,"abstract":"<div><div>Pair bonding (PB) is a stable affiliative relationship that confers profound behavioral and physiological advantages. The prairie vole (<em>Microtus ochrogaster</em>), one of the few socially monogamous mammals, provides a tractable model for dissecting the neurobiological substrates of social interactions. We previously showed that social co-habitation with mating (SCM) increases cell proliferation and neuronal differentiation in the subventricular zone (SVZ) and dentate gyrus (DG), implicating adult neurogenesis in bond formation. Here, we characterized the underlying molecular programs by bulk RNA-seq of the SVZ, DG and nucleus accumbens (NAc) at two time points, 48 h and 120 h, following SCM or isolated (control) housing. Across ∼ 18000 expressed genes, 286 differentially expressed genes (DEGs) emerged in the female SVZ and 540 in the females DG (120 h vs 48 h SCM), whereas male niches displayed markedly fewer transcriptional shifts, confirming pronounced sexual dimorphism. Gene ontology analysis revealed sustained upregulation of mitochondrial and oxidative-phosphorylation modules, coupled with downregulation of neurogenesis, synaptic plasticity, and cell migration pathways in females at 120 h. In vitro, SVZ-derived neurospheres from females mirrored these signatures: SCM increased the sphere number at 48 h, but neuronal output normalized by 120 h, indicating a transient neurogenic surge. Numerous zinc-finger transcripts and unannotated long non-coding RNAs were also regulated, hinting at vole-specific epigenetic controls. Strikingly, &gt; 100 DEGs mapped to human psychiatric-risk loci. Autism disorder spectrum (ADS) and schizophrenia-associated orthologues (e.g., GRIN2A/B, KMT2A, UBE3A) were predominantly downregulated during bond consolidation in females, whereas isolation elevated major depressive disorder (MDD) markers (e.g., CACNA1H) in both sexes. These data suggest that pair-bond formation recruits transcriptional networks that overlap the genetic architecture of neuropsychiatric diseases, and that social isolation elicits an opposing, disorder-linked profile. Together, our results identified sex-specific, temporally phased molecular pathways that couple adult neurogenesis, energy metabolism, and psychiatric-risk gene networks to the establishment of enduring social bonds.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"253 ","pages":"Article 102831"},"PeriodicalIF":6.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092316","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":"Neural entrainment by speech in human auditory cortex revealed by intracranial recordings","authors":"Serdar Akkol ,&nbsp;Akash Mishra ,&nbsp;Noah Markowitz ,&nbsp;Elizabeth Espinal ,&nbsp;Menoua Keshishian ,&nbsp;Nima Mesgarani ,&nbsp;Charles Schroeder ,&nbsp;Ashesh D. Mehta ,&nbsp;Stephan Bickel","doi":"10.1016/j.pneurobio.2025.102823","DOIUrl":"10.1016/j.pneurobio.2025.102823","url":null,"abstract":"<div><div>Humans live in an environment that contains rich auditory stimuli, which must be processed efficiently. The entrainment of neural oscillations to acoustic inputs may support the processing of simple and complex sounds. However, the characteristics of this entrainment process have been shown to be inconsistent across species and experimental paradigms. It is imperative to establish whether neural activity in response to speech is a result of combination of simple evoked responses or of entrainment of neural oscillations in human participants. In this study, 12 participants with intracranial electrodes listened to natural speech and neural entrainment as evidenced by oscillatory activity persisting beyond the evoked responses was assessed. Neural activity was recorded from 165 contacts in Heschl’s gyrus and superior temporal gyrus. First, acoustic edges in the speech envelope induced coherence between speech and auditory cortex activity. Further, entrainment in the theta-alpha band outlasted the acoustic stimulation. This activity exceeded what could be expected from a simple evoked response. These findings suggest that speech has the potential to entrain neural oscillations in the human auditory cortex.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"253 ","pages":"Article 102823"},"PeriodicalIF":6.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034119","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":"PDGFR mediates lumbar spinal stenosis-induced neuropathic pain by regulating JAK2/STAT3 signaling in activated macrophages","authors":"Kyung Jin Seo ,&nbsp;Chan Sol Park ,&nbsp;Mi So Park ,&nbsp;Won Ho Na ,&nbsp;Jee Youn Lee ,&nbsp;Tae Young Yune","doi":"10.1016/j.pneurobio.2025.102822","DOIUrl":"10.1016/j.pneurobio.2025.102822","url":null,"abstract":"<div><div>Lumbar spinal stenosis (LSS) is one of the most common spinal disorders in elderly people and is often accompanied by neuropathic pain. Although our previous studies have demonstrated that infiltrating macrophage contribute to chronic neuropathic pain in LSS rat model, the molecular mechanisms underlying macrophage activation and infiltration have not been fully elucidated. In this study, we examined the critical role of platelet-derived growth factor receptor (PDGFR) signaling pathway in neuropathic pain associated with macrophage infiltration and activation in LSS rats. The LSS rat model was induced by cauda equina compression using a silicone block placed within the epidural spaces of the L5-L6 vertebrae, with neuropathic pain developing four weeks after compression. We found that the PDGFR and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathways were upregulated in infiltrated macrophages at 28 days in the LSS model. Administration of the PDGFR inhibitor imatinib significantly alleviated LSS-induced macrophages activation and infiltration. Imatinib also reduced LSS-induced chronic mechanical allodynia and inhibited the expression of inflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin beta (IL-1β), interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Furthermore, imatinib significantly alleviated the activation of RAW 264.7 macrophage cell line by lipopolysaccharide (LPS). These findings suggest that PDGFR signaling mediates neuropathic pain by promoting macrophage infiltration and activation following cauda equina compression and may serve as a potential therapeutic target for neuropathic pain in LSS patients.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"253 ","pages":"Article 102822"},"PeriodicalIF":6.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008427","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":"Rodent models of Alzheimer's disease: Critical analysis of current hypotheses and pathways for future research","authors":"Pasindu Hansana Singhaarachchi ,&nbsp;Peter Antal ,&nbsp;Frédéric Calon ,&nbsp;Carsten Culmsee ,&nbsp;Jean-Christophe Delpech ,&nbsp;Martin Feldotto ,&nbsp;Jorine Geertsema ,&nbsp;Emmy E. Hoeksema ,&nbsp;Aniko Korosi ,&nbsp;Sophie Layé ,&nbsp;Jonathan McQualter ,&nbsp;Susanne R. de Rooij ,&nbsp;Christoph Rummel ,&nbsp;Mary Slayo ,&nbsp;Luba Sominsky ,&nbsp;Sarah J. Spencer","doi":"10.1016/j.pneurobio.2025.102821","DOIUrl":"10.1016/j.pneurobio.2025.102821","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) was first described over a century ago. However, the mechanisms underlying the disease are not well understood to this day. This has negatively impacted our ability to create animal models to design and test targeted reliable treatments for the disease. Amyloid β plaque accumulation, aggregation of neurofibrillary tangles, neuroinflammation, neurodegeneration, and, of course, cognitive decline, are few of the many observed pathological features associated with AD. However, there is a concern that the animal models of AD that are based on these frameworks may not be accurately representing AD in people. As such, the results from preclinical trials have not historically translated well to the clinic. In this article, we review the current major hypotheses to describe AD; we outline the major strengths and weaknesses of the commonly used rodent models used to replicate features of these hypotheses; and we provide a strategy for the field for future research.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102821"},"PeriodicalIF":6.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925331","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":"Stimulus-driven rivalry among V1 neurons.","authors":"Jiayu Wang, Rui Zhang, Xingya Cai, Rendong Tang, Zhuoyue Dai, Haidong D Lu","doi":"10.1016/j.pneurobio.2025.102820","DOIUrl":"https://doi.org/10.1016/j.pneurobio.2025.102820","url":null,"abstract":"<p><p>Binocular rivalry (BR) is a fascinating phenomenon that occurs when the two eyes are presented with dissimilar images, causing observers to perceive continuous alternations between the two images. During BR, cortical activation relies on both stimulus factors (e.g., incongruency), and top-down cognitive factors (e.g., attention). However, differentiating the influences of these factors has been proven challenging. Anesthetized animals provide a valuable model for studying pure stimulus-driven neural activity, free from high-level cognitive and behavioral influences. Using two-photon calcium imaging, we recorded neuronal responses to BR stimuli in V1 and V2 of anesthetized macaques. Under BR stimulation, V1 neurons exhibited continuous fluctuations in response, with varying fluctuation strengths that similar to their activity under stimulus alternation (SA) conditions. The main features of the fluctuations mirrored those observed in BR perception. The fluctuation strength of different neurons was associated with their ocular dominance and orientation selectivity. Similar observations in V2 suggest that such rivalry activity was successfully propagated along the visual pathway. These findings indicate that stimulus processing mechanisms in V1 are capable of generating rivalry-like alternations in the absence of consciousness.</p>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":" ","pages":"102820"},"PeriodicalIF":6.1,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966530","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":"Auditory regulation of hippocampal locomotion circuits by a non-canonical reticulo-limbic pathway","authors":"Jessica Winne ,&nbsp;George Nascimento ,&nbsp;Rafael Pedrosa ,&nbsp;Margareth Nogueira ,&nbsp;Cristiano S. Simões ,&nbsp;Klas Kullander ,&nbsp;Katarina E. Leão ,&nbsp;Richardson N. Leão","doi":"10.1016/j.pneurobio.2025.102811","DOIUrl":"10.1016/j.pneurobio.2025.102811","url":null,"abstract":"<div><div>The ability to rapidly detect and respond to unexpected auditory stimuli is critical for adaptive behavior, especially during locomotion. Since movement suppresses auditory cortical activity, it remains unclear how salient auditory information influences locomotor circuits. In this work, using in vivo calcium imaging, electrophysiology, chemo- and optogenetics, we investigate the path that relays loud broadband sounds to the dorsal hippocampus (dHPC) and modulates theta oscillations. We demonstrate that noise accelerates theta frequency and decreases its power, effects mediated by entorhinal cortex (EC) and medial septum (MS) inputs while independent of the primary auditory cortex. Activation of dorsal cochlear nucleus (DCN) neurons projecting to the pontine reticular nucleus (PRN) mimics noise-driven hippocampal responses, supporting a brainstem-limbic auditory processing route. Furthermore, noise selectively modulates CA1 pyramidal neuron and interneuron activity, reflecting diverse circuit dynamics. Finally, loud broadband noise stimulus increased theta coherence between the dHPC and the medial prefrontal cortex (mPFC), enhancing interregional synchronization. These results highlight the mechanisms in which the DCN filters behaviorally relevant sounds promoting acoustic motor integration in the hippocampus during locomotion, without direct influence of the auditory cortex.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102811"},"PeriodicalIF":6.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842491","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":"Eye movements organize excitability state, information coding and network connectivity in the human hippocampus","authors":"Marcin Leszczynski ,&nbsp;Elizabeth Espinal ,&nbsp;Elliot Smith ,&nbsp;Catherine Schevon ,&nbsp;Sameer Sheth ,&nbsp;Charles E. Schroeder","doi":"10.1016/j.pneurobio.2025.102812","DOIUrl":"10.1016/j.pneurobio.2025.102812","url":null,"abstract":"<div><div>Natural vision is an active sensing process that entails frequent eye movements to sample the environment. Nonetheless vision is often studied using passive viewing with eye position held constant. Using closed-loop eye-tracking, with saccade-contingent stimulation and simultaneous intracranial recordings in surgical epilepsy patients, we tested the critical role of eye movement signals during natural visual processing in the hippocampus and hippocampal-amygdala circuit. Prior work shows that saccades elicit phase reset of ongoing neural excitability fluctuations across a broad array of cortical and subcortical areas. Here we show that saccade-related phase reset systematically modulates neuronal ensemble responses to visual input, enables phase-coding of information across the saccade-fixation cycle and modulates network connectivity between hippocampus and amygdala. The saccade-fixation cycle thus emerges as a fundamental sampling unit, organizing a range of neural operations including input representation, network connectivity and information coding.</div></div><div><h3>Summary</h3><div>Saccade-fixation cycle: a fundamental sampling unit, organizing input representation, information coding and network coordination.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102812"},"PeriodicalIF":6.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859560","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":"Npas4 drives the effects of early social isolation on social behaviors and prefrontal parvalbumin neurons","authors":"Keshav Jindal ,&nbsp;Amanda Ringland ,&nbsp;Sydney Fitzcharles ,&nbsp;Chase Redd ,&nbsp;Damian G. Wheeler ,&nbsp;Laurence Coutellier","doi":"10.1016/j.pneurobio.2025.102810","DOIUrl":"10.1016/j.pneurobio.2025.102810","url":null,"abstract":"<div><div>Social behaviors mature during the adolescent period. Prefrontal parvalbumin (PV) neurons have been shown to play a critical role in this process, and their deregulation by early social isolation leads to social deficits in adulthood. However, the molecular mechanisms by which early social isolation affects prefrontal PV neurons causing social impairments remain unclear. Here, we identified the neuronal-specific transcription factor Npas4 as a key player in this process. We first showed that social isolation results in aberrant adolescent developmental trajectories of Npas4 and PV expression in the prefrontal cortex (PFC) leading to prolonged downregulation of Npas4 and upregulation of PV, suggesting an Npas4-driven over-inhibition of prefrontal circuits following early social isolation. Using Npas4 knockout (KO) mice and iDISCO whole brain cFos mapping, we then further implicated Npas4-dependent reduction in prefrontal activity with appearance of sociability deficits in adulthood: Npas4 KO mice failed to show an age-increase in sociability and in activity of the anterior cingulate cortex (ACC) that we observed in wild-type mice during the transition from adolescence to adulthood. Finally, using a viral approach to restore prefrontal Npas4 expression during early adolescence, we were able to rescue the sociability deficits and aberrant expression of PV in the AAC induced by social isolation. Altogether, our findings identified Npas4 as a novel molecular mediator of early social isolation on social deficits, through the role it plays on the adolescent maturation of prefrontal PV neurons.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102810"},"PeriodicalIF":6.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856204","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 hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice","authors":"Mouna Haidar ,&nbsp;Aida Viden ,&nbsp;Christin Daniel ,&nbsp;Brittany Cuic ,&nbsp;Taide Wang ,&nbsp;Marius Rosier ,&nbsp;Doris Tomas ,&nbsp;Samuel A. Mills ,&nbsp;Alistair Govier-Cole ,&nbsp;Elvan Djouma ,&nbsp;Nirma D. Perera ,&nbsp;Sophia Luikinga ,&nbsp;Valeria Rytova ,&nbsp;Samantha K. Barton ,&nbsp;David G. Gonsalvez ,&nbsp;Lucy M. Palmer ,&nbsp;Catriona McLean ,&nbsp;Matthew C. Kiernan ,&nbsp;Steve Vucic ,&nbsp;Bradley J. Turner","doi":"10.1016/j.pneurobio.2025.102809","DOIUrl":"10.1016/j.pneurobio.2025.102809","url":null,"abstract":"<div><div>Degeneration of both upper motor neurons in the brain and lower motor neurons in the spinal cord defines amyotrophic lateral sclerosis (ALS), but how they are linked in ALS pathophysiology is unclear. Here, we uncover a cortical origin of neurodegeneration in ALS mediated by upper motor neuron hyperexcitability. Chronic hyperexcitability of upper motor neurons induced by excitatory chemogenetics in healthy adult mice induced progressive motor deficits, weakness and core pathological hallmarks of ALS, including upper motor neurons loss, synaptic pathology, corticospinal tract degeneration and reactive gliosis. Importantly, upper motor neuron hyperexcitability and loss were sufficient to drive degeneration of lower motor neurons and their distal axons and neuromuscular junctions, associated with astrocyte and microglial activation in spinal cord. Cortical hyperexcitability also triggered cytoplasmic TAR DNA binding protein 43 (TDP-43) aggregation in upper motor neurons and lower motor neurons, placing hyperexcitability upstream of TDP-43 proteinopathy in ALS. These findings establish a cortical origin of ALS mediated by upper motor neurons, consistent with an anterograde mechanism of neurodegeneration throughout the central and peripheral nervous systems.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102809"},"PeriodicalIF":6.1,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817410","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}