European Journal of Neuroscience最新文献

{"title":"Distinct Brain Electrical Activity Patterns in Dominant and Submissive Mice: Implications for Cognitive Impairments","authors":"Maryia Bairachnaya,&nbsp;Alexey Shnyder,&nbsp;Albert Pinhasov,&nbsp;Izhak Michaelevski","doi":"10.1111/ejn.70184","DOIUrl":"https://doi.org/10.1111/ejn.70184","url":null,"abstract":"<div>\u0000 \u0000 <p>The prefrontal, visual, and posterior parietal cortices are key to cognition, social interaction, and novelty recognition, but the impact of social hierarchy and inherent stress sensitivity on their interplay remains underexplored. Our findings reveal significant neural differences between stress-resilient dominant (Dom) and stress-sensitive submissive (Sub) mice, particularly in theta band power, inter-regional coherence, and phase–amplitude coupling. Dom mice exhibited reduced theta coherence and dynamic changes in theta-gamma phase amplitude coupling between the prefrontal and visual cortices, which were associated with better memory recall and cognitive flexibility. In addition, Dom mice showed increased left-to-right visual cortex connectivity during the recognition task, linked to successful novelty discrimination, while Sub mice lacked this theta-driven causality. These results suggest that stress sensitivity associated with social rank alters neural activity and connectivity, contributing to the differing performance of Dom and Sub mice in novelty recognition tasks, providing potential diagnostic and therapeutic implications for targeting theta-driven connectivity.</p>\u0000 </div>","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CARE Competition “Exploring the Necessity of Animal Experiments”","authors":"Christelle Baunez","doi":"10.1111/ejn.70201","DOIUrl":"https://doi.org/10.1111/ejn.70201","url":null,"abstract":"&lt;p&gt;Within FENS, the CARE committee was originally created to better inform the neuroscientific community and homogenize the actions taken to improve animal well-being in our research and apply the 3Rs (Refine, Reduce, Replace). In parallel, however, the actions taken against animal use in research forced the European parliament to take action and re-evaluate animal experimentation. As CARE committee, we have thus engaged in activities to better coordinate with other organizations (such as EARA [European Association on Research using Animals], EBC [European Brain Council], CAR of SFN) to meet and inform politicians, the public, and the scientific community at large, regarding the continued need to use animals in research. Our message is that animal experiments are an essential part of progress in neuroscience and are being done with great responsibility and maximal care to reduce harm and improve well-being, in line with the 3Rs. In neuroscience, nonanimal methods currently complement animal experiments, as each model offers unique strengths for addressing different aspects of research questions. However, phasing out animal research remains on the agenda and it is important that the next generation of scientists is prepared to take responsibility and advocate for the use of animals in brain research for as long as necessary. In order to make this generation of scientists share their reflections about this often highly emotional topic, the CARE committee launched a writing competition under the motto: “Why do we still need animal research in neurosciences?”. Two categories of assays could be submitted “scientific assays” or “literary assays”. The call for participation was launched via the FENS newsletter, our CARE webpage (https://www.fens.org/about-fens/our-organisation/fens-committees/care-committee) and various social media platforms (Facebook, X, LinkedIn etc.). A total of 43 entries were received from 23 different countries as diverse as Canada, India, Nigeria, Denmark, Ireland, and so on. All members of CARE acted as member of the jury and all converged towards the same impression that all assays reflected a deep thinking and a great sense of responsibility from each participant. One winner and two runners-up of each category have been nominated and are published in the FENS official journal EJN as a special issue. The two winners also received a €500 prize, and their text was highlighted at the FENS Forum 2024 in Vienna. The winner of the best scientific assay is Cassandre Vielle (current PhD student in ethology at Concordia University, Montreal, Canada; holder of a PhD in Neurosciences from Aix-Marseille University, France). She has written an assay on the use of animals in drug-addiction research and how it could be improved for better translatability towards human patients suffering from addiction. The winner of the literary assay is Ivan Montiel (current post-doc at Institut Pasteur, Paris, France). He has written an assay entitled “Bey","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejn.70201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cortical Morphometry of Contralesional Inferior Frontal Gyrus and Structural Connections of Fronto-Thalamic Circuitry Correlate With Language Outcomes in Poststroke Aphasia","authors":"Qing Ye,&nbsp;Jie Zhang,&nbsp;Zhenyu Shu,&nbsp;Yingqiao Wang,&nbsp;Shuangshuang Zhang,&nbsp;Yating Chen,&nbsp;Xiangming Ye","doi":"10.1111/ejn.70178","DOIUrl":"https://doi.org/10.1111/ejn.70178","url":null,"abstract":"<div>\u0000 \u0000 <p>The extended Broca's system, including its connected subcortical structures, plays a central role in language production. However, the contribution of its right hemisphere homologs to language recovery after stroke remains uncertain. This study aimed to investigate structural changes in the right inferior frontal gyrus (IFG) and fronto-thalamic pathways and their associations with language outcomes in subacute poststroke aphasia. Twenty-eight patients with subacute poststroke aphasia and 35 healthy controls were enrolled and underwent language assessments and magnetic resonance imaging. Surface-based morphometry of the right IFG and microstructural analysis of fronto-thalamic tracts were performed. Compared with healthy controls, patients exhibited significantly reduced cortical thickness in the right pars triangularis and pars orbitalis (false discovery rate [FDR]-corrected <i>p</i> &lt; 0.05). Among the IFG-thalamic connections, fiber density (FD) of the tracts linking the right pars triangularis to the thalamus was significantly reduced (FDR-<i>p</i> &lt; 0.05). In patients, cortical thickness of the right pars orbitalis was negatively correlated with overall and single-word repetition scores (ρ = −0.535 and ρ = −0.563, respectively), and FD of the right triangular-thalamic connection was negatively correlated with single-word repetition (ρ = −0.526) and sentence comprehension scores (ρ = −0.570 to −0.514) (all FDR-<i>p</i> &lt; 0.05). In conclusion, reduced cortical thickness in the right IFG and impaired fronto-thalamic connectivity may reflect contralesional adaptations in subacute poststroke aphasia, with these structural alterations potentially serving as neuroanatomical targets for prognostic evaluation and therapeutic strategies to enhance language recovery.</p>\u0000 </div>","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in Higuchi Fractal Dimension Across Age in Healthy Human EEG Are Anticorrelated With Changes in Oscillatory Power and 1/f Slope","authors":"Srishty Aggarwal,&nbsp;Supratim Ray","doi":"10.1111/ejn.70193","DOIUrl":"https://doi.org/10.1111/ejn.70193","url":null,"abstract":"<div>\u0000 \u0000 <p>Nonlinear dynamical methods such as Higuchi fractal dimension (HFD) are often used to study the complexities of brain activity. In human electroencephalogram (EEG), although power in the gamma band (30–70 Hz) and the slope of the power spectral density (PSD) have been shown to reduce with healthy ageing, there are conflicting findings regarding how HFD and other measures of complexity vary with ageing. Further, the dependence of HFD on features obtained from PSD (such as gamma power and slope) has not been thoroughly probed. To address these issues, we computed time- and frequency-resolved HFD for EEG data collected from an elderly population (<i>N</i> = 217), aged between 50 and 88 years, for baseline (BL) eyes open state and during a fixation task in which visual grating stimuli that induce strong gamma oscillations were presented. During BL, HFD increased with age for frequencies up to 150 Hz but surprisingly showed an opposite trend at higher frequencies. Interestingly, this change in HFD was opposite to the age-related change in PSD 1/<i>f</i> slope. Further, stimulus-related changes in HFD were anticorrelated with the changes in oscillatory power. However, stimulus- and age-related changes in HFD persisted even after normalization with surrogates, showing the effect of nonlinear dynamics on HFD. Further, age classification using HFD was slightly better than classification using spectral features (power and slope). Therefore, HFD could be jointly sensitive to various spectral features as well as some nonlinearities not captured using spectral analysis, which could enhance our understanding of brain dynamics underlying healthy ageing.</p>\u0000 </div>","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reorganization of Social Representations in the Insular Cortex During Conspecific Familiarization and Discrimination","authors":"Masaaki Sato,&nbsp;Eric T. N. Overton,&nbsp;Shuhei Fujima,&nbsp;Toru Takumi","doi":"10.1111/ejn.70190","DOIUrl":"https://doi.org/10.1111/ejn.70190","url":null,"abstract":"<div>\u0000 \u0000 <p>The familiarity of socially interacting peers markedly impacts behavior. However, the neuronal representations that distinguish familiar from novel conspecifics within the social brain network are not fully understood. Following our previous findings that neurons in the agranular insular cortex represent ongoing social interactions, we monitored the activity of neurons in the agranular insular cortex using microendoscopic calcium imaging in mice during social recognition memory and linear chamber social discrimination tasks. In the social recognition memory task, repeated interactions with the same target activated largely nonoverlapping cells during each session. The fraction of cells associated with social investigation (hereafter called social cells) decreased as the subject repeatedly interacted with the same target, whereas the substitution of a second novel target and subsequent exchange with the first familiar target recruited more new social cells. In the linear chamber social discrimination task, adding a novel target transiently increased the number of cells responding to both targets, followed by an eventual increase in the number of cells responding to the novel target. These results demonstrate that social cell ensembles in the agranular insular cortex decrease in size while changing their participating neurons during conspecific familiarization. They also rapidly reorganize at the single-cell level to represent interactions with novel peers rather than familiar peers during conspecific discrimination.</p>\u0000 </div>","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rearing in a Shelved Environment Chronically Modifies Offspring Behaviour and Physiology","authors":"Logan J. Bigelow,&nbsp;Emily K. Pope,&nbsp;Carey G. Ousley,&nbsp;Ariana E. McGrattan,&nbsp;Debra S. MacDonald,&nbsp;Paul B. Bernard","doi":"10.1111/ejn.70199","DOIUrl":"https://doi.org/10.1111/ejn.70199","url":null,"abstract":"<p>The study of environmental enrichment in rodents has primarily focused on adolescents and adults, with less information available for nursing dams and their pups. While we have previously observed some differences in behaviour and physiology of pups reared in shelved versus single-level cages, further examination of this relationship is necessary. To understand the impact of rearing in shelved cages, we assessed various parameters in pups including body weight, ultrasonic vocalizations, hair corticosterone concentration, behaviour in the open field and elevated plus maze and spatial working memory in the spontaneous alternation task. In addition, dams were assessed in the open field and elevated plus maze to identify any changes in stress-related behaviour. As adults, rats reared in enriched cages had significantly lower body weights, higher hair corticosterone concentrations and spent less time in the open arms of the elevated plus maze compared to those in standard cages. Additionally, rats reared in enriched cages emitted a lower number of frequency-modulated calls. In agreement with the behaviour observed in their pups, dams housed in enriched cages spent significantly less time in the centre of the open field. The results indicate that there are long-term changes in behaviour and physiology based upon different rearing conditions, reinforcing the importance of considering rearing environment when planning studies of a developmental nature. Furthermore, determining optimal rearing conditions will not only improve laboratory animal welfare but also improve reproducibility in animal research through the standardization of rearing conditions across institutions and laboratories.</p>","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejn.70199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase-Amplitude Coupling in Sleep EEG—Stable Trait or Shaped by Experience? (Commentary on Cross et al., 2025)","authors":"Niels Niethard","doi":"10.1111/ejn.70204","DOIUrl":"https://doi.org/10.1111/ejn.70204","url":null,"abstract":"&lt;p&gt;The consolidation of newly encoded memories into long-term storage critically depends on plasticity processes during sleep. It is assumed that memory representations are facilitated by repeated reactivation of neuronal firing patterns during sleep, which promotes synaptic plasticity and thereby strengthens memory traces. A growing body of evidence shows that such memory reactivations occur during specific oscillatory patterns in the EEG that are unique to sleep (Brodt et al. &lt;span&gt;2023&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;In particular, cortical slow oscillations (SOs) and thalamocortical spindles have been consistently associated with enhanced memory consolidation during sleep. SOs are large-amplitude, low-frequency fluctuations lasting between 0.5 and 2 s, reflecting transitions between cortical down states (neuronal silence due to hyperpolarization) and up states (neuronal depolarization and increased excitability). Sleep spindles, another hallmark of NREM sleep, are brief bursts of activity in the 11 to 16 Hz frequency range characterized by waxing and waning amplitudes. Crucially, the precise temporal coupling between SOs and spindles has emerged as a key mechanism supporting synaptic plasticity and the stabilization of memory traces during NREM sleep (Schreiner et al. &lt;span&gt;2021&lt;/span&gt;; Brodt et al. &lt;span&gt;2023&lt;/span&gt;; Staresina &lt;span&gt;2024&lt;/span&gt;). Prior research has shown that aging alters this SO-spindle coupling, and that such alterations are associated with cognitive decline and impaired memory performance (Helfrich et al. &lt;span&gt;2017&lt;/span&gt;; Muehlroth et al. &lt;span&gt;2019&lt;/span&gt;; Hahn et al. &lt;span&gt;2020&lt;/span&gt;). However, it remains unclear whether SO-spindle coupling represents a stable, trait-like feature of an individual's sleep architecture or whether it is an adaptive mechanism that can vary depending on recent experiences, such as memory encoding.&lt;/p&gt;&lt;p&gt;To investigate whether SO-spindle coupling is influenced by prior learning, Cross et al. (&lt;span&gt;2025&lt;/span&gt;) conducted a study involving 41 participants who underwent overnight polysomnographic recordings. Participants experienced two experimental conditions: one night following a word-pair learning task and a control night without any preceding learning. The study also manipulated learning load across groups—participants either learned 40 or 120 word pairs—and introduced a performance-based criterion for one of the 40-word-pair groups. Specifically, the criterion group was required to achieve at least 60% correct recall to proceed, whereas the other 40-word and 120-word groups were exposed to the word pairs twice, regardless of recall performance. While Cross and colleagues observed a correlation between memory performance and the phase of SO-spindle coupling in the group that met the learning criterion, they did not find any significant differences in SO-spindle coupling between the learning and control nights across any of the experimental conditions. Notably, they also reported a strong correlation bet","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejn.70204","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When Stopping Requires Going: Physiological Similarities Between Action Cancellation and the Cancellation of Action Cancellation","authors":"Simon Weber,&nbsp;Sauro E. Salomoni,&nbsp;Mark R. Hinder","doi":"10.1111/ejn.70182","DOIUrl":"https://doi.org/10.1111/ejn.70182","url":null,"abstract":"<p>The reactive cancellation of real-world actions typically requires complex combinations of both muscle contraction and/or muscle suppression. However, current experimental paradigms solely examine contexts in which action cancellation requires muscle suppression. To provide fundamental insights into inhibitory control mechanisms, we directly compared the latency of action cancellation in novel paradigms where ‘stopping’ required either suppression of planned activation or reinstatement of ongoing activity. Twenty healthy adults (mean age = 32.2 years) completed novel variants of the stop signal task (SST) in which each trial began with tonic force production to depress two buttons. When a go signal appeared, participants were required to release these buttons. On a subset of trials, a stop signal occurred after a brief delay, and participants were required to cancel the release of one of the buttons. Data in these variants were compared to conventional response-selective SSTs, in which the go signal required bilateral button presses and stop signals necessitated the cancellation of one of these responses. Electromyographic (EMG) recordings allowed a detailed comparison of the characteristics of muscle contraction and suppression (i.e., stopping speed) across these tasks. When physiological evidence of synchronous action cancellation in both hands was observed (supporting recent models of complex stopping), EMG measures of action cancellation speed did not differ (<i>p</i> = 0.863, <i>BF</i>₀₁ = 8.49) between cancellation of releases and cancellation of presses conditions. This result suggests that response inhibition may broadly characterise reactive control to maintain a current physiological state rather than specific cancellation of a voluntary response.</p>","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejn.70182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSK-3β and mTOR Phosphorylation Mediate the Reversible Regulation of Hypomagnetic Field on Adult Neural Stem Cell Proliferation","authors":"Jie Ren,&nbsp;Fulai Li,&nbsp;Jianxun Shen,&nbsp;Lanxiang Tian,&nbsp;Yongxin Pan","doi":"10.1111/ejn.70202","DOIUrl":"https://doi.org/10.1111/ejn.70202","url":null,"abstract":"<p>Exposure to hypomagnetic field (HMF) of &lt; 5 μT has been demonstrated to impair cognitive behaviors in mammals by disrupting neurogenesis. This process could potentially be modulated by the protein phosphorylation of adult neural stem cells (aNSCs) that are highly sensitive to environmental changes. However, the effects of HMF on aNSCs protein phosphorylation remain unclear. Here, we found that HMF reversibly regulates the effects on aNSC proliferation by modulating protein phosphorylation in aNSCs. Specifically, HMF inhibits aNSCs proliferation by reducing glycogen synthase kinase 3β (GSK-3β) phosphorylation, and when aNSCs are returned from HMF to the geomagnetic field (rGMF), rGMF activates mammalian target of rapamycin (mTOR) phosphorylation to restore their proliferation. These findings not only advance our understanding of the molecular basis of HMF-induced biological effects but also illuminate potential therapeutic targets for maintaining neural homeostasis in extreme environments.</p>","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejn.70202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization and Regulation of Alpha-Synuclein Phosphorylation in Enteric Neurons","authors":"Gaëlle Pinard,&nbsp;Hannah Elena Kunz,&nbsp;Giuseppe Madaro,&nbsp;Thibauld Oullier,&nbsp;Simon Lassozé,&nbsp;Adrien de Guilhem de Lataillade,&nbsp;Pierre-François Charbonneau,&nbsp;Martial Caillaud,&nbsp;Jan-Hendrik Egberts,&nbsp;Thilo Wedel,&nbsp;Laurène Leclair-Visonneau,&nbsp;Malvyne Rolli-Derkinderen,&nbsp;François Cossais,&nbsp;Pascal Derkinderen","doi":"10.1111/ejn.70198","DOIUrl":"https://doi.org/10.1111/ejn.70198","url":null,"abstract":"<div>\u0000 \u0000 <p>Alpha-synuclein is a 140 aa neuronal protein pathologically and genetically linked to Parkinson's disease (PD). In PD, the major protein modification of alpha-synuclein is phosphorylation at serine 129. Alpha-synuclein phosphorylation also occurs at low levels in normal brains and cultured CNS neurons, but its regulation and role are only beginning to be investigated. The enteric nervous system is now recognized as a second brain in its own right, and therefore, we set out to examine the regulation of alpha-synuclein phosphorylation in enteric neurons. To this end, primary cultures of rat enteric nervous system (ENS) and enteric neurons, which both express alpha-synuclein, were either depolarized or treated with forskolin and analyzed by western blot. We found that membrane depolarization and forskolin induced alpha-synuclein phosphorylation via a Ca²⁺-calmodulin-dependent protein kinase and cAMP/exchange protein directly activated by cyclic AMP (EPAC) signaling pathway, respectively. Both pathways converged on Polo-like kinase 2 (PLK2) to phosphorylate alpha-synuclein. PLK2 inhibition increased the amount of alpha-synuclein secretion while reducing its intracellular phosphorylation level in both cytoplasmic and membranous fractions. To investigate alpha-synuclein phosphorylation in the ENS further, specimens of human colon were analyzed to show that the distribution of phosphorylated alpha-synuclein in the ENS was highly variable and that the amount of soluble phosphorylated alpha-synuclein did not differ between PD and control subjects. Our study is the first to show that alpha-synuclein phosphorylation can be regulated in enteric neurons, providing a basis to unravel the functions of alpha-synuclein and its phosphorylation in the ENS.</p>\u0000 </div>","PeriodicalId":11993,"journal":{"name":"European Journal of Neuroscience","volume":"62 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}