Frontiers in Molecular Neuroscience最新文献

{"title":"Transcorneal electrical stimulation restores DNA methylation changes in retinal degeneration.","authors":"Ben Yi Tew, Gerald C Gooden, Pei-An Lo, Dimitrios Pollalis, Brandon Ebright, Alex J Kalfa, Alejandra Gonzalez-Calle, Biju Thomas, David N Buckley, Thomas Simon, Zeyi Yang, Ege Iseri, Cody L Dunton, Vadim Backman, Stan Louie, Gianluca Lazzi, Mark S Humayun, Bodour Salhia","doi":"10.3389/fnmol.2024.1484964","DOIUrl":"10.3389/fnmol.2024.1484964","url":null,"abstract":"<p><strong>Background: </strong>Retinal degeneration is a major cause of irreversible blindness. Stimulation with controlled low-level electrical fields, such as transcorneal electrical stimulation (TES), has recently been postulated as a therapeutic strategy. With promising results, there is a need for detailed molecular characterization of the therapeutic effects of TES.</p><p><strong>Methods: </strong>Controlled, non-invasive TES was delivered using a custom contact lens electrode to the retinas of Royal College of Surgeons (RCS) rats, a model of retinal degeneration. DNA methylation in the retina, brain and cell-free DNA in plasma was assessed by reduced representation bisulfite sequencing (RRBS) and gene expression by RNA sequencing.</p><p><strong>Results: </strong>TES induced DNA methylation and gene expression changes implicated in neuroprotection in the retina of RCS rats. We devised an epigenomic-based retinal health score, derived from DNA methylation changes observed with disease progression in RCS rats, and showed that TES improved the epigenomic health of the retina. TES also induced DNA methylation changes in the superior colliculus: the brain which is involved in integrating visual signaling. Lastly, we demonstrated that TES-induced retinal DNA methylation changes were detectable in cell-free DNA derived from plasma.</p><p><strong>Conclusion: </strong>TES induced DNA methylation changes with therapeutic effects, which can be measured in circulation. Based on these changes, we were able to devise a liquid biopsy biomarker for retinal health. These findings shed light on the therapeutic potential and molecular underpinnings of TES, and provide a foundation for the further development of TES to improve the retinal health of patients with degenerative eye diseases.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1484964"},"PeriodicalIF":3.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy.","authors":"Michael Aschner, Anatoly V Skalny, Rongzhu Lu, Airton C Martins, Yousef Tizabi, Sergey V Nekhoroshev, Abel Santamaria, Anton I Sinitskiy, Alexey A Tinkov","doi":"10.3389/fnmol.2024.1504802","DOIUrl":"10.3389/fnmol.2024.1504802","url":null,"abstract":"<p><p>Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1504802"},"PeriodicalIF":3.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential timing of mitochondrial activation in rat dorsal striatum induced by procedural learning and swimming.","authors":"Rogelio Pegueros-Maldonado, Antonio Fuentes-Ibañez, Mónica M Monroy, Oscar A Gutiérrez, Norma Serafín, Santiago M Pech-Pool, Mauricio Díaz-Muñoz, Gina L Quirarte","doi":"10.3389/fnmol.2024.1495027","DOIUrl":"10.3389/fnmol.2024.1495027","url":null,"abstract":"<p><p>Stressful experiences form stronger memories due to enhanced neural plasticity mechanisms linked to glucocorticoid hormones (cortisol in humans, corticosterone in rats). Among other neural structures, the dorsal striatum plays a role in the corticosterone-induced consolidation of stressful memories, particularly in the cued water maze task. Neural plasticity is related to mitochondrial activity due to the relevance of energy production and signaling mechanisms for functional and morphological neuronal adaptations. Corticosterone has been shown to enhance brain mitochondrial activity by activating glucocorticoid receptors. In this context, striatum functions are susceptible to change in relation to mitochondrial responses. Based on this evidence, we hypothesized that training in the cued water maze would induce an increase in corticosterone levels and mitochondrial activity (mitochondrial membrane potential and calcium content) in the dorsal striatum, and that these adaptations might be related to memory consolidation of the task. We used an ELISA assay to evaluate plasma and striatal corticosterone levels; mitochondrial activity was determined with the florescent probes MitoTracker Red (mitochondrial membrane potential) and Rhod-2 (calcium content) in brain slices containing the dorsal striatum of rats trained in the cued water maze and euthanized at different times after training (0.5, 1.5, or 6.0 h). We also analyzed the effect of post-training inhibition of striatal mitochondrial activity by OXPHOS complex 1 inhibitor rotenone, on the consolidation of the cued water maze task. We found that cued water maze training induced an increase in corticosterone levels and a time-dependent elevation of mitochondrial membrane potential and mitochondrial calcium content in the dorsal striatum. Unexpectedly, rotenone administration facilitated the retention test. Altogether, our results suggest that enhanced mitochondrial activity in the dorsal striatum is relevant for cued water maze consolidation. The increase in mitochondrial activity was contextually associated with an elevation of corticosterone in plasma and the dorsal striatum. Additionally, our swimming groups also showed an increase in mitochondrial activity in the dorsal striatum, but with a different pattern, which could suggest a differential functional adaptation in this structure.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1495027"},"PeriodicalIF":3.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum: Mechanisms of mitophagy and oxidative stress in cerebral ischemia-reperfusion, vascular dementia, and Alzheimer's disease.","authors":"Yujie Lyu, Zhipeng Meng, Yunyun Hu, Bing Jiang, Jiao Yang, Yiqin Chen, Jun Zhou, Mingcheng Li, Huping Wang","doi":"10.3389/fnmol.2024.1507345","DOIUrl":"10.3389/fnmol.2024.1507345","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fnmol.2024.1394932.].</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1507345"},"PeriodicalIF":3.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-autonomous action of <i>Slit2</i> in radial migration of cortical projection neurons.","authors":"Tian Jiang, Guozhen Niu, Chunping Wu, Xiaomeng Tu, Jian Xiao, Xue Li, Jie-Guang Chen, Huateng Cao","doi":"10.3389/fnmol.2024.1505434","DOIUrl":"10.3389/fnmol.2024.1505434","url":null,"abstract":"<p><p>Neuronal radial migration is a fundamental process for cortical development, the disruption of which causes neurological and psychiatric dysfunctions. SLIT2 plays diverse functions in brain development and is a well-known axon guidance molecule. In this study, we investigated the radial migration of projection neurons in the developing cerebral cortex by <i>in utero</i> knockdown (KD) of <i>Slit2</i> in mice. KD of <i>Slit2</i> did not interfere with the neurogenesis and fate-determination but led to the accumulation of the transfected cells in the intermediate zone (IZ), suggesting that the expression of <i>Slit2</i> is crucial for the radial migration of the cortical neurons. KD of <i>Slit2</i> hindered the transition of cells from a multipolar to a bipolar shape, which is necessary for glia-guided locomotion. Interestingly, reducing Slit2 did not affect the migration of neighboring untransfected cells, indicating a cell-autonomous action by SLIT2. In addition, the action of SLIT2 KD was mimicked by a dominant negative mutant of ROBO2, a canonical membrane receptor of SLIT2, supporting that SLIT2 acted locally as a secretory molecule. Our results suggest that SLIT2 is indispensable for the radial migration of cortical neurons through an autocrine signaling mechanism.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1505434"},"PeriodicalIF":3.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMAO is involved in sleep deprivation-induced cognitive dysfunction through regulating astrocytic cholesterol metabolism via SREBP2.","authors":"Shan Zhu, Yue Wang, Yansong Li, Na Li, Yige Zheng, Qiao Li, Hongyan Guo, Jianyu Sun, Qian Zhai, Yaomin Zhu","doi":"10.3389/fnmol.2024.1499591","DOIUrl":"10.3389/fnmol.2024.1499591","url":null,"abstract":"<p><p>Sleep deprivation (SD) contributes to cognitive impairment. Astrocytic cholesterol biosynthesis is crucial for brain cholesterol homeostasis and cognitive function. However, the underlying mechanism of astrocytic cholesterol metabolism in SD-induced cognitive impairment has not been fully explored. Trimethylamine N-oxide (TMAO), a product of liver flavin-containing monooxygenase-3 (FMO3), has been shown to be increased in the urine of sleep-deprived humans and implicated with peripheral cholesterol metabolism. Nevertheless, how TMAO affects brain cholesterol metabolism remains unclear. In our study, increased FMO3 and brain TMAO levels were observed in the SD mice, and elevated levels of TMAO were confirmed to lead to SD-induced cognitive dysfunction. In addition, we found that the expression of sterol regulatory element-binding protein 2 (SREBP2) is decreased in the brain of SD mice, resulting in the reduction in brain cholesterol content, which in turn causes synaptic damage. Moreover, we demonstrated that TMAO inhibits the expression of SREBP2. In contrast, FMO3 inhibitor 3,3'-diindolylmethane (DIM) alleviates SD-induced cognitive impairment by targeting the liver-brain axis. In conclusion, our study revealed that the TMAO pathway is involved in memory impairment in SD mice through deregulating astrocytic cholesterol metabolism.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1499591"},"PeriodicalIF":3.5,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of histone demethylase KDM5B on long-term cognitive impairment in neonatal rats induced by sevoflurane.","authors":"Yanhong Wang, Yun Chen, Mengxiao Zhang, Chengdong Yuan, Yu Zhang, Xingjian Liu, Yi Zhang, Xiaoli Liang","doi":"10.3389/fnmol.2024.1459358","DOIUrl":"10.3389/fnmol.2024.1459358","url":null,"abstract":"<p><strong>Introduction: </strong>Whether repeated inhalation of sevoflurane during the neonatal period causes long-term learning and memory impairments in humans is unclear. Some recent investigations have indicated that general anesthesia drugs affect histone methylation modification and may further affect learning and memory ability. This study aimed to explore the role and mechanism of histone methylation in long-term cognitive dysfunction caused by repeated inhalation of sevoflurane during the neonatal period.</p><p><strong>Methods: </strong>Neonatal SD rats were assigned into three groups. Sevoflurane group and sevoflurane +AS8351 group were exposed to 2% sevoflurane for 4 h on postnatal day 7 (P7), day 14 (P7) and day 21 (P21), and the control group was inhaled the air oxygen mixture at the same time. From postnatal day 22 to 36, rats in the +AS8351 group were treated with AS8351 while those in the Sevoflurane group and control group were treated with normal saline. Half of the rats were carried out Y-maze, Morris water maze (MWM), western blot and transmission electron microscope at P37, and the remaining rats were fed to P97 for the same experiment.</p><p><strong>Results: </strong>Neonatal sevoflurane exposure affected histone demethylase expression in hippocampus, changed histone methylation levels, Down-regulated synapse-associated protein expression, impaired synaptic plasticity and long-term cognitive dysfunction and KDM5B inhibitors partially restored the negative reaction caused by sevoflurane exposure.</p><p><strong>Discussion: </strong>In conclusion, KDM5B inhibitor can save the long-term learning and memory impairment caused by sevoflurane exposure in neonatal period by inhibiting KDM5B activity.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1459358"},"PeriodicalIF":3.5,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11632109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toll-like receptors as a missing link in Notch signaling cascade during neurodevelopment.","authors":"Mario Stojanovic, Svjetlana Kalanj-Bognar","doi":"10.3389/fnmol.2024.1465023","DOIUrl":"10.3389/fnmol.2024.1465023","url":null,"abstract":"<p><p>Neurodevelopment encompasses a complex series of molecular events occuring at defined time points distinguishable by the specific genetic readout and active protein machinery. Due to immense intricacy of intertwined molecular pathways, extracting and describing all the components of a single pathway is a demanding task. In other words, there is always a risk of leaving potential transient molecular partners unnoticed while investigating signaling cascades with core functions-and the very neglected ones could be the turning point in understanding the context and regulation of the signaling events. For example, signaling pathways of Notch and Toll-like receptors (TLRs) have been so far unrelated in the vast body of knowledge about neurodevelopment, however evidence from available literature points to their remarkable overlap in influence on identical molecular processes and reveals their potential functional links. Based on data demonstrating Notch and TLR structural engagement and functions during neurodevelopment, along with our description of novel molecular binding models, here we hypothesize that TLR proteins act as likely crucial components in the Notch signaling cascade. We advocate for the hypothesized role of TLRs in Notch signaling by: elaborating components and features of their pathways; reviewing their effects on fates of neural progenitor cells during neurodevelopment; proposing molecular and functional aspects of the hypothesis, along with venues for testing it. Finally, we discuss substantial indications of environmental influence on the proposed Notch-TLR system and its impact on neurodevelopmental outcomes.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1465023"},"PeriodicalIF":3.5,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Antiviral drugs: neurotoxicity and neurodevelopmental effects.","authors":"Isabella Zanella, Daniela Zizioli, Eugenia Quiros-Roldan, Aditya N Bade","doi":"10.3389/fnmol.2024.1526357","DOIUrl":"10.3389/fnmol.2024.1526357","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1526357"},"PeriodicalIF":3.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optogenetic elevation of postsynaptic cGMP in the hippocampal dentate gyrus enhances LTP and modifies mouse behaviors.","authors":"Jelena Borovac, Jayant Rai, Megan Valencia, Hang Li, John Georgiou, Graham L Collingridge, Keizo Takao, Kenichi Okamoto","doi":"10.3389/fnmol.2024.1479360","DOIUrl":"10.3389/fnmol.2024.1479360","url":null,"abstract":"<p><p>A major intracellular messenger implicated in synaptic plasticity and cognitive functions both in health and disease is cyclic GMP (cGMP). Utilizing a photoactivatable guanylyl cyclase (BlgC) actuator to increase cGMP in dentate granule neurons of the hippocampus by light, we studied the effects of spatiotemporal cGMP elevations in synaptic and cognitive functions. At medial perforant path to dentate gyrus (MPP-DG) synapses, we found enhanced long-term potentiation (LTP) of synaptic responses when postsynaptic cGMP was elevated during the induction period. Basal synaptic transmission and the paired-pulse ratio were unaffected, suggesting the cGMP effect on LTP was postsynaptic in origin. In behaving mice implanted with a fiber optic and wireless LED device, their performance following DG photoactivation (5-10 min) was studied in a variety of behavioral tasks. There were enhancements in reference memory and social behavior within tens of minutes following DG BlgC photoactivation, and with time (hours), an anxiogenic effect developed. Thus, postsynaptic cGMP elevations, specifically in the DG and specifically during conditions that evoke synaptic plasticity or during experience, are able to rapidly modify synaptic strength and behavioral responses, respectively. The optogenetics technology and new roles for cGMP in the DG may have applications in brain disorders that are impacted by dysregulated cGMP signaling, such as Alzheimer's disease.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1479360"},"PeriodicalIF":3.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}