Frontiers in Molecular Neuroscience最新文献

{"title":"GPCRs in hypothalamic neurons and their roles in controlling food intake and metabolism.","authors":"Tian Qiu, Ou Fu","doi":"10.3389/fnmol.2025.1536577","DOIUrl":"10.3389/fnmol.2025.1536577","url":null,"abstract":"<p><p>G-protein coupled receptor (GPCR) subtypes within the hypothalamus play a pivotal role in maintaining body homeostasis, particularly in the regulation of food intake and energy metabolism. This review provides an overview of classical loss and gain-of-function studies on GPCRs related to feeding and metabolism, with a focus on emerging cell-type-specific investigations. These studies reveal that diverse GPCR-expressing neuronal populations are intricately linked to feeding and energy balance. We also discuss recent findings that highlight the interaction of distinct peptide-GPCR systems in modulating complex feeding behaviors.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1536577"},"PeriodicalIF":3.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457689","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":"The effect of AKT inhibition in α-synuclein-dependent neurodegeneration.","authors":"Bedri Ranxhi, Zoya R Bangash, Zachary M Chbihi, Sokol V Todi, Peter A LeWitt, Wei-Ling Tsou","doi":"10.3389/fnmol.2025.1524044","DOIUrl":"10.3389/fnmol.2025.1524044","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of individuals worldwide. A hallmark of PD pathology is the accumulation of α-synuclein (α-Syn), a small protein known to support neuronal development and function. However, in PD, α-Syn cumulatively misfolds into toxic aggregates that disrupt cellular processes and contribute to neuronal damage and neurodegeneration. Previous studies implicated the AKT signaling pathway in α-Syn toxicity in cellular models of PD, suggesting AKT as a potential therapeutic target. Here, we investigated the effect of AKT inhibition in a <i>Drosophila</i> model of synucleinopathy. We observed that administration of the AKT inhibitor, A-443654 led to mild improvements in both survival and motor function in flies expressing human α-Syn. Genetic studies revealed that reduction of AKT levels decreased α-Syn protein levels, concomitant with improved physiological outcomes. The protective effects of AKT reduction appear to operate through the fly ortholog of NF-κB, Relish, suggesting a link between AKT and NF-κB in regulating α-Syn levels. These findings highlight the AKT cascade as a potential therapeutic target for synucleinopathies and provide insights into mechanisms that could be utilized to reduce α-Syn toxicity in PD and related disorders, such as multiple system atrophy.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1524044"},"PeriodicalIF":3.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457640","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":"Ectopic expression of the cation-chloride cotransporter KCC2 in blood exosomes as a biomarker for functional rehabilitation.","authors":"L Caccialupi Da Prato, A Rezzag Lebza, A Consumi, M Tessier, A Srinivasan, C Rivera, J Laurin, C Pellegrino","doi":"10.3389/fnmol.2025.1522571","DOIUrl":"10.3389/fnmol.2025.1522571","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) is a major cause of disabilities in industrialized countries. Cognitive decline typically occurs in the chronic phase of the condition, following cellular and molecular processes. In this study, we described the use of KCC2, a neuronal-specific potassium-chloride cotransporter, as a potent biomarker to predict cognitive dysfunction after TBI.</p><p><strong>Methods: </strong>Using neuronal and total exosome collections from the blood serum of the controls and patients with TBI, we were able to anticipate the decline in cognitive performance.</p><p><strong>Results: </strong>After TBI, we observed a significant and persistent loss of KCC2 expression in the blood exosomes, which was correlated with the changes in the network activity and cellular processes such as secondary neurogenesis. Furthermore, we established a correlation between this decrease in KCC2 expression and the long-term consequences of brain trauma and identified a link between the loss of KCC2 expression and the emergence of depressive-like behavior observed in the mice.</p><p><strong>Conclusion: </strong>We successfully validated our previous findings, supporting the potential therapeutic benefits of bumetanide in mitigating post-traumatic depression (PTD) following TBI. This effect was correlated with the recovery of KCC2 expression in the blood exosomes, the prevention of extensive neuronal loss among the interneurons, and changes in secondary neurogenesis.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1522571"},"PeriodicalIF":3.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457688","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: Nervous regeneration and functional recovery in the central and peripheral nervous systems: diagnostic methods, gene/cell therapies, and interventions.","authors":"Dipa Natarajan, Ryo Hotta, Naho Fujiwara, Silvia Perin","doi":"10.3389/fnmol.2025.1555390","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1555390","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1555390"},"PeriodicalIF":3.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449046","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":"Clinicopathological and molecular characterization of astrocytoma.","authors":"Xiaoyan Wu, Wenfeng Peng, Xu Zhang, Tao Tang, Ling Deng, Yuxia Xu, Xiaoyun Liu, Fang Wang, Wujian Peng, Jianrong Huang, Xiaoni Zhong","doi":"10.3389/fnmol.2025.1483833","DOIUrl":"10.3389/fnmol.2025.1483833","url":null,"abstract":"<p><strong>Introduction: </strong>Astrocytoma is a rare tumour of the central nervous system that often manifests with non-specific clinical symptoms and lacks distinct histological features. There is a pressing need for further understanding of the clinicopathological and molecular characteristics of astrocytoma. Identifying mutant genes can aid in reliable and early diagnosis, as well as provide insights for the development of targeted therapies.</p><p><strong>Methods: </strong>This study aims to investigate the clinicopathologic and molecular characteristics of astroblastoma. A total of four patients diagnosed with astroblastoma were included in the analysis. Clinical features, histological findings, and immunohistochemistry results were reviewed and analyzed. Genetic alterations were identified using fluorescence <i>in situ</i> hybridization (FISH) and next-generation sequencing (NGS), followed by patient follow-up.</p><p><strong>Results: </strong>The study included four female patients, ranging in age from 8 to 44 years. One patient had a tumour in the right parietal lobe, while the other three had tumours in the spinal cord. Histology is usually characterized by pseudorosettes of astroblasts and hyalinization of blood vessels. These tumors showed a growth pattern similar to traditional intracranial astroblastoma, and the histological manifestations of the four patients were all high-grade, showing features of high-density areas of tumor cells or necrosis. Immunohistochemical staining revealed that all four patients expressed OLIG2, EMA, and vimentin, while three patients also expressed GFAP and S-100. The Ki-67 positivity index was approximately 15% in three cases and 10% in one case. Fluorescence <i>in situ</i> hybridization (FISH) using break-apart probes showed EWRS1 breaks in three patients and MN1 breaks in one. Further DNA or RNA-targeted biallelic sequencing identified an EWSR1(Exon1-7)-BEND2(Exon2-14) fusion in case 1, and an EWSR1(Exon1-7)-BEND2(Intergenic) fusion in case 2. In case 3, an EWSR1(Exon1-7)-NUDT10(Intergenic) fusion was present, and in case 4, an MN1(Exon1)-BEND2(Exon2) fusion was identified. The EWSR1-NUDT10 gene fusion is a new fusion type in astroblastoma. The patients were followed up for 76.5, 17.6, 33.7, and 61.3 months, respectively. Three cases experienced tumour recurrences at the spinal cord site, with multiple recurrences in case 4.</p><p><strong>Discussion: </strong>Our study unveiled the distinctive clinicopathological and molecular mutational characteristics of astrocytoma, while also identifying rare mutated genes. Additionally, the detection of MN1 or EWSR1 gene fusion through FISH or next-generation sequencing can provide valuable insights into the molecular mechanisms and aid in the differential diagnosis of astrocytoma.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1483833"},"PeriodicalIF":3.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440602","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":"Impaired peroxisomal beta-oxidation in microglia triggers oxidative stress and impacts neurons and oligodendrocytes.","authors":"Ali Tawbeh, Catherine Gondcaille, Fatima-Ezzahra Saih, Quentin Raas, Damien Loichot, Yannick Hamon, Céline Keime, Alexandre Benani, Francesca Di Cara, Mustapha Cherkaoui-Malki, Pierre Andreoletti, Stéphane Savary","doi":"10.3389/fnmol.2025.1542938","DOIUrl":"10.3389/fnmol.2025.1542938","url":null,"abstract":"<p><p>Microglia, the immune cells of the central nervous system, activate neuroinflammatory pathways in response to homeostatic disturbances, a process implicated in the pathogenesis of various neurodegenerative diseases. Emerging evidence identifies abnormal microglial activation as a causal factor at the onset of peroxisomal leukodystrophies, including X-linked adrenoleukodystrophy (X-ALD). This study investigates how primary peroxisomal deficiencies influence oxidative properties of microglia and examines the subsequent impact on neurons and oligodendrocytes. Using BV-2 microglial cells lacking ABCD1, ABCD2, or ACOX1, peroxisomal proteins that play key roles in the very-long-chain fatty acid beta-oxidation, we analyzed their response under basal condition and after stimulation by lipopolysaccharide (LPS). Transcriptomic analysis of the mutant microglial cells revealed numerous differentially expressed genes, particularly in redox-related pathways following LPS exposure. These changes are consistent with the increased production of reactive oxygen species (ROS) and nitric oxide (NO). Conditioned media (CM) from the mutant cells were then applied to cultures of neuron and oligodendrocyte cell lines. Exposure to CM from LPS-stimulated mutant microglial cells significantly increased apoptosis in both cell types. Furthermore, treated neurons exhibited a reduction in cell complexity and an increased ability to secrete neuropeptides. These findings demonstrate that peroxisomal impairments in microglia exacerbate inflammatory response and ROS/NO production, affecting the survival of neurons and oligodendrocytes, as well as neuronal morphology and function. This dysfunction might contribute to the early neurodegenerative events in X-ALD by triggering and sustaining neuroinflammatory cascades. Therapeutic strategies that target microglial activation and secretion profiles could hold promise in managing peroxisomal disorders such as X-ALD.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1542938"},"PeriodicalIF":3.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11826809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432641","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":"Short- and long-term changes in neurological, behavioural, and blood biomarkers following repeated mild traumatic brain injury in rats-potential biological sex-dependent effects.","authors":"Rodrigo Moraga-Amaro, Oscar Moreno, Jordi Llop, Marion Bankstahl, Jens P Bankstahl","doi":"10.3389/fnmol.2025.1488261","DOIUrl":"10.3389/fnmol.2025.1488261","url":null,"abstract":"<p><strong>Introduction: </strong>Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease resulting from repeated mild traumatic brain injuries (rmTBI). The necessity for diagnosis of CTE, which can so far only be confirmed after post-mortem, is a pressing need. New approaches to early diagnose this disease are crucial to facilitate the translation of novel treatment strategies to the clinic. Several studies have found suitable candidate biomarkers, but the results are not straightforward. As biological sex is suggested to be a major confounding factor, we explored how sex influences behavioural and candidate blood biomarkers during CTE-like progression following experimental rmTBI.</p><p><strong>Methods: </strong>To induce CTE-like development, we subjected male and female rats to three mTBIs at a 5-day interval. We then monitored and analysed differences in neurological, behavioural, and physiological parameters up to 12 weeks after the injuries-both by sex and grouped-and underwent further analysis using generalised estimated equation (GEE). To determine long-term changes in tau aggregation as a hallmark of CTE, we used [¹⁸F]-florzolotau (florzolotau) autoradiography in brain slices.</p><p><strong>Results: </strong>Both short-term weight gain and time-to-right after rmTBI were increased in grouped animals, with male rats showing more prominent changes. The neurological state was impaired after each mTBI and still 12 weeks later, independent of the sex. A protracted anhedonic-like behaviour due to rmTBI was found at the group level only at week 2 but remained continuously present in male rats. While spatial memory was not impaired, male rats showed increased anxiety-like behaviour. Moreover, neuron-specific enolase (NSE) was elevated in the blood 1 day after rmTBI, but only in females. On the contrary, blood p-tau was increased 3 days after rmTBI only in males. In addition, male rats showed significantly increased florzolotau binding in the brain after 12 weeks, suggesting brain contusion causes increased tau aggregation. Interestingly, brain neurofibrillary tangles (NFTs) at 12 weeks after rmTBI showed a strong correlation with the neurological state at 1 day after rmTBI.</p><p><strong>Discussion: </strong>Taken together, our findings suggest that male rats may be more susceptible to short-and long-term consequences of rmTBI in the applied model. These sex differences should be considered when translating preclinical biomarker candidates to the clinic. Understanding these differences could guide the diagnosis and treatment of CTE in a personalized manner, offering hope for more effective treatments in the future.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1488261"},"PeriodicalIF":3.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407095","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":"Regulatory mechanism of Reelin activity: a platform for exploiting Reelin as a therapeutic agent.","authors":"Mitsuharu Hattori","doi":"10.3389/fnmol.2025.1546083","DOIUrl":"10.3389/fnmol.2025.1546083","url":null,"abstract":"<p><p>Reelin is a secreted glycoprotein that was initially investigated in the field of neuronal development. However, in recent decades, its role in the adult brain has become increasingly important, and it is now clear that diminished Reelin function is involved in the pathogenesis and progression of neuropsychiatric and neurodegenerative disorders, including schizophrenia and Alzheimer's disease (AD). Reelin activity is regulated at multiple steps, including synthesis, posttranslational modification, secretion, oligomerization, proteolytic processing, and interactions with extracellular molecules. Moreover, the differential use of two canonical receptors and the presence of non-canonical receptors and co-receptors add to the functional diversity of Reelin. In this review, I summarize recent findings on the molecular mechanisms of Reelin activity. I also discuss possible strategies to enhance Reelin's function. A complete understanding of Reelin function and its regulatory mechanisms in the adult central nervous system could help ameliorate neuropsychiatric and neurodegenerative disorders.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1546083"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11808024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390590","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":"Brain network and energy imbalance in Parkinson's disease: linking ATP reduction and <i>α</i>-synuclein pathology.","authors":"Hirohisa Watanabe, Sayuri Shima, Kazuya Kawabata, Yasuaki Mizutani, Akihiro Ueda, Mizuki Ito","doi":"10.3389/fnmol.2024.1507033","DOIUrl":"10.3389/fnmol.2024.1507033","url":null,"abstract":"<p><p>Parkinson's disease (PD) involves the disruption of brain energy homeostasis. This encompasses broad-impact factors such as mitochondrial dysfunction, impaired glycolysis, and other metabolic disturbances, like disruptions in the pentose phosphate pathway and purine metabolism. Cortical hubs, which are highly connected regions essential for coordinating multiple brain functions, require significant energy due to their dense synaptic activity and long-range connections. Deficits in ATP production in PD can severely impair these hubs. The energy imbalance also affects subcortical regions, including the massive axonal arbors in the striatum of substantia nigra pars compacta neurons, due to their high metabolic demand. This ATP decline may result in <i>α</i>-synuclein accumulation, autophagy-lysosomal system impairment, neuronal network breakdown and accelerated neurodegeneration. We propose an \"ATP Supply-Demand Mismatch Model\" to help explain the pathogenesis of PD. This model emphasizes how ATP deficits drive pathological protein aggregation, impaired autophagy, and the degeneration of key brain networks, contributing to both motor and non-motor symptoms.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1507033"},"PeriodicalIF":3.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254346","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":"A localized tracing technique to explore intra-amygdala functional and structural correlates of individual variability in behavioral response.","authors":"Allie Lipshutz, Victoria Saltz, Kristin R Anderson, Alessia Manganaro, Dani Dumitriu","doi":"10.3389/fnmol.2025.1347539","DOIUrl":"10.3389/fnmol.2025.1347539","url":null,"abstract":"<p><strong>Introduction: </strong>The neurobiological basis for individual variability in behavioral responses to stimuli remains poorly understood. Probing the neural substrates that underlie individual variability in stress responses may open the door for preventive approaches that use biological markers to identify at-risk populations. New developments of viral neuronal tracing tools have led to a recent increase in studies on long range circuits and their functional role in stress responses and social behavior. While these studies are necessary to untangle largescale connectivity, most social behaviors are mediated and fine-tuned by local subregional circuitry.</p><p><strong>Methods: </strong>In order to probe this local, interregional connectivity, we present a new combination of a neuronal tracing system with immediate early gene immunohistochemistry for examining structural and functional connectivity within the same animal. Specifically, we combine a retrograde transsynaptic rabies tracing system with cFos colocalization immediately after an acute stressor to elucidate local structural and stress-activated connectivity within the amygdala complex in female and male mice.</p><p><strong>Results and discussion: </strong>We show how specific structural and functional connections can predict individual variability along a spectrum of social approach/avoidance following acute social defeat stress. We demonstrate how our robust method can be used to elucidate structural and functional differences in local connectivity that mediate individual variability in behavioral response.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1347539"},"PeriodicalIF":3.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364401","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}