Molecular Brain最新文献

{"title":"The medial prefrontal cortex encodes procedural rules as sequential neuronal activity dynamics.","authors":"Shuntaro Ohno, Masanori Nomoto, Kaoru Inokuchi","doi":"10.1186/s13041-025-01230-w","DOIUrl":"10.1186/s13041-025-01230-w","url":null,"abstract":"<p><p>The prefrontal cortex plays a crucial role in procedural rule learning; however, the specific neuronal mechanism through which it represents rules is unknown. We hypothesized that sequential neuronal activities in the prefrontal cortex encode these rules. To investigate this, we recorded neuronal activities in the medial prefrontal cortex of mice during rule learning using Ca²⁺ imaging. We utilized a method based on convolutional negative matrix factorization, iSeq, to automatically detect temporal neuronal sequences in the recorded data. As rule learning advanced, these neuronal sequences began to encode critical information for rule execution. In mice that had mastered the rule, the dynamics of neuronal sequences could predict success and failure of reward acquisition. Furthermore, the composition of cell populations within the neuronal sequences was rearranged throughout the learning process. These findings suggest that as animals learn a rule, the medial prefrontal cortex continually updates its neuronal sequences to assign significance to behavioural actions crucial for reward acquisition.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"56"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540935","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":"Systemic semaglutide provides a mild vasoprotective and antineuroinflammatory effect in a rat model of ocular hypertensive glaucoma.","authors":"Zaynab A Mouhammad, Anne Rombaut, Mariana Yolotzin García Bermúdez, Rupali Vohra, James R Tribble, Pete A Williams, Miriam Kolko","doi":"10.1186/s13041-025-01224-8","DOIUrl":"10.1186/s13041-025-01224-8","url":null,"abstract":"<p><p>Glaucoma is a neurodegenerative disease affecting retinal ganglion cells (RGCs), with a multifactorial genesis that includes inflammation and vascular dysfunction. Emerging evidence suggests that glucagon-like peptide 1 receptor agonist (GLP-1RAs) may serve as promising neuroprotective agents in glaucoma. In this study, we investigated the neuroprotective potential of the GLP-1RA semaglutide (SEM) in a rat model of ocular hypertension (OHT) induced by paramagnetic bead injections in Brown Norwegian rats. Rats were divided into four cohorts, two normotensive (NT) cohorts, and two OHT cohorts, treated with either SEM or saline (HBSS), which served as control. Systemic SEM or HBSS administration was initiated simultaneously with OHT induction. We observed that SEM administration seemed to delay the increase in intraocular pressure (IOP) associated with OHT. Although SEM administration did not improve RGC survival, it significantly improved astrocytic fractal dimension value and lacunarity. In conclusion, our findings suggest that GLP-1RAs may exert neuroprotective effects by delaying IOP elevation and preventing OHT-induced reactive astrocyte and vascular remodeling. These findings highlight the potential of GLP-1RAs for retinal neuroprotection, but further studies are needed to elucidate their applicability in glaucoma.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"54"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540934","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":"CSF Amyloid-β42 associates with neuropsychiatric and cognitive outcomes via cerebral glucose metabolism.","authors":"Ali Azargoonjahromi, Hamide Nasiri","doi":"10.1186/s13041-025-01229-3","DOIUrl":"10.1186/s13041-025-01229-3","url":null,"abstract":"<p><p>Amyloid-β42 (Aβ42) regulates synaptic plasticity and memory formation at physiological levels in the brain, but in Alzheimer's disease (AD), it can disrupt brain function and glucose metabolism. This disruption contributes to cognitive decline and neuropsychiatric symptoms, highlighting the need to better understand its complex effects. This study investigated the associations among cerebrospinal fluid (CSF) Aβ42 levels, cerebral glucose metabolism (assessed via FDG-PET), neuropsychiatric symptoms (evaluated using the NPI), and cognitive performance (measured by ADAS-Cog13 and MoCA) in individuals with AD, mild cognitive impairment (MCI), and cognitively normal (CN) participants. After adjusting for age, gender, education, and ApoE ɛ4 status, a significant positive relationship between CSF Aβ42 levels and cerebral glucose metabolism was observed in the MCI and AD groups, but not in the CN group. In the MCI group, higher cerebral glucose metabolism was associated with reductions in both neuropsychiatric and depressive symptoms, suggesting that higher glucose metabolism reflect higher activation state of investigated brain regions. In contrast, in the CN group, elevated CSF Aβ42 levels were directly linked to increased depressive symptoms, indicating that higher CSF Aβ42 may contribute to depression even in the absence of cognitive decline. Further analysis revealed that CSF Aβ42 levels were indirectly associated with reduced neuropsychiatric and depressive symptoms through enhanced cerebral glucose metabolism as mediator solely in the MCI group. Regarding cognitive performance, cerebral glucose metabolism showed a strong relationship with cognition in both the MCI and AD groups. Furthermore, higher CSF Aβ42 levels were positively associated with better cognitive performance in the MCI and AD groups, with cerebral glucose metabolism potentially mediating this relationship, while no effect was seen in the CN group. In short, CSF Aβ42 positively influenced cerebral glucose metabolism, which was linked to reduced neuropsychiatric and depressive symptoms as well as improved cognitive performance in MCI and AD groups.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"55"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540925","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":"Distinct composition of different types of Abeta plaques in the pathogenesis of Alzheimer's disease and the role of neutrophil-derived myeloperoxidase.","authors":"Jianru Sun, Xiangqi Shao, Xue Wang, Xiang-Sha Yin, Wenying Qiu, Xiaojing Qian, Fan Liu, Yongmei Chen, Chao Ma","doi":"10.1186/s13041-025-01226-6","DOIUrl":"10.1186/s13041-025-01226-6","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Different types of Aβ plaques are likely to play distinct roles in the brains of patients with AD. In this study, through the combination of pathological techniques and analysis of the human brain database, we discovered that focal Aβ plaques (FAPs), rather than diffuse Aβ plaques (DAPs), are significantly correlated with AD-related neuropathological changes and cognitive impairment. By using laser capture microdissection in conjunction with microproteomics, the protein components of different Aβ plaques were characterized. Bioinformatic analysis indicated that FAP-enriched proteins are associated mainly with immune-related pathways, such as neutrophil extracellular trap formation. We further confirmed that myeloperoxidase (MPO) is significantly upregulated in the AD brain and colocalizes with FAPs but not with DAPs. Immunohistochemical staining demonstrated that neutrophils expressing MPO accumulated in the capillary lumen and brain parenchyma. The number of neutrophils significantly increases in the cortex and hippocampus of AD donors. Our study revealed a potential role for neutrophil-derived MPO in FAPs, providing insights into the pathogenesis mechanisms and potential therapeutic targets of AD.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"53"},"PeriodicalIF":3.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369082","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":"Effects of vincristine on the properties of low threshold mechanoreceptors and high threshold mechanoreceptors in the hindpaw glabrous skin of mice.","authors":"Akihiro Yamada, Ayaka I Yamada, Jennifer Ling, Jianguo G Gu","doi":"10.1186/s13041-025-01223-9","DOIUrl":"10.1186/s13041-025-01223-9","url":null,"abstract":"<p><p>Vincristine is an important chemotherapy drug to treat various types of cancer, but it induces peripheral neuropathy, leading to numbness and mechanical allodynia in the hands and feet of patients. The peripheral neuropathy is a dose-limiting toxicity of vincristine chemotherapy. How vincristine treatment causes numbness and mechanical allodynia remains incompletely understood. In the present study, we utilized Nav1.8-ChR2 transgenic mice in which Nav1.8-ChR2-positive and Nav1.8-ChR2-negative mechanoreceptors could be characterized using the opto-electrophysiological method. Nav1.8-ChR2-negative Aβ- and Aδ-fiber mechanoreceptors are primarily low-threshold mechanoreceptors (LTMRs). On the other hand, Nav1.8-ChR2-positive Aβ- and Aδ-fiber mechanoreceptors are mainly high-threshold mechanoreceptors (HTMRs). We have shown that the mechanical threshold of Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors, but not Nav1.8-ChR2-negative Aδ-fiber mechanoreceptors, were increased significantly in the animals treated with vincristine. In contrast, the mechanical threshold of Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors were significantly reduced following vincristine treatment. Vincristine treatment did not significantly affect the mechanical sensitivity of Nav1.8-ChR2-positive Aδ- and C-fiber mechanoreceptors. Vincristine treatment also did not affect the opto-sensitivity of Nav1.8-ChR2-positive Aβ-, Aδ-, and C-fiber mechanoreceptors. Our findings suggest that mechanical sensitivity is decreased in Aβ-fiber LTMRs and increased in Aβ-HTMRs following vincristine treatment, providing insights into vincristine-induced numbness and mechanical allodynia.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"52"},"PeriodicalIF":3.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317501","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":"Chronic voluntary exercise induces plasticity of noradrenaline-activated dopamine D₁-like receptor signaling.","authors":"Katsunori Kobayashi","doi":"10.1186/s13041-025-01219-5","DOIUrl":"10.1186/s13041-025-01219-5","url":null,"abstract":"<p><p>Physical exercise has lasting positive influence on mental health. However, its cellular substrate remains to be elucidated. Recently, dopamine D₁-like receptor activation induced by noradrenaline has been suggested to underlie exercise-dependent augmentation of antidepressant effects. The present study demonstrates that exercise induces a long-term enhancement of this atypical catecholaminergic signaling. Noradrenaline potentiates hippocampal mossy fiber synaptic transmission by activating D₁-like receptors in mice. Voluntary exercise by wheel running enhanced this noradrenaline-D₁-like receptor signaling within 5 days. The enhancement of the noradrenaline-D₁-like receptor signaling did not require the integrity of noradrenergic fibers and was maintained for more than 2 weeks after cessation of wheel running. Notably, the effect of exercise was more robustly seen in D₁-like receptor signaling activated by noradrenaline as compared with dopamine, indicating particular responsiveness of the noradrenaline-activated D₁-like receptor signaling to exercise. These results suggest that exercise could exert lasting influence on brain functioning via plasticity of the hippocampal noradrenaline-D₁-like receptor signaling.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"51"},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310223","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":"Recent developments in peptide vaccines against Glioblastoma, a review and update.","authors":"Reza Salahlou, Safar Farajnia, Effat Alizadeh, Siavoush Dastmalchi","doi":"10.1186/s13041-025-01221-x","DOIUrl":"10.1186/s13041-025-01221-x","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most prevalent invasive CNS tumor, with a high incidence rate and a high likelihood of recurrence in most patients. Despite available treatments, recurrent glioblastoma (rGBM) exhibits growing resistance to chemotherapy and radiotherapy, which necessitates the development of newer methods of treatment. Peptide vaccines, a type of cancer immunotherapy, have recently attracted attention as a potentially practical therapeutic approach because they target tumor-associated or tumor-specific antigens to generate an effective immune response against cancer cells. These vaccines have been included in several clinical trials, demonstrating their safety and effectiveness by eliciting protective immune responses. However, peptide vaccines for glioblastoma face challenges due to the complex nature of intracranial brain tumors that require innovative approaches and in-depth research to increase their efficacy. The main topics covered in this article include immunological inhibitors and immune characteristics of the CNS and GBM, the basis of immunity, and the significant results of clinical trials of peptide vaccine therapy for GBM. Additionally, it examines the potential causes of the low effectiveness of these vaccines and recommends future research to address the specific challenges associated with immunotherapy in GBM. The evaluation of preliminary phase studies and phase III clinical trials will provide insights into potential immunological responses, biosecurity precautions, and clinical outcomes, guiding future vaccination initiatives to promote higher effectiveness.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"50"},"PeriodicalIF":3.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294126","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":"ATP stimulates appetite by enhancing the expression of hypothalamic orexigenic neuropeptides.","authors":"Nayoun Kim, Eun-Kyoung Kim","doi":"10.1186/s13041-025-01220-y","DOIUrl":"10.1186/s13041-025-01220-y","url":null,"abstract":"<p><p>Hypothalamic neuropeptides play a pivotal role in regulating appetite and energy homeostasis. Extracellular ATP, a key signaling molecule in the hypothalamus, is associated with neuronal activity and metabolic processes. However, its role in appetite control remains unclear. This study explored how sustained extracellular ATP regulates the expression of hypothalamic orexigenic neuropeptides Agrp and Npy. The administration of ATP alone reduced food intake, body weight, and orexigenic neuropeptide expression in mice. Conversely, inhibition of ATP conversion into AMP using the ectonucleoside triphosphate diphosphohydrolase inhibitor ARL67156 caused a transient increase in these parameters. Prolonged extracellular ATP was shown to upregulate Agrp and Npy expression via purinergic P2X4 receptor (P2X4R) activation in AGRP/NPY-expressing cells. Activation of P2X4R induced CaMKII phosphorylation, which subsequently led to CREB phosphorylation and upregulation of orexigenic neuropeptides. Our findings reveal a mechanism whereby extracellular ATP accumulation promotes appetite through P2X4R-CaMKII-CREB signaling, shedding light on how extracellular ATP impacts hypothalamic appetite control.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"49"},"PeriodicalIF":3.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266697","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":"Effects of intermittent theta burst stimulation on the inflammatory response and cerebral blood flow in promoting neurovascular repair after ischemic stroke.","authors":"Jingjun Zhang, Siyue Li, Dan Huang, Jiale Fu, Shuying Chen, Na Ren, Pengkun Yang, Di Song, Xiaochen Bai, Hongyu Xie, Gang Liu, Kewei Yu, Shamay S M Ng, Junfa Wu, Xiao Xiao, Yi Wu","doi":"10.1186/s13041-025-01222-w","DOIUrl":"10.1186/s13041-025-01222-w","url":null,"abstract":"<p><p>Secondary injuries from ischemia‒reperfusion in stroke, such as edema and hemorrhagic transformation, can significantly impact brain function. This study investigated the effects of intermittent theta burst stimulation (iTBS) on neurological function and cerebral blood flow in a mouse model of ischemia‒reperfusion injury. Laser speckle flowmetry was used to assess changes in cortical blood flow before and after ischemia‒reperfusion. Behavioral assessments were conducted to evaluate motor function recovery. The impact of iTBS on neuronal damage and apoptosis in the peri-infarct area was evaluated via Nissl staining and a TUNEL assay. RNA transcriptome sequencing and immunofluorescence staining were performed to investigate the effects of iTBS on microglial and astrocyte activation and the associated inflammatory response. Our findings demonstrated that iTBS significantly mitigated abnormal perfusion in the infarcted hemisphere, reduced neuronal damage and apoptosis in the peri-infarct area, and enhanced motor function in ischemic mice. Furthermore, iTBS promoted the polarization of microglia and astrocytes toward the anti-inflammatory M2 and A2 phenotypes. Therefore, iTBS provides neurovascular protection by modulating microglial and astrocyte activation and regulating the inflammatory response in the peri-infarct area, thereby improving abnormal cerebral blood flow in both the acute and subacute phases after ischemic brain injury.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"48"},"PeriodicalIF":3.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258597","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":"Sonication dissociates the synaptic cleft and allows purification of postsynaptic densities with associated postsynaptic membrane.","authors":"Ayse Dosemeci, Jung-Hwa Tao-Cheng","doi":"10.1186/s13041-025-01217-7","DOIUrl":"10.1186/s13041-025-01217-7","url":null,"abstract":"<p><p>In the synaptic junction, pre-and post compartments are anchored to each other through trans-synaptic bridges spanning the synaptic cleft. Here we demonstrate that mild mechanical disturbance through sonication dissociates the synaptic cleft, and releases PSDs adjoined to the postsynaptic membrane, but devoid of presynaptic elements. It is the first time, to our knowledge, that dissection of the synaptic cleft has been achieved without the use of chemical/enzymatic treatments. This observation suggests that some of the protein-protein interactions involved in the anchoring of pre- and postsynaptic compartments are relatively weak non-covalent associations. We describe a method for the further fractionation of PSDs with the associated postsynaptic membrane. This PSD preparation provides a valuable tool for studies of postsynaptic membrane components, such as glutamatergic receptors, in an environment closer to their native state.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"47"},"PeriodicalIF":3.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187410","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}