Pub Date : 2025-02-04DOI: 10.1016/j.brainres.2025.149483
Guo-She Lee , Yi-Hui Liao
Complex sounds elicit auditory brainstem response (ABR) that can reflect sustained phase-locking in the auditory system. Common stimuli include synthetic speech sounds like the consonant–vowel /da/ (CV-da). We introduce three geometric pulse click (GPC) stimuli: compound click-sawtooth wave (CSW), compound click-square wave (CQW), and compound click-triangular wave (CTW), to elicit ABR. These mathematically generated stimuli had a similar time-lock stimulation pattern to CV-da. ABRs were recorded from twenty-seven healthy adult volunteers, with all stimuli standardized to a peak-to-peak intensity of 40 dB SPL above the sensation level. The results revealed that ABR amplitudes were significantly greater for CSW and CV-da. CQW and CTW exhibited additional response peaks due to the presence of additional broadband energy within these stimuli. The correlations between the unfiltered stimulation wave and the response wave were also higher for GPC stimuli, with CSW reached a moderate level of correlation (r2 = 0.33). Response latencies strongly related to occurrence of energy spikes concentrated in ≥4 kHz. The three GPC stimuli evoked a strong and similar time-locking response compared to CV-da. Given the ease of modifying the energy and time-lock patterns of GPC stimuli, they hold potential for future basic and clinical applications.
{"title":"Auditory brainstem response elicited by synthetic consonant-vowel /da/ and three geometric pulse click stimuli","authors":"Guo-She Lee , Yi-Hui Liao","doi":"10.1016/j.brainres.2025.149483","DOIUrl":"10.1016/j.brainres.2025.149483","url":null,"abstract":"<div><div>Complex sounds elicit auditory brainstem response (ABR) that can reflect sustained phase-locking in the auditory system. Common stimuli include synthetic speech sounds like the consonant–vowel /da/ (CV-da). We introduce three geometric pulse click (GPC) stimuli: compound click-sawtooth wave (CSW), compound click-square wave (CQW), and compound click-triangular wave (CTW), to elicit ABR. These mathematically generated stimuli had a similar time-lock stimulation pattern to CV-da. ABRs were recorded from twenty-seven healthy adult volunteers, with all stimuli standardized to a peak-to-peak intensity of 40 dB SPL above the sensation level. The results revealed that ABR amplitudes were significantly greater for CSW and CV-da. CQW and CTW exhibited additional response peaks due to the presence of additional broadband energy within these stimuli. The correlations between the unfiltered stimulation wave and the response wave were also higher for GPC stimuli, with CSW reached a moderate level of correlation (r<sup>2</sup> = 0.33). Response latencies strongly related to occurrence of energy spikes concentrated in ≥4 kHz. The three GPC stimuli evoked a strong and similar time-locking response compared to CV-da. Given the ease of modifying the energy and time-lock patterns of GPC stimuli, they hold potential for future basic and clinical applications.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1851 ","pages":"Article 149483"},"PeriodicalIF":2.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350304","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}
Pub Date : 2025-02-04DOI: 10.1016/j.brainres.2025.149492
Yingning Zhang , Sujuan Shi , E Mao , Yuling Chen , Jing Chen , Miao Tian , Fensheng Huang , Zhiping Cai , Yunqing Li , Zhenzhen Kou
Itch is a distinct and bothersome sensation closely associated with a strong urge to scratch. Both the parabrachial nucleus (PBN) and the central amygdala (CeA) are responsive to itch stimuli and contain neurons that express tachykinin 1 (Tac1), which are known for their significant involvement in itch-induced scratching at both spinal and supraspinal levels. Significantly, the PBN neurons project their axons to form close connections with the CeA neurons. However, the role of the PBNTac1-CeATac1 pathway in modulating itch remains to be determined. We utilized immunohistochemistry, fiber photometry, chemogenetic, and behavioral techniques to investigate the role of the PBNTac1-CeATac1 pathway in itch. Our results indicate that neurons in the CeA can be more activated by acute itch than chronic itch. Notably, in response to acute itch stimuli, both CeATac1 and PBNTac1 neurons were specifically activated by histamine (His)-induced itch. Furthermore, the Tac1-positive terminals from the PBNTac1 neurons formed close connections with CeATac1 neurons. We also demonstrated that activating the PBNTac1-CeA pathway using a chemogenetic approach could increase scratching behaviors in His-induced itch, other than chloroquine (CQ)-induced itch. Conversely, inhibiting the PBNTac1-CeA pathway decreased scratching behaviors in mice with His-induced itch. Taken together, these results suggest that the PBNTac1-CeATac1 pathway may play a specific role in modulating His-induced acute itch.
{"title":"Tac1-expressing neurons in the central amygdala predominantly mediate histamine-induced itch by receiving inputs from parabrachial Tac1-expressing neurons","authors":"Yingning Zhang , Sujuan Shi , E Mao , Yuling Chen , Jing Chen , Miao Tian , Fensheng Huang , Zhiping Cai , Yunqing Li , Zhenzhen Kou","doi":"10.1016/j.brainres.2025.149492","DOIUrl":"10.1016/j.brainres.2025.149492","url":null,"abstract":"<div><div>Itch is a distinct and bothersome sensation closely associated with a strong urge to scratch. Both the parabrachial nucleus (PBN) and the central amygdala (CeA) are responsive to itch stimuli and contain neurons that express tachykinin 1 (Tac1), which are known for their significant involvement in itch-induced scratching at both spinal and supraspinal levels. Significantly, the PBN neurons project their axons to form close connections with the CeA neurons. However, the role of the PBN<sup>Tac1</sup>-CeA<sup>Tac1</sup> pathway in modulating itch remains to be determined. We utilized immunohistochemistry, fiber photometry, chemogenetic, and behavioral techniques to investigate the role of the PBN<sup>Tac1</sup>-CeA<sup>Tac1</sup> pathway in itch. Our results indicate that neurons in the CeA can be more activated by acute itch than chronic itch. Notably, in response to acute itch stimuli, both CeA<sup>Tac1</sup> and PBN<sup>Tac1</sup> neurons were specifically activated by histamine (His)-induced itch. Furthermore, the Tac1-positive terminals from the PBN<sup>Tac1</sup> neurons formed close connections with CeA<sup>Tac1</sup> neurons. We also demonstrated that activating the PBN<sup>Tac1</sup>-CeA pathway using a chemogenetic approach could increase scratching behaviors in His-induced itch, other than chloroquine (CQ)-induced itch. Conversely, inhibiting the PBN<sup>Tac1</sup>-CeA pathway decreased scratching behaviors in mice with His-induced itch. Taken together, these results suggest that the PBN<sup>Tac1</sup>-CeA<sup>Tac1</sup> pathway may play a specific role in modulating His-induced acute itch.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1851 ","pages":"Article 149492"},"PeriodicalIF":2.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363541","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}
Stress can be beneficial for adapting to dangerous situations in the short term but can be damaging in the long term, especially in the hippocampus. The noradrenergic and orexinergic systems play important roles in stress response. This study investigated the effect of noradrenergic activation on changes induced by chronic stress in the hippocampus and the involvement of orexinergic modulation in this process.
This study examined five groups of 40 male Wistar rats (4 + 4 animals/ group): control, chronic stress, acute stress, control with noradrenergic activation, and chronic stress with noradrenergic activation. Hippocampal tissue and blood plasma were the primary specimens analyzed. The researchers measured plasma corticosterone (CORT) using a fluorometric method, examined the expression of prepro-orexin (prepro-OX), orexin receptor-1 (OXr1), and glucocorticoid receptor (GR) through RT-PCR, and quantified neuronal populations using Nissl staining.
Acute and chronic stress increased plasma CORT levels and gene expression of prepro-OX, OXr1, and GR, while decreasing neuronal numbers, with chronic stress having a more pronounced effect. Yohimbine-treated and/or stressed rats exhibited elevated plasma CORT levels. Chronic stress substantially upregulated GR and increased prepro-OX and OXr1 expressions whereas yohimbine recovered those profiles in chronically stressed animals. Conversely, chronic stress reduced hippocampal neuronal populations, and chronic stress combined with yohimbine partially compensated for the neuronal numbers compared to chronic stress alone.
These results suggest that noradrenergic signalling can reverse chronic stress-induced impairments in prepro-OX, OXr1 and GR expressions, and neuronal populations.
{"title":"Modulation of noradrenergic signalling reverses stress-induced changes in the hippocampus: Involvement of orexinergic systems","authors":"Masoumeh Sarfi, Mahmoud Elahdadi Salmani, Taghi Lashkarbolouki, Iran Goudarzi","doi":"10.1016/j.brainres.2025.149491","DOIUrl":"10.1016/j.brainres.2025.149491","url":null,"abstract":"<div><div>Stress can be beneficial for adapting to dangerous situations in the short term but can be damaging in the long term, especially in the hippocampus. The noradrenergic and orexinergic systems play important roles in stress response. This study investigated the effect of noradrenergic activation on changes induced by chronic stress in the hippocampus and the involvement of orexinergic modulation in this process.</div><div>This study examined five groups of 40 male Wistar rats (4 + 4 animals/ group): control, chronic stress, acute stress, control with noradrenergic activation, and chronic stress with noradrenergic activation. Hippocampal tissue and blood plasma were the primary specimens analyzed. The researchers measured plasma corticosterone (CORT) using a fluorometric method, examined the expression of prepro-orexin (prepro-OX), orexin receptor-1 (OXr1), and glucocorticoid receptor (GR) through RT-PCR, and quantified neuronal populations using Nissl staining.</div><div>Acute and chronic stress increased plasma CORT levels and gene expression of prepro-OX, OXr1, and GR, while decreasing neuronal numbers, with chronic stress having a more pronounced effect. Yohimbine-treated and/or stressed rats exhibited elevated plasma CORT levels. Chronic stress substantially upregulated GR and increased prepro-OX and OXr1 expressions whereas yohimbine recovered those profiles in chronically stressed animals. Conversely, chronic stress reduced hippocampal neuronal populations, and chronic stress combined with yohimbine partially compensated for the neuronal numbers compared to chronic stress alone.</div><div>These results suggest that noradrenergic signalling can reverse chronic stress-induced impairments in prepro-OX, OXr1 and GR expressions, and neuronal populations.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1851 ","pages":"Article 149491"},"PeriodicalIF":2.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254921","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}
The role of environmental contaminants in causing Parkinson’s disease (PD) is well known, with rotenone and paraquat being the notable neurotoxins. Traces of the metalloid arsenic are frequently found in drinking water which is considered a threat to the brain’s health. Pre-clinical and epidemiological studies have associated arsenic with PD whereby behavioral and neurochemical alterations were observed. However, the impact of arsenic toxicity on the dopaminergic neurons of substantia nigra (SN), the hallmark region which degenerates in PD, has not been shown yet. In the present study, administration of 20 mg/kg b.w., arsenic for 28 days caused significant loss of dopaminergic neurons and their terminals respectively in the SN and striatum regions of mice brain. Moreover, the arsenic-fed rodents exhibited depleted striatal dopamine, prolonged latency to move and correct posture, and reduced exploratory behavior and neurological severity. Further, mitochondrial complexes II and IV were found to be inhibited in the SN, cortex, striatum, and hippocampus of arsenic-fed mice. Additionally, inflammatory marker glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expressed in glial cells and neurons respectively were enhanced in the nigrostriatal pathway of arsenic-fed animals. The present study for the first time reports that arsenic causes Parkinsonism by degenerating nigrostriatal dopaminergic neurons through mitochondrial complex inhibition and inflammatory stress. The study further puts forward validatory evidence for the potential of arsenic in causing PD and the reliability of the arsenic-induced PD model for exploring the disease pathogenesis and treatment.
{"title":"Arsenic-induced mice model of Parkinson’s disease: Revealing the neurotoxicity of arsenic through mitochondrial complexes inhibition and dopaminergic neurodegeneration in the substantia nigra region of brain","authors":"Ankumoni Dutta , Rubina Roy , Mritunjay Pandey , Sushila Chhetry , Banashree Chetia Phukan , Abhideep Roy , Pallab Bhattacharya , Anupom Borah","doi":"10.1016/j.brainres.2025.149493","DOIUrl":"10.1016/j.brainres.2025.149493","url":null,"abstract":"<div><div>The role of environmental contaminants in causing Parkinson’s disease (PD) is well known, with rotenone and paraquat being the notable neurotoxins. Traces of the metalloid arsenic are frequently found in drinking water which is considered a threat to the brain’s health. Pre-clinical and epidemiological studies have associated arsenic with PD whereby behavioral and neurochemical alterations were observed. However, the impact of arsenic toxicity on the dopaminergic neurons of substantia nigra (SN), the hallmark region which degenerates in PD, has not been shown yet. In the present study, administration of 20 mg/kg b.w., arsenic for 28 days caused significant loss of dopaminergic neurons and their terminals respectively in the SN and striatum regions of mice brain. Moreover, the arsenic-fed rodents exhibited depleted striatal dopamine, prolonged latency to move and correct posture, and reduced exploratory behavior and neurological severity. Further, mitochondrial complexes II and IV were found to be inhibited in the SN, cortex, striatum, and hippocampus of arsenic-fed mice. Additionally, inflammatory marker glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expressed in glial cells and neurons respectively were enhanced in the nigrostriatal pathway of arsenic-fed animals. The present study for the first time reports that arsenic causes Parkinsonism by degenerating nigrostriatal dopaminergic neurons through mitochondrial complex inhibition and inflammatory stress. The study further puts forward validatory evidence for the potential of arsenic in causing PD and the reliability of the arsenic-induced PD model for exploring the disease pathogenesis and treatment.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1851 ","pages":"Article 149493"},"PeriodicalIF":2.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254948","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}
Pub Date : 2025-02-02DOI: 10.1016/j.brainres.2025.149484
Bao Liu , Yuxin Wang , Lei Gao , Zhenxin Cai
Accurate recognition and classification of motor imagery electroencephalogram (MI-EEG) signals are crucial for the successful implementation of brain-computer interfaces (BCI). However, inherent characteristics in original MI-EEG signals, such as nonlinearity, low signal-to-noise ratios, and large individual variations, present significant challenges for MI-EEG classification using traditional machine learning methods.
To address these challenges, we propose an automatic feature extraction method rooted in deep learning for MI-EEG classification. First, original MI-EEG signals undergo noise reduction through discrete wavelet transform and common average reference. To reflect the regularity and specificity of brain neural activities, a convolutional neural network (CNN) is used to extract the time-domain features of MI-EEG. We also extracted spatial features to reflect the activity relationships and connection states of the brain in different regions. This process yields time series containing spatial information, focusing on enhancing crucial feature sequences through talking-heads attention. Finally, more abstract spatial–temporal features are extracted using a temporal convolutional network (TCN), and classification is done through a fully connected layer. Validation experiments based on the BCI Competition IV-2a dataset show that the enhanced EEG model achieves an impressive average classification accuracy of 85.53% for each subject. Compared with CNN, EEGNet, CNN-LSTM and EEG-TCNet, the classification accuracy of this model is improved by 11.24%, 6.90%, 11.18% and 6.13%, respectively. Our work underscores the potential of the proposed model to enhance intention recognition in MI-EEG significantly.
{"title":"Enhanced electroencephalogram signal classification: A hybrid convolutional neural network with attention-based feature selection","authors":"Bao Liu , Yuxin Wang , Lei Gao , Zhenxin Cai","doi":"10.1016/j.brainres.2025.149484","DOIUrl":"10.1016/j.brainres.2025.149484","url":null,"abstract":"<div><div>Accurate recognition and classification of motor imagery electroencephalogram (MI-EEG) signals are crucial for the successful implementation of brain-computer interfaces (BCI). However, inherent characteristics in original MI-EEG signals, such as nonlinearity, low signal-to-noise ratios, and large individual variations, present significant challenges for MI-EEG classification using traditional machine learning methods.</div><div>To address these challenges, we propose an automatic feature extraction method rooted in deep learning for MI-EEG classification. First, original MI-EEG signals undergo noise reduction through discrete wavelet transform and common average reference. To reflect the regularity and specificity of brain neural activities, a convolutional neural network (CNN) is used to extract the time-domain features of MI-EEG. We also extracted spatial features to reflect the activity relationships and connection states of the brain in different regions. This process yields time series containing spatial information, focusing on enhancing crucial feature sequences through talking-heads attention. Finally, more abstract spatial–temporal features are extracted using a temporal convolutional network (TCN), and classification is done through a fully connected layer. Validation experiments based on the BCI Competition IV-2a dataset show that the enhanced EEG model achieves an impressive average classification accuracy of 85.53% for each subject. Compared with CNN, EEGNet, CNN-LSTM and EEG-TCNet, the classification accuracy of this model is improved by 11.24%, 6.90%, 11.18% and 6.13%, respectively. Our work underscores the potential of the proposed model to enhance intention recognition in MI-EEG significantly.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1851 ","pages":"Article 149484"},"PeriodicalIF":2.7,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187655","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}
The study aims to explore Resveratrol (RES) as a potential therapeutic agent for Glioblastoma multiforme (GBM), a challenging brain cancer. RES, a polyphenolic compound with known benefits in various diseases including cancer, has shown promise in inhibiting glioma progression through its effects on the AKT signaling pathways. However, its limited ability to cross the blood–brain barrier restricts its clinical application in GBM treatment. This study seeks to enhance efficacy of RES by developing RES-loaded nanoparticles designed to improve penetration into glioma cells and potentially overcome the blood–brain barrier, thereby enhancing therapeutic outcomes.
Methods
Albumin nanoparticles were prepared and characterized using FT-IR, X-RD, and SEM to determine particle size. In vitro experiments were conducted using the C6 glioma cell line, employing MTT assays, Immunofluorescence, DC-FDA staining, and western blot analysis. Molecular docking studies were also performed to assess ability of RES to inhibit the AKT/GSK-3β/NF-kB pathway.
Results
In vitro results demonstrated that RES-loaded nanoparticles induced apoptosis and reduced proliferation of C6 glioma cells compared to controls. Molecular docking studies confirmed RES’s potential as an inhibitor targeting the AKT/GSK-3β/NF-kB pathway. Western blot analysis revealed downregulation of AKT and GSK-3β expression in cells treated with RES-loaded nanoparticles, accompanied by increased caspase 1 levels and decreased bcl2 expression, indicative of apoptosis.
Conclusion
The findings suggest that RES effectively targets the AKT/GSK-3β/NF-kB signaling pathway in glioma cells. Furthermore, RES-loaded albumin nanoparticles significantly enhance therapeutic efficacy by improving cellular penetration, highlighting their potential in advancing GBM treatment strategies.
{"title":"Nanoparticle-enhanced delivery of resveratrol for targeted therapy of glioblastoma: Modulating the Akt/GSK-3β/NF-kB pathway in C6 glioma cells","authors":"Gurpreet Singh , Paras Famta , Saurabh Shah , Ganesh Vambhurkar , Giriraj Pandey , Rahul Kumar , Prakash Kumar , Atul Mourya , Jitender Madan , Saurabh Srivastava , Dharmendra Kumar Khatri","doi":"10.1016/j.brainres.2024.149411","DOIUrl":"10.1016/j.brainres.2024.149411","url":null,"abstract":"<div><h3>Objective</h3><div>The study aims to explore Resveratrol (RES) as a potential therapeutic agent for Glioblastoma multiforme (GBM), a challenging brain cancer. RES, a polyphenolic compound with known benefits in various diseases including cancer, has shown promise in inhibiting glioma progression through its effects on the AKT signaling pathways. However, its limited ability to cross the blood–brain barrier restricts its clinical application in GBM treatment. This study seeks to enhance efficacy of RES by developing RES-loaded nanoparticles designed to improve penetration into glioma cells and potentially overcome the blood–brain barrier, thereby enhancing therapeutic outcomes.</div></div><div><h3>Methods</h3><div>Albumin nanoparticles were prepared and characterized using FT-IR, X-RD, and SEM to determine particle size. <em>In vitro</em> experiments were conducted using the C6 glioma cell line, employing MTT assays, Immunofluorescence, DC-FDA staining, and western blot analysis. Molecular docking studies were also performed to assess ability of RES to inhibit the AKT/GSK-3β/NF-kB pathway.</div></div><div><h3>Results</h3><div><em>In vitro</em> results demonstrated that RES-loaded nanoparticles induced apoptosis and reduced proliferation of C6 glioma cells compared to controls. Molecular docking studies confirmed RES’s potential as an inhibitor targeting the AKT/GSK-3β/NF-kB pathway. Western blot analysis revealed downregulation of AKT and GSK-3β expression in cells treated with RES-loaded nanoparticles, accompanied by increased caspase 1 levels and decreased bcl2 expression, indicative of apoptosis.</div></div><div><h3>Conclusion</h3><div>The findings suggest that RES effectively targets the AKT/GSK-3β/NF-kB signaling pathway in glioma cells. Furthermore, RES-loaded albumin nanoparticles significantly enhance therapeutic efficacy by improving cellular penetration, highlighting their potential in advancing GBM treatment strategies.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1848 ","pages":"Article 149411"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881173","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}
Pub Date : 2025-02-01DOI: 10.1016/j.brainres.2025.149456
Carlos Alberto de Carvalho Fraga , Leandro Tiburske , Gabriel Victor Lucena da Silva , Adriana Simizo , Mauro Cesar Cafundó de Morais , Ana Kelly da Silva Fernandes Duarte , Henry David Mogollón García , Thiago Dominguez Crespo Hirata , Helder I. Nakaya
Brain metastasis is the most common type of brain cancer, associated with significant neurological dysfunction and a poor prognosis. We investigated the transcriptome of 128,421 single-cells of 36 brain metastases, originating from a variety of primary tumors, including melanoma, breast, lung, ovarian, colorectal, and renal cancers. Our aim was to identify common molecular factors across these tumors, shedding light on key interactions that facilitate tumor establishment in the brain. We specifically focused on the dynamics of the blood-tumor barrier and its effects on endothelial cells, pericytes, and astrocytes. Our analysis decoded complex cell–cell communications, emphasizing the crucial role of astrocytes in the tumor microenvironment (TME). This provided insights into how these interactions impact the permeability of the blood-tumor barrier and contribute to the development of brain metastases. We identified the VEGFA, SEMA3, and SPP1 pathways as key regulators in brain metastasis, affecting vascular permeability and cellular dynamics. Spatial transcriptome analysis confirmed our findings and linked these pathways to TME enrichment. The pronounced expression of VEGFA by cancer cells suggests a significant activation of angiogenic pathways, influencing vascular responses and the intricate architecture of brain tissue. The interplay of these signaling pathways underlines the complexity of molecular interactions that define the microenvironment of brain metastases.
{"title":"Revealing shared molecular drivers of brain metastases from distinct primary tumors","authors":"Carlos Alberto de Carvalho Fraga , Leandro Tiburske , Gabriel Victor Lucena da Silva , Adriana Simizo , Mauro Cesar Cafundó de Morais , Ana Kelly da Silva Fernandes Duarte , Henry David Mogollón García , Thiago Dominguez Crespo Hirata , Helder I. Nakaya","doi":"10.1016/j.brainres.2025.149456","DOIUrl":"10.1016/j.brainres.2025.149456","url":null,"abstract":"<div><div>Brain metastasis is the most common type of brain cancer, associated with significant neurological dysfunction and a poor prognosis. We investigated the transcriptome of 128,421 single-cells of 36 brain metastases, originating from a variety of primary tumors, including melanoma, breast, lung, ovarian, colorectal, and renal cancers. Our aim was to identify common molecular factors across these tumors, shedding light on key interactions that facilitate tumor establishment in the brain. We specifically focused on the dynamics of the blood-tumor barrier and its effects on endothelial cells, pericytes, and astrocytes. Our analysis decoded complex cell–cell communications, emphasizing the crucial role of astrocytes in the tumor microenvironment (TME). This provided insights into how these interactions impact the permeability of the blood-tumor barrier and contribute to the development of brain metastases. We identified the VEGFA, SEMA3, and SPP1 pathways as key regulators in brain metastasis, affecting vascular permeability and cellular dynamics. Spatial transcriptome analysis confirmed our findings and linked these pathways to TME enrichment. The pronounced expression of VEGFA by cancer cells suggests a significant activation of angiogenic pathways, influencing vascular responses and the intricate architecture of brain tissue. The interplay of these signaling pathways underlines the complexity of molecular interactions that define the microenvironment of brain metastases.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1851 ","pages":"Article 149456"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078105","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}
Whisker-mediated tactile perception is essential for rodent navigation, food acquisition, and social interactions. However, the molecular mechanisms underlying tactile information processing, learning, and memory have not been studied to the same extent as for other modalities. Using immunohistochemical staining, we investigated changes in regional c-Fos expression as an index of neuronal activity and phosphorylated (p)ERK1/2 as an index of ERK1/2 activity in mice trained on a tactile-cued 8-arm radial maze task. Over 12 trials, mice learned to selectively explore four baited arms covered with wire as the tactile cue while avoiding un-baited uncovered arms. The density of c-Fos+ cells was significantly higher in somatosensory cortex but not frontal cortex or amygdala of mice exposed to tactile cue – bait pairing compared to mice exposed to the same maze with all arms baited with or without tactile cues (unpaired conditions). The density of pERK1/2+ cells was also increased after paired trials 7 and 12 but not after paired trials 1 and 3 in frontal cortex, amygdala, and somatosensory cortex compared to mice exposed to the unpaired condition. The MEK1/2 inhibitor SL327 reduced c-Fos expression in frontal cortex and amygdala when applied during early trials, but impaired working memory when applied before later trials without affecting c-Fos expression. Heterozygous BDNF knockout mice exhibited impaired task learning and reduced pERK1/2 expression in frontal cortex and amygdala but not somatosensory cortex. These findings suggest that the BDNF/MEK/ERK1/2 pathway selectively promotes memory trace formation in frontal cortex and amygdala but not encoding in somatosensory cortex.
{"title":"Distinct contributions of BDNF/MEK/ERK1/2 signaling pathway components to whisker-dependent tactile learning and memory","authors":"Hitomi Soumiya, Shingo Mori, Kohta Kageyama, Masateru Kawakami, Aoi Nara, Shoei Furukawa, Hidefumi Fukumitsu","doi":"10.1016/j.brainres.2024.149404","DOIUrl":"10.1016/j.brainres.2024.149404","url":null,"abstract":"<div><div>Whisker-mediated tactile perception is essential for rodent navigation, food acquisition, and social interactions. However, the molecular mechanisms underlying tactile information processing, learning, and memory have not been studied to the same extent as for other modalities. Using immunohistochemical staining, we investigated changes in regional c-Fos expression as an index of neuronal activity and phosphorylated (p)ERK1/2 as an index of ERK1/2 activity in mice trained on a tactile-cued 8-arm radial maze task. Over 12 trials, mice learned to selectively explore four baited arms covered with wire as the tactile cue while avoiding un-baited uncovered arms. The density of c-Fos<sup>+</sup> cells was significantly higher in somatosensory cortex but not frontal cortex or amygdala of mice exposed to tactile cue – bait pairing compared to mice exposed to the same maze with all arms baited with or without tactile cues (unpaired conditions). The density of pERK1/2<sup>+</sup> cells was also increased after paired trials 7 and 12 but not after paired trials 1 and 3 in frontal cortex, amygdala, and somatosensory cortex compared to mice exposed to the unpaired condition. The MEK1/2 inhibitor SL327 reduced c-Fos expression in frontal cortex and amygdala when applied during early trials, but impaired working memory when applied before later trials without affecting c-Fos expression. Heterozygous BDNF knockout mice exhibited impaired task learning and reduced pERK1/2 expression in frontal cortex and amygdala but not somatosensory cortex. These findings suggest that the BDNF/MEK/ERK1/2 pathway selectively promotes memory trace formation in frontal cortex and amygdala but not encoding in somatosensory cortex.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1848 ","pages":"Article 149404"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852670","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}
Pub Date : 2025-02-01DOI: 10.1016/j.brainres.2024.149394
Yunqi Xie , Mingxue Yang , Haochen Wang, Yuting Chen, Xiaobo Shi, Huanwen Tang, Qian Sun
Background
Smoking is detrimental to health, with tobacco use being a critical factor in the development of various neurodegenerative diseases, including Alzheimer’s disease (AD), which progressively impairs brain function and poses a significant threat to public health. This study aims to examine the potential genetic alterations induced by smoking that are associated with AD and to investigate the underlying regulatory mechanisms. The research will provide theoretical foundations for targeted prevention and treatment strategies for AD.
Methods
This study analyzed datasets from the Gene Expression Omnibus (GEO) and the Comparative Toxicogenomics Database (CTD) to identify genes affected by tobacco smoke exposure and those altered in patients with AD relative to normal controls. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using OmicShare tools to screen for key pathways. Key genes were identified by constructing protein–protein interaction networks (PPI) in the STRING database with the aid of CytoHubba. Additionally, the binding activity of the proteins encoded by these key genes to nicotine, the main component of tobacco, was analyzed using molecular docking techniques. Finally, the analytical results were verified using Quantitative Real-Time Polymerase Chain Reaction.
Results
The CTD identified 12,164 CE-related genes affected by tobacco smoke exposure. A comparison of these datasets yielded 94 common genes that were both influenced by tobacco and differentially expressed across all brain regions. The GO and KEGG pathway enrichment analyses showed that these common differentially expressed genes (DEGs) were predominantly enriched in the Wnt/β-catenin and PI3K-AKT signaling pathways. The DEGs’ PPI network, constructed using the STRING database, highlighted key genes such as HSP90AB1, SOS2, MAGI1, and YWHAZ. Molecular docking studies demonstrated that nicotine binds effectively to the protein structures of these key genes, primarily through amino acid residues such as Ser and Glu. Experimental validation showed that HSP90AB1 and YWHAZ exhibited notable expression discrepancies under varying concentrations of cigarette smoke extract (CSE) treatments, particularly demonstrating a pronounced down-regulation trend at elevated concentrations.
Conclusion
The study indicates that tobacco may impact the function of transmembrane transporter proteins and contribute to the development of AD by affecting key genes such as HSP90AB1 and YWHAZ, as well as signaling pathways like PI3K-AKT.
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Pub Date : 2025-01-30DOI: 10.1016/j.brainres.2025.149479
Feng Yashuo , Guan Chong , Yang Zhe , Cao Lu , Xie Hongyu , Wu Yi , Wang Nianhong
Aims
This study aimed to observe the effect of electroacupuncture (EA) at Zusanli point (ST36) on motor function of cerebral ischemia mice, and to observe the effect of EA on mitochondrial morphology of peri-infarct cortex neurons in cerebral ischemia mice.
Methods
Middle cerebral artery occlusion (MCAO) was used to develop an ischemic stroke mice model. EA treatment was performed for three consecutive days for 15 min per day after MCAO modeling. We investigated the therapeutic effects of EA on MCAO mice by performing neurobehavioral assessment (modified Neurological Severity Score, Rotarod test, Open-field test and Gait analysis) and TTC staining. The morphology and function of neuronal mitochondria were evaluated by transmission electron microscopy, qRT-PCR, chemiluminescence, and western blot. Nissl staining, TUNEL staining and immunofluorescence staining were used to observe neuronal morphology and apoptosis. Furthermore, ELISA was employed to measure the expression levels of inflammatory factors in mouse serum.
Results
EA alleviated motor dysfunction and infarct volume in mice with cerebral ischemia. It improved the neuronal mitochondria damage in MCAO mice, and decreased the protein and mRNA expression level of mitochondrial fission related proteins (FIS1 and Drp1). In addition, EA can reduce neuronal damage and apoptosis of nerve cells, and decrease the level of inflammatory factors (IL-1β, TNF-α, IL-6 and IL-8) in cerebral ischemia mice.
Conclusion
EA therapy can improve motor dysfunction and alleviate the damage of neuron mitochondria in cerebral ischemic mice.
{"title":"Electroacupuncture promotes neural function recovery by alleviating mitochondria damage in cerebral ischemia mice","authors":"Feng Yashuo , Guan Chong , Yang Zhe , Cao Lu , Xie Hongyu , Wu Yi , Wang Nianhong","doi":"10.1016/j.brainres.2025.149479","DOIUrl":"10.1016/j.brainres.2025.149479","url":null,"abstract":"<div><h3>Aims</h3><div>This study aimed to observe the effect of electroacupuncture (EA) at Zusanli point (ST36) on motor function of cerebral ischemia mice, and to observe the effect of EA on mitochondrial morphology of <em>peri</em>-infarct cortex neurons in cerebral ischemia mice.</div></div><div><h3>Methods</h3><div>Middle cerebral artery occlusion (MCAO) was used to develop an ischemic stroke mice model. EA treatment was performed for three consecutive days for 15 min per day after MCAO modeling. We investigated the therapeutic effects of EA on MCAO mice by performing neurobehavioral assessment (modified Neurological Severity Score, Rotarod test, Open-field test and Gait analysis) and TTC staining. The morphology and function of neuronal mitochondria were evaluated by transmission electron microscopy, qRT-PCR, chemiluminescence, and western blot. Nissl staining, TUNEL staining and immunofluorescence staining were used to observe neuronal morphology and apoptosis. Furthermore, ELISA was employed to measure the expression levels of inflammatory factors in mouse serum.</div></div><div><h3>Results</h3><div>EA alleviated motor dysfunction and infarct volume in mice with cerebral ischemia. It improved the neuronal mitochondria damage in MCAO mice, and decreased the protein and mRNA expression level of mitochondrial fission related proteins (FIS1 and Drp1). In addition, EA can reduce neuronal damage and apoptosis of nerve cells, and decrease the level of inflammatory factors (IL-1β, TNF-α, IL-6 and IL-8) in cerebral ischemia mice.</div></div><div><h3>Conclusion</h3><div>EA therapy can improve motor dysfunction and alleviate the damage of neuron mitochondria in cerebral ischemic mice.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1851 ","pages":"Article 149479"},"PeriodicalIF":2.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073824","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}
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