Brain Research最新文献

{"title":"The neuroplastic brain: current breakthroughs and emerging frontiers","authors":"Parisa Gazerani","doi":"10.1016/j.brainres.2025.149643","DOIUrl":"10.1016/j.brainres.2025.149643","url":null,"abstract":"<div><div>Neuroplasticity, the brain’s capacity to reorganize itself by forming new neural connections, is central to modern neuroscience. Once believed to occur only during early development, research now shows that plasticity continues throughout the lifespan, supporting learning, memory, and recovery from injury or disease. Substantial progress has been made in understanding the mechanisms underlying neuroplasticity and their therapeutic applications. This overview article examines synaptic plasticity, structural remodeling, neurogenesis, and functional reorganization, highlighting both adaptive (beneficial) and maladaptive (harmful) processes across different life stages. Recent strategies to harness neuroplasticity, ranging from pharmacological agents and lifestyle interventions to cutting-edge technologies like brain-computer interfaces (BCIs) and targeted neuromodulation are evaluated in light of current empirical evidence. Contradictory findings in the literature are addressed, and methodological limitations that hamper widespread clinical adoption are discussed. The ethical and societal implications of deploying novel neuroplasticity-based interventions, including issues of equitable access, data privacy, and the blurred line between treatment and enhancement, are then explored in a structured manner. By integrating mechanistic insights, empirical data, and ethical considerations, the aim is to provide a comprehensive and balanced perspective for researchers, clinicians, and policymakers working to optimize brain health across diverse populations.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1858 ","pages":"Article 149643"},"PeriodicalIF":2.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockout of 5-HT7 receptor in the mouse mildly modifies the structure and function of dorsal raphe neurons","authors":"Agnieszka Kania ,&nbsp;Michał Kiełbiński ,&nbsp;Marcin Siwiec ,&nbsp;Grzegorz Hess","doi":"10.1016/j.brainres.2025.149655","DOIUrl":"10.1016/j.brainres.2025.149655","url":null,"abstract":"<div><div>The serotonin (5-HT) type 7 receptor (5-HT7R) mediates numerous physiological actions of 5-HT in the brain. Mice with a targeted disruption of the 5-HT7R-coding gene are characterized by an altered behavioral phenotype. Modifications of the serotonergic modulation of brain development and of the activity of the 5-HT system in adulthood that are related to ablation of functional 5-HT7Rs might, potentially, underlie the behavioral phenotype described in the literature. The present study was aimed at finding the consequences of 5-HT7R deficiency for the structure and function of single 5-HT neurons of the midline region of the dorsal raphe nucleus (DRN). It was found that while the amplitude of spontaneous excitatory postsynaptic currents recorded from tryptophan hydroxylase-immunoreactive DRN neurons was elevated in 5-HT7R-deficient animals, the excitability of these cells was mildly reduced. A lack of 5-HT7Rs was accompanied by a minor modification of DRN 5-HT neuron morphology. Our findings support the hypothesis that ablation of the 5-HT7R results in an alteration of the function of mouse DRN projection neurons. Further experiments are needed to fully elucidate the effects of the knockout of the 5-HT7R coding gene on the brain 5-HT system.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149655"},"PeriodicalIF":2.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does masking alter the mismatch negativity response to gaps?","authors":"Victoria Duda ,&nbsp;Thomas M.D. Augereau ,&nbsp;Kenneth Campbell ,&nbsp;Amineh Koravand","doi":"10.1016/j.brainres.2025.149651","DOIUrl":"10.1016/j.brainres.2025.149651","url":null,"abstract":"<div><h3>Objective</h3><div>Difficulties perceiving speech in noise can be studied using temporal resolution measures. This study investigates the processing of silent gaps in the central auditory system in various noise conditions.</div></div><div><h3>Methods</h3><div>Event-related potentials and psychoacoustic thresholds were measured in 14 normal hearing adult subjects. A multi-deviant paradigm was used to present an 80 <!--> <!-->dB SPL standard stimulus and a series of gapped deviants with gap durations ranging from 2 to 40 <!--> <!-->ms. The stimuli were presented in three noise conditions in which the noise (i.e. the masker) was either absent, presented at a low intensity (60 <!--> <!-->dB SPL) or high intensity (80 <!--> <!-->dB SPL). A composite N1 + mismatch negativity called a deviant-related negativity (DRN) and the following positive component (P2) measured peak-to-peak were compared to behavioral accuracy rates.</div></div><div><h3>Results</h3><div>The amplitude of the DRN-P2 increased as gap duration increased in the no and low masking conditions. However, this was not the case in the high masking condition. Behavioral gap detection correlated with all masking conditions. However, with high intensity masking, the gap detection accuracy was reduced, and the peak-to-peak measurement was no longer able to reliably code the temporal aspects of the signal.</div></div><div><h3>Conclusions</h3><div>This study demonstrates that high masking noise make the detection of gaps very difficult as demonstrated by using electrophysiology and behavioural measures. However, low levels of masking have little effect on the presence of the gap and the auditory system appears to withstand some level of noise with results similar to no masking at all.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149651"},"PeriodicalIF":2.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel mechanism for short-term post-tetanic plasticity in thalamocortical neurons","authors":"Kathleen R. Louis-Gray,&nbsp;Joseph A. Beatty,&nbsp;Charles L. Cox","doi":"10.1016/j.brainres.2025.149654","DOIUrl":"10.1016/j.brainres.2025.149654","url":null,"abstract":"<div><div>Information transfer through the thalamus is a dynamic process, which can be influenced by multiple factors within the thalamocortical circuit. Activity-dependent changes in neuronal excitability and synaptic efficacy can impact both short- and long-term processing through the thalamocortical circuit. In these experiments, we investigate the mechanism of a novel form of post-tetanic synaptic plasticity, induced by tetanic stimulation of excitatory afferents onto thalamocortical neurons. We show that tetanic activation of excitatory afferents produces a short-lasting (10–15 min) facilitation of excitatory postsynaptic currents in ventrobasal thalamocortical neurons. This potentiation is mediated by a calcium-dependent, presynaptic mechanism. This potentiation is partly due to the activation of adenylyl cyclase and involves alteration in the hyperpolarization-activated mixed cation current, I_h. This activity-dependent facilitation of excitatory synaptic transmission provides a mechanism through which prolonged excitatory enhancement may impact sensory processing through thalamocortical circuits.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149654"},"PeriodicalIF":2.7,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of Dipteryx alata Vog. in modulating anxiety, metabolic health, and reproductive parameters in rats treated during pregnancy and lactation","authors":"Diego Elias Pereira ,&nbsp;Rita de Cássia de Araújo Bidô ,&nbsp;Maciel da Costa Alves ,&nbsp;Ana Carolina dos Santos Costa ,&nbsp;Larissa Maria Gomes Dutra ,&nbsp;Vanessa Bordin Viera ,&nbsp;Sócrates Golzio dos Santos ,&nbsp;Adriano Francisco Alves ,&nbsp;Daline Fernandes de Araújo ,&nbsp;Gerlane Coelho Bernardo Guerra ,&nbsp;Camila Carolina de Menezes Santos Bertozzo ,&nbsp;Juliana Késsia Barbosa Soares","doi":"10.1016/j.brainres.2025.149639","DOIUrl":"10.1016/j.brainres.2025.149639","url":null,"abstract":"<div><div>The objective of this study was to evaluate the effects of baru oil and almonds on anxiety behavior, and biochemical, physical, and reproductive parameters in Wistar rats treated during gestation and lactation. The rats were randomized into three groups: Control (CG) and two experimental groups, treated with 2,000 mg of baru almond or oil/kg of weight via gavage. Reproductive parameters were analyzed at the end of gestation, and behavioral tests were conducted at the end of lactation. Maternal blood was collected for biochemical profile analysis, along with brain tissue, liver, and feces for fatty acid profile analysis. Colon histology and oxidative stress in the brain were also measured. The results demonstrated that treatment with oil and almonds did not affect reproductive rates. In the elevated plus maze, mothers from the experimental groups showed an increased number of entries, more time spent in the open arms, and a greater number of head dips compared to the CG. In the open field, locomotion increased while grooming decreased in the experimental groups, and defecation was reduced in the almond group. The groups spent more time in the clear area of the light–dark box (LDB) and exhibited higher levels of glutathione and lower levels of malondialdehyde in the brain. Both treatments decreased plasma levels of glucose, total cholesterol, and triglycerides while preserving renal, hepatic, and cardiovascular function. Colon histology and the omega-6/3 ratio in feces indicated an inflammatory profile in the oil group. These findings support the use of baru almonds in the diets of pregnant/lactating women as a safe alternative for managing anxiety and promoting metabolic health.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1858 ","pages":"Article 149639"},"PeriodicalIF":2.7,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Asiatic acid on brain cancer by altering astrocytes and the AKT1-PRKCB signaling pathway: A genomic and network pharmacology perspective","authors":"Amit Kumar Singh ,&nbsp;Adarsh Kumar Pathak ,&nbsp;Pradeep Kumar ,&nbsp;Anand Kumar Singh ,&nbsp;Manjeet Kumar Sah Gond ,&nbsp;Rohit Singh Negi ,&nbsp;Richa Das ,&nbsp;Shreni Agrawal ,&nbsp;Sunil Kumar Mishra ,&nbsp;Kavindra Nath Tiwari","doi":"10.1016/j.brainres.2025.149652","DOIUrl":"10.1016/j.brainres.2025.149652","url":null,"abstract":"<div><div>The most common primary brain tumor, glioblastoma (GBM), currently has a dismal prognosis because of its fast growth and dissemination. Recent research indicates that Asiatic acid (AA), which is extracted from <em>Trema orientalis</em> L., has potential as a medicinal agent. AA, which was obtained from a methanolic extract of <em>Trema orientalis</em> L. and examined utilizing high-resolution mass spectroscopy (HRMS) analysis, was employed in this investigation. Then, in order to forecast the therapeutic advantages of AA in managing GBM, we conducted an in silico study. Online web servers like SwissADME, pKCSM, and Protox-II were used to assess AA. Then, the major targets of the AA (from Swiss Target Prediction and TargetNet) and GBM (from GeneCards and DisGeNET) were identified. The important genes were then merged into the STRING and ShinyGo databases to examine the protein–protein interaction (PPI) network, gene annotation, and KEGG pathways, with the goal of identifying the core mechanisms involved in GBM management. The top five hub gene targets of the built network (AKT1, SRC, IL-6, TNF, and EGFR) were investigated, along with some contemporaneous additional major targets (PRKCB, GSK3B, ITGB1, BRAF, and PTPN6). These targets were tightly linked to GO activities such as synoviocyte proliferation, cytokine activity, and EGFR tyrosine kinase inhibitor resistance, as well as proteoglycans in cancer-related pathways. Furthermore, a survival study was conducted to assess the chronicity of targets, as well as molecular docking activity between important targets and AA against GBM to determine binding effectiveness. Overall, the study found that AKT1 is the most powerful receptor for AA, having a binding energy of −8.19 kcal/mol, followed by PRKCB (−7.53 kcal/mol). Finally, docking studies suggest that AA has the potential to be an effective treatment for GBM. Furthermore, clinical studies will provide more precise insights into the AA’s efficacy as a medicine in the future.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149652"},"PeriodicalIF":2.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma and urinary metabolomic signatures differentiate genetic and idiopathic Parkinson’s disease","authors":"Juliana Cordovil Cotrin ,&nbsp;Gilson Costa dos Santos Junior ,&nbsp;André Simões Cadaxo ,&nbsp;Joao Santos Pereira ,&nbsp;Mariana Spitz ,&nbsp;Ana Lúcia Zuma de Rosso ,&nbsp;Renato Peixoto Veras ,&nbsp;Ana Paula Valente ,&nbsp;Márcia Mattos Gonçalves Pimentel ,&nbsp;Cíntia Barros Santos-Rebouças","doi":"10.1016/j.brainres.2025.149625","DOIUrl":"10.1016/j.brainres.2025.149625","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is marked by alpha-synuclein accumulation and progressive dopaminergic neuron loss. Using Nuclear Magnetic Resonance (NMR)-based metabolomics, we uncovered metabolic disturbances in idiopathic PD (iPD) and PD linked to <em>LRRK2, GBA1</em>, and <em>PRKN</em> variants in a Brazilian ethnically diverse cohort, free of comorbidities, in comparison to healthy, age-matched controls. In plasma, significant PD-associated metabolites included histidine, acetate, acetoacetate, glutamine, glucose, lipids and lipoproteins, N-acetyl-glycoproteins, and sarcosine. Urine samples revealed alterations in creatine, creatinine, L-asparagine, trimethylamine, 3-beta-hydroxybutyrate, isovaleric acid, glutamine, urea, glycine, choline, arginine, and cysteine in association with PD. Notably, creatine, creatinine, acetate, glucose, and histidine showed pathway influences from <em>LRRK2, GBA1</em>, and <em>PRKN</em> variants. Enrichment analyses highlighted disruptions in glyoxylate and dicarboxylate metabolism (plasma) as well as serine, threonine, and glycine metabolism (urine). Additionally, a metabolite-gene-disease interaction network identified 15 genes associated with PD that interact with key metabolites, highlighting <em>MAPT</em>, <em>SNCA</em>, <em>RERE</em>, and <em>KCNN3</em> as key players in both plasma<!--> <!-->and<!--> <!-->urine. NMR in saliva samples did not show significant differences between PD groups and controls. Our findings underscore PD-associated metabolites, particularly related to arginine metabolism, the urea cycle, glutamate metabolism, glucose metabolism, and gut microbiota. These pathways and gene interactions may serve as potential biomarkers for PD diagnosis and precision medicine strategies.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1858 ","pages":"Article 149625"},"PeriodicalIF":2.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted structural network resilience in atherosclerosis: A large-scale cohort study","authors":"Hui Tang ,&nbsp;Wanlin Zhu ,&nbsp;Jing Jing ,&nbsp;Yijun Zhou ,&nbsp;Hao Liu ,&nbsp;Shiping Li ,&nbsp;Zixiao Li ,&nbsp;Ziyang Liu ,&nbsp;Chang Liu ,&nbsp;Yuesong Pan ,&nbsp;Xueli Cai ,&nbsp;Xia Meng ,&nbsp;Yilong Wang ,&nbsp;Hao Li ,&nbsp;Yong Jiang ,&nbsp;Suying Wang ,&nbsp;Haijun Niu ,&nbsp;Tiemin Wei ,&nbsp;Yongjun Wang ,&nbsp;Tao Liu","doi":"10.1016/j.brainres.2025.149653","DOIUrl":"10.1016/j.brainres.2025.149653","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis is a major factor in cognitive decline among aging individuals and is frequently linked to the accumulation of white matter hyperintensities. Brain resilience, which represents the brain’s capacity to withstand external disruptions, remains poorly understood in terms of how atherosclerosis impacts it and, in turn, influences cognition. Here, we investigated the relationship between atherosclerosis, white matter hyperintensities, and structural network resilience, along with their combined effects on cognitive performance.</div></div><div><h3>Methods</h3><div>We utilized data from the large-scale community cohort Polyvascular Evaluation for Cognitive Impairment and Vascular Events (n = 2160). Whole-brain structural connections were constructed, and structural disconnections were simulated based on white matter hyperintensities. SNR, serving as a marker to quantify structural network resilience, is defined by the similarity of hub nodes between the original network and its disconnected counterpart.</div></div><div><h3>Results</h3><div>SNR showed higher odds ratios compared to white matter hyperintensities in relation to arterial status. Additionally, chain mediation analysis indicated that cognitive decline associated with atherosclerosis was partially mediated by both white matter hyperintensities and structural network resilience. Atherosclerosis accelerates the degradation of brain structural network resilience as age increases.</div></div><div><h3>Conclusions</h3><div>These findings suggest that SNR could offer complementary insights into cognitive decline caused by atherosclerosis and serve as a potential biomarker of brain health in atherosclerotic conditions. Additionally, SNR may act as an indicator for guiding the selection of future therapies for atherosclerosis.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149653"},"PeriodicalIF":2.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of mitochondrial O-GlcNAcylation in pericytes after mechanical injury","authors":"Ji Hyun Park ,&nbsp;Dong Bin Back ,&nbsp;Shuzhen Guo ,&nbsp;Masayoshi Tanaka ,&nbsp;Hajime Takase ,&nbsp;Michael J. Whalen ,&nbsp;Ken Arai ,&nbsp;Kazuhide Hayakawa ,&nbsp;Eng H. Lo","doi":"10.1016/j.brainres.2025.149647","DOIUrl":"10.1016/j.brainres.2025.149647","url":null,"abstract":"<div><div>Damage to vascular cells comprise an important part of traumatic brain injury (TBI) but the underlying pathophysiology remains to be fully elucidated. Here, we investigate the loss of O-Linked β-N-acetylglucosamine<!--> <!-->(O-GlcNAc) modification (O-GlcNAcylation) and mitochondrial disruption in vascular pericytes as a candidate mechanism. In mouse models in vivo, TBI rapidly induces vascular oxidative stress and down-regulates mitochondrial O-GlcNAcylation. In pericytes but not brain endothelial cultures in vitro, mechanical stretch injury down-regulates mitochondrial O-GlcNAcylation. This is accompanied by disruptions in mitochondrial dynamics, comprising a decrease in mitochondrial fusion and an increase in mitochondrial fission proteins. Pharmacologic rescue of endogenous mitochondrial O-GlcNAcylation with an O-GlcNAcase inhibitor Thiamet-G or addition of exogenous O-GlcNAc-enhanced extracellular mitochondria ameliorates the mitochondrial disruption in pericytes damaged by mechanical injury. Finally, in a pericyte-endothelial co-culture model, mechanical injury increased <em>trans</em>-cellular permeability; adding Thiamet-G or O-GlcNAc-enhanced extracellular mitochondria rescued <em>trans</em>-cellular permeability following mechanical injury. These proof-of-concept findings suggest that mitochondrial O-GlcNAcylation in pericytes may represent a novel therapeutic target for ameliorating oxidative stress and vascular damage after mechanical injury following TBI.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149647"},"PeriodicalIF":2.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143867765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menopause triggers microglia-associated neuroinflammation in Parkinson’s disease","authors":"Sehar Usman,&nbsp;Amal Chandra Mondal","doi":"10.1016/j.brainres.2025.149649","DOIUrl":"10.1016/j.brainres.2025.149649","url":null,"abstract":"<div><div>Microglia, the immune cells of brain, can drive neurodegenerative diseases like Parkinson’s disease (PD). The resting microglia can polarize into two extremes, either proinflammatory M1 or anti-inflammatory M2 phenotype under a specific microenvironment. Different transcriptional factors and the release of various cytokines characterize these states. The released proinflammatory markers from M1 microglia lead to neuroinflammation that ultimately causes irreversible loss of dopaminergic neurons in PD patients, on the contrary, the M2 microglia possess neuroprotective activity. PD is caused by aggregation and misfolding of α-synuclein in the affected dopaminergic neurons. The misfolded α-synuclein is cytotoxic and can propagate like a prion from one cell to the other, acting like a template, that can initiate the conversion of normal proteins into abnormal conformation. The extracellular α-synuclein can interact and polarize the microglia into the M1 phenotype resulting in inflammation, thereby driving the progression of PD. The progression of neuroinflammation-mediated neurodegeneration in PD is seen higher in menopausal women; likely due to the low circulating estrogen levels. Estrogen hormones possess neuroprotective activity, and one of the ways is that they can polarize the microglia into M2 phenotype<del>s</del> and reduce α-synuclein-mediated microglial activation. A detailed understanding of the signaling mechanisms underlying microglial polarization between M1 and M2 phenotypes is crucial for identifying druggable targets to reduce PD symptoms, including in menopausal women.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149649"},"PeriodicalIF":2.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855489","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}