Cellular and Molecular Neurobiology最新文献

{"title":"Amyloid-β, Tau, and α-Synuclein Protein Interactomes as Therapeutic Targets in Neurodegenerative Diseases.","authors":"D Mohan Kumar, Priti Talwar","doi":"10.1007/s10571-025-01604-7","DOIUrl":"https://doi.org/10.1007/s10571-025-01604-7","url":null,"abstract":"<p><p>Alzheimer's and Parkinson's disease are the most prevalent neurological diseases. Amyloid-β, tau, and α-synuclein proteins are known to be implicated in neurodegenerative disease (NDD). Elucidation of precise therapeutic targets remains a challenge. Therefore, the identification of interactomes of amyloid-β precursor protein (APP), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) proteins is of great interest, aimed at unraveling novel targets. An integrated analysis was employed to identify direct interactors as therapeutic targets, considering protein-protein interactions and subsequent network analysis. Further, it was proposed to identify hub proteins, intended targets, regulatory factors, disease-gene associations, functional enrichment analyses of the protein interactors interfered with gene ontologies and disease-driving pathways. Protein interactome centered on APP, MAPT, and SNCA identified the top hundred high-confidence protein-protein interactions that revealed BACE1, PSEN1, SORL1, GSK3B, CDK5, SNCAIP, PRKN, and APOE as physical and functional protein interactors. The top ten hub proteins were ranked based on multiple centrality measures and topological algorithms. Further, the integrated network of all three protein interactomes contained distinct nodes with edges. Interestingly, regulatory mechanisms have revealed possible regulatory modules, including cleavage, phosphorylation, and ubiquitination. Top interacting proteins were enriched in several ontology terms, such as regulation of neuronal apoptotic processes, amyloid beta fibril formation, and tau protein binding. Pathway analysis mapped the pathways of neurodegeneration-multiple disease, with a significant level of interacting proteins. Finally, the most comprehensive interactome associated with NDD provides insights into protein interactors, regulating the mechanisms of key proteins that can serve as novel therapeutic targets.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"84"},"PeriodicalIF":4.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231472","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":"Uncovering Necroptosis in Alzheimer's Disease: A Systematic Review of Evidence Across Experimental Models.","authors":"Nishi Shah, Gopal Natesan, Richa Gupta","doi":"10.1007/s10571-025-01601-w","DOIUrl":"10.1007/s10571-025-01601-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD), one of the most challenging neurodegenerative disorders, with high prevalence worldwide, is characterized by progressive cognitive decline and accumulation of amyloid-β plaques and neurofibrillary tau tangles. Despite significant research, the limited efficacy of current treatments underscores the critical need to identify novel pathogenic mechanisms and therapeutic targets. Necroptosis, a regulated and highly inflammatory form of programmed cell death, has emerged as one of the key contributors to AD pathogenesis. This systematic review comprises 25 high-quality in vivo, in vitro, and autopsy studies, published between 2015 and 2025, extracted from PubMed, Scopus, and Science Direct databases. The keywords include \"necroptosis\", \"RIPK1\", \"RIPK3\", \"MLKL\", \"pMLKL\", \"necroptosis inhibitors\", \"Alzheimer's disease\", and \"neurodegeneration\". The review summarizes the multiple molecular mechanisms, including TNF-α/TNFR1 signaling, TRIF-mediated RIPK3 activation, and RHIM-dependent MLKL phosphorylation, associated with necroptosis in the pathogenesis of AD. All the studies converge on necroptosis as a central pathogenic pathway linking key molecular and cellular abnormalities observed in AD. The accumulated evidence strongly supports prioritizing the development of brain-penetrant necroptosis inhibitors and clinical validation of associated biomarkers. These insights signal a significant shift in AD therapeutics, moving from symptomatic treatment to mechanistically targeted interventions that can alter disease progression.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"83"},"PeriodicalIF":4.8,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211757","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}

{"title":"Ca²⁺ Inhibits Reactive Oxygen Species Scavenging in Naked Mole-Rat Cortical Homogenates.","authors":"Bizav Jaffer, Hang Cheng, Matthew E Pamenter","doi":"10.1007/s10571-025-01603-8","DOIUrl":"https://doi.org/10.1007/s10571-025-01603-8","url":null,"abstract":"<p><p>Deleterious perturbations in reactive oxygen species (ROS) and calcium (Ca²⁺) handling are key initiators of cell death in hypoxia-intolerant mammalian brain. Elevated cellular Ca²⁺ can also inhibit ROS scavengers, exacerbating the deleterious impact of hypoxia on redox homeostasis. Conversely, such perturbations are typically absent in the brain of hypoxia-tolerant animals, including naked mole-rats (NMRs; Heterocephalus glaber), in which a remarkable ability to scavenge ROS has been observed in cardiac and skeletal muscle. We asked if NMR brain possesses a similar ability to detoxify ROS and whether Ca²⁺ impairs ROS scavenging in NMR brain. To test these questions, we used the Amplex ultrared assay to measure the impact of Ca²⁺ on the ability of NMR brain homogenates to detoxify a bolus (50 µl of 10 µm H₂O₂) of exogenously applied H₂O₂ during different states of mitochondrial respiration. We report that (1) NMR brain mitochondria are net consumers of H₂O₂, (2) thioredoxin reductase is a major contributor to this scavenging capacity, and (3) Ca²⁺ inhibits ROS scavenging in all conditions tested. The rate of ROS consumption by NMR cortical homogenates is considerably greater than previously published measurements from rat and mouse brain and is less sensitive to inhibition by exogenous Ca²⁺, suggesting that NMRs have evolved an enhanced capacity to detoxify ROS. This ability is likely neuroprotective in this animal, which experiences regular bouts of intermittent hypoxia and reoxygenation of varying severity in its natural underground burrow habitat.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"82"},"PeriodicalIF":4.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12390887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944661","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}

{"title":"Multi-dimensional Multi-omics Integrative Study to Identify Target Genes for Ischemic Stroke and Related Chronic Pain.","authors":"Yuanlin Wang, Dan Liu, Shuai Wang, Ruizhi Zhang, Xianwen Wang, Yonghao Yu","doi":"10.1007/s10571-025-01602-9","DOIUrl":"https://doi.org/10.1007/s10571-025-01602-9","url":null,"abstract":"<p><p>Chronic pain is the most common complications and after-effects for ischemic stroke. Through exploring immune related cell death target genes of ischemic stroke is essential for understanding ischemic stroke and chronic pain complications. Referred to three types of immune related cell deaths' marker genes, mRNA and microRNA transcriptomics data from mice MCAO model were firstly analyzed through multi algorithms. Then, screening common gene with brain chronic pain related dataset. At the single-cell level, we performed immune cell identification and differentially expressional analysis for entire stroke brain environment and pseudo-time analysis for candidate immune cells. Based on GWAS and eQTLs, colocalization analysis, and drug target mendelian randomization methods were used to evaluate causal relationships and drug target effects. Furthermore, to explore spatial characters spatial transcriptomic analysis was conducted. At last, PCR experiments in animal model were conducted. Cell death state is positively correlated with immune infiltration degree. Five core mRNAs, S100a6, Anxa3, Ncf4, Capg, and Arpc1b, and key microRNA, miR-298-5p, were screened as biomarkers for immune related cell death. Among them, S100a6 play key roles. Toll like receptor pathway and CD4⁺ _γδ T cells were identified as core immune pathway and cells. By comparing with chronic pain GWAS results, S100a6 is screened as promising target. In single-cell analysis, S100a6 participated in CD4⁺ _γδ T cells differentiation and immune activation on IS. Drug target MR analysis showed that activation of S100a6 was able to decrease 23-54% probabilities to develop into IS. Furtherly, S100a6 gene could balance the negative effects of Cd4 expressed immune cells and protect neuronal function in brain injury spatial zone. In PCR experiment, differentially expressed level of five core genes got proved. In conclusion, our study revealed S100a6 played causal protective roles for ischemic stroke and related chronic pain, could be seen as potential drug target.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"81"},"PeriodicalIF":4.8,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944631","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}

{"title":"The Cerebral Lymphatic System: Function, Controversies, and Therapeutic Approaches for Central Nervous System Diseases.","authors":"Jingxi Pan, Yinqi Fu, Peng Yang, Wenfu Li, Zhifeng Luo, An Zhang, Jiashu Du, Fen Mei, Fan Liu, Songtao Qi, Yun Bao","doi":"10.1007/s10571-025-01598-2","DOIUrl":"10.1007/s10571-025-01598-2","url":null,"abstract":"<p><p>The meninges serve as critical barriers that maintain immune homeostasis in the central nervous system (CNS) and play vital roles in immune surveillance and defense. Traditionally, the brain has been regarded as an \"immune-privileged\" organ owing to the absence of conventional lymphatic vessels. However, the rediscovery of meningeal lymphatic vessels (MLVs) has revealed a mechanism for the directional transport of cerebrospinal fluid (CSF) to the deep cervical lymph nodes (dCLNs), demonstrating that the brain possesses a distinct fluid communication pathway with the peripheral system that is independent of blood circulation. Additionally, the identification of the glymphatic system has revealed a perivascular mechanism for solute exchange between the CSF and brain parenchyma, primarily mediated by the astrocytic water channel protein aquaporin-4 (AQP4). These discoveries have significantly expanded our understanding of brain fluid dynamics and CNS homeostasis. This review provides a comprehensive overview of the structure, regulation, and function of MLVs and the glymphatic system, which together constitute lymphatic system of the brain. We also discuss recent evidence, particularly conflicting perspectives, on the role of meningeal immunity in various central nervous system (CNS) disorders, such as multiple sclerosis, Parkinson's disease, and epilepsy. Furthermore, we explore the therapeutic potential of targeting the brain lymphatic system to treat these conditions. Given their critical roles in CNS homeostasis, MLVs and the glymphatic system have emerged as promising therapeutic targets, potentially offering novel treatment strategies for currently incurable neurological diseases.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"80"},"PeriodicalIF":4.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12364799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871689","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}

{"title":"Mitochondrial Quality Control: Insights into Intracerebral Hemorrhage.","authors":"Tong Shang, Binglin Kuang, Lei Zheng, Baiwen Zhang, Xueting Liu, Yaxin Shang, Jia Zheng, Baochun Luo, Wei Zou","doi":"10.1007/s10571-025-01599-1","DOIUrl":"10.1007/s10571-025-01599-1","url":null,"abstract":"<p><p>Mitochondrial dysfunction has been identified as a key factor in the pathophysiological changes associated with intracerebral hemorrhage (ICH). As the core of intracellular energy metabolism, mitochondrial homeostasis is highly dependent on the precise regulation of its mitochondrial quality control (MtQC) system. After ICH, dysfunctional mitochondria lead to impaired oxidative phosphorylation and cellular bioenergetic stress, inducing oxidative stress, inflammatory responses, and programmed cell death, further exacerbating cellular damage. To counteract this injury, cells activate a series of MtQC mechanisms for compensatory repair, including mitochondrial dynamics, mitochondrial biogenesis, mitophagy, and intercellular mitochondrial transfer. These stringent mechanisms help maintain the mitochondrial network, restore the integrity of mitochondrial structural and functional integrity, improve neural function, and mitigate brain injury. In this review, we discuss key evidence regarding the role of mitochondrial dysfunction in ICH, focusing on the MtQC mechanisms involved in ICH. We also summarize potential therapeutic strategies targeting MtQC to intervene in ICH, providing valuable insights for clinical applications.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"79"},"PeriodicalIF":4.8,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854719","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}

{"title":"Role of Repressive Histone Lysine Demethylases and Methylases in Susceptibility to Depression Using a Novel Progressive Social Defeat Stress Mouse Model.","authors":"Arpan Mukhoti, P K Annapoorna, Ashutosh Kumar, Pratishtha Wadnerkar, Ayesha Atqa Khan, Salil Saurav Pathak, Sumana Chakravarty, Arvind Kumar","doi":"10.1007/s10571-025-01597-3","DOIUrl":"10.1007/s10571-025-01597-3","url":null,"abstract":"<p><p>Major depressive disorder (MDD) results from repeated and constant exposure to stress over prolonged periods. The highly variable response to stress and the low heritability suggests that MDD has a strong epigenetic basis. Studies show global dysregulation of histone modifications in both susceptible and resilient animals after chronic stress suggesting involvement of epigenetics in stress response in the brain. Given that the hippocampus and dentate gyrus (DG) show epigenetic changes in neurogenesis in Rodent models of stress that is known to be highly affected in MDD, we hypothesized that epigenetic changes might be involved in the advent of depressive phenotype during the progressive stress paradigm. To study the stress progression into the depression-like phenotype at the molecular level, we designed a novel progressive social defeat stress (PSDS) paradigm based on the popular chronic social defeat stress (CSDS) paradigm but involving only 5 days of defeat stress. Our molecular studies revealed consistent downregulation of H3K9me2 marks in the hippocampus and DG after the 4th day of stress while H3K27me2 showed an early upregulation in the hippocampus and a late downregulation after the 5th day of stress in the DG. In parallel, an early increase in phf8 and phf2 in hippocampus and DG, respectively, was observed. These findings of variable changes like repressive histone methylation marks and expression of corresponding demethylase genes after different durations of defeat stress, led to better understanding of the important role epigenetics play in stress progression into depression at molecular level in establishing resilient and susceptible phenotypes.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"78"},"PeriodicalIF":4.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12339800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815888","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}

{"title":"Identification of Novel Scaffolds Against GSK-3β for Targeting Alzheimer's Disease Through Molecular Modeling Techniques.","authors":"Shafiul Haque, Darin M Mathkor, Mohd Wahid, Harshika Suri, Faraz Ahmad","doi":"10.1007/s10571-025-01568-8","DOIUrl":"10.1007/s10571-025-01568-8","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is one of the most common causes of dementia in elderly populations. A multifactorial and complex etiology has hindered the establishment of successful disease-modifying and retarding treatments. An important molecular target that has a close link with the disease's pathophysiology is glycogen synthase kinase 3β (GSK-3β). GSK-3β is thought to be an important bridge between amyloid and tau pathologies, the two principle pathogenic hallmarks of the disease. In particular, its kinase activity is thought to be a contributing factor for initiating aberrant tau hyperphosphorylation toward neurodegenerative progression. To identify potential inhibitors for GSK-3β, a pharmacophore-based virtual screening was used on the VITAS-M Lab database, a large database of small molecules. A co-crystal ligand employed as the template allowed the screening of roughly 200,000 compounds. Compounds successfully screened were selected on the basis of the Phase screen score combining vector alignments, volume scores, and site matching parameters. Using a cutoff score of 1.7, 174 compounds were docked using the Glide tool for molecular docking to further identify potential high-affinity binding ligands. Finally, four chemicals with the best binding scores (cutoff Glide GScore values of - 8 kcal/mol) were identified. Among these, 3-(2-oxo-2H-chromen-3-yl)-N-(4-sulfamoylphenyl) benzamide (VL-1) and trimethylsilyl trifluoromethanesulfonate (VL-2) showed strong and stable binding interactions, as evidenced by molecular dynamics simulation (MDS). The results suggest that VL-1 and VL-2 may serve as promising lead compounds for GSK-3β-based anti-AD therapeutics. However, further in vivo mechanistic validation is warrantied to confirm their therapeutic applicability.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"77"},"PeriodicalIF":4.8,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783615","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}

{"title":"A GWAS Meta-meta-analysis and In-depth Silico Pharmacogenomic Investigations in Identification of APOE and Other Genes Associated with Pain, Anti-inflammatory, and Immunomodulating Agents in Opioid Use Disorder (OUD) Derived from 14.91 M Subjects.","authors":"Alireza Sharafshah, Majid Motovali-Bashi, Kenneth Blum, Kai-Uwe Lewandrowski, Mark S Gold, Parvaneh Keshavarz, Panayotis K Thanos","doi":"10.1007/s10571-025-01587-5","DOIUrl":"10.1007/s10571-025-01587-5","url":null,"abstract":"<p><p>This study aimed to integrate genome-wide association studies (GWAS) with pharmacogenomics data to develop personalized pain and inflammatory therapeutics. Despite recent developments in the clinical utilities of pharmacogenomics, it needs more investigations for uncovering the complicated mechanisms of drugs from a genetic standpoint. The research addresses the increasing misuse of opioids during recovery, emphasizing personalized interventions for opioid use disorder (OUD). Key pain-related pathways were analyzed to uncover their interactions. Five GWAS traits, including pain, inflammatory biomarkers, immune system abnormalities, and opioid-related traits, were examined. Candidate genes extracted from GWAS datasets were refined through in silico analyses, including protein-protein interactions (PPIs), TF-miRNA coregulatory interactions, enrichment analysis (EA), and clustering enrichment analysis (CEA). A network of 50 highly connected genes was identified, with APOE emerging as a top candidate due to its role in cholesterol metabolism and opioid-induced lipid effects. Pharmacogenomics analysis highlighted significant gene annotations, including OPRM1, DRD2, APOE, GRIN2B, and GPR98, linking them to opioid dependence, neurological disorders, and lipid traits. Protein interaction analyses further validated these connections, with implications for epigenetic repair. Our findings reveal a strong association between APOE, opioid use, and Alzheimer's disease, suggesting potential for novel recovery strategies. Combining HDL-boosting drugs with pro-dopaminergic regulators like KB220 may help prevent relapse. This study underscores the importance of integrating genetic and pharmacogenomic data to advance personalized therapies.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"76"},"PeriodicalIF":4.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752528","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}

{"title":"Neural Circuit Mapping and Neurotherapy-Based Strategies.","authors":"Hany E Marei","doi":"10.1007/s10571-025-01595-5","DOIUrl":"10.1007/s10571-025-01595-5","url":null,"abstract":"<p><p>Recent developments in neural circuit mapping and neurotherapy are changing our understanding of the dynamic network structure of the brain and offering new treatment options. In many neurological and psychiatric diseases, targeted control of specific brain circuits has proven to be a successful strategy to reduce cognitive, behavioral, and motor abnormalities. Sophisticated retrograde tracing techniques, transcranial magnetic stimulation (TMS), chemogenetics, optogenetics, and other technologies have greatly improved our ability to outline, observe, and control neuronal circuits with remarkable accuracy. These sophisticated techniques have revealed crucial information on neuroplasticity, circuit remodeling following injury, and the therapeutic potential of neuromodulatory interventions. Disorders include depression, anxiety, stroke, and neurodegenerative diseases are treated using techniques such as optogenetic stimulation, chemogenetic activation, and non-invasive brain stimulation to restore circuit function. Emerging multifunctional probes like Tetracysteine Display of Optogenetic Elements (Tetro-DOpE) provide real-time monitoring and modification of neuronal populations, improving circuit-level interventions' precision. At the same time, especially following severe brain injury and neurodegeneration, stem cell treatments combined with neurogenesis-promoting strategies show great promise in increasing circuit repair and functional recovery. The development of drug delivery methods like tailored nanoparticle systems and multifunctional probes is helping to improve the accuracy and safety of treatments by reducing off-target effects. These developments taken together draw attention to a notable shift toward precision neuromedicine. These techniques are meant to offer more efficient, focused, and specialized treatments for various neurological and psychiatric diseases by combining sophisticated circuit mapping with tailored therapeutic interventions.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"75"},"PeriodicalIF":4.8,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717633","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}