Pub Date : 2025-12-23DOI: 10.1016/j.neuroscience.2025.12.056
Ayan Geng , Wenxuan Hu , Junfan Shen , Qinglei Wang , Shizhe Zhu , Youxin Sui , Chaojie Kan , Ying Shen , Tong Wang , Chuan Guo
This study investigated how varying time intervals between priming continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) affect motor cortex plasticity in healthy adults. Using a randomized crossover design, 31 participants underwent four cTBS-iTBS protocols with intervals of 0, 5, 10, or 15 min, with motor-evoked potential (MEP) amplitudes measured at baseline and post-intervention. The results revealed significant main effects of both the stimulation condition and time point on normalized MEP amplitudes. Among the four protocols, the cTBS-10 min-iTBS protocol elicited the greatest facilitatory effect, producing significantly greater MEP enhancement than the 0-, 5-, and 15-minute intervals. The normalized MEP amplitudes showed a time-dependent decline, with the highest values observed at 0 min and the lowest at 30 min post-intervention. These findings suggest that the time intervals between cTBS and iTBS may influence the resulting facilitation effects, offering preliminary evidence that may inform future optimization of TBS-based therapeutic applications.
{"title":"Optimizing plasticity: the impact of time intervals between priming cTBS and subsequent iTBS on motor-evoked potentials","authors":"Ayan Geng , Wenxuan Hu , Junfan Shen , Qinglei Wang , Shizhe Zhu , Youxin Sui , Chaojie Kan , Ying Shen , Tong Wang , Chuan Guo","doi":"10.1016/j.neuroscience.2025.12.056","DOIUrl":"10.1016/j.neuroscience.2025.12.056","url":null,"abstract":"<div><div>This study investigated how varying time intervals between priming continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) affect motor cortex plasticity in healthy adults. Using a randomized crossover design, 31 participants underwent four cTBS-iTBS protocols with intervals of 0, 5, 10, or 15 min, with motor-evoked potential (MEP) amplitudes measured at baseline and post-intervention. The results revealed significant main effects of both the stimulation condition and time point on normalized MEP amplitudes. Among the four protocols, the cTBS-10 min-iTBS protocol elicited the greatest facilitatory effect, producing significantly greater MEP enhancement than the 0-, 5-, and 15-minute intervals. The normalized MEP amplitudes showed a time-dependent decline, with the highest values observed at 0 min and the lowest at 30 min post-intervention. These findings suggest that the time intervals between cTBS and iTBS may influence the resulting facilitation effects, offering preliminary evidence that may inform future optimization of TBS-based therapeutic applications.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"594 ","pages":"Pages 142-150"},"PeriodicalIF":2.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.neuroscience.2025.12.058
Yuting Li , Shuwen Bo , Jian-Feng Qu , Xiuhang Ruan , Bin Chen , Mengyan Li , Yujian Zou , Changzheng Shi , Xinhua Wei
Emerging neuroimaging evidence has propelled the formulation of the hypothesis that freezing of gait (FOG) in Parkinson’s disease (PD) arises from dysfunction within the locomotor network. However, to date, there has been a lack of functional connectivity analyses targeting the hyperdirect pathway (HDP) to explore this hypothesis. In this study, we investigate impaired communication within the HDP neural circuitry in FOG patients. Fifty-nine PD patients (33 PD-nFOG and 26 PD-FOG) and thirty matched healthy controls underwent resting-state functional magnetic resonance imaging. Both ROI-wise and voxel-wise based resting-state functional connectivity were calculated in this study. No group differences were observed in the ROI-wise functional connectivity among the regions within the HDP. However, significant reduced functional connectivity based on voxel-wise analysis were observed between the HDP and several brain regions, including the default mode network (DMN), sensorimotor cortex, limbic system and cerebellum in PD, which were associated with psychiatric symptoms, emotional decline, and motor dysfunction. Of note, compared to PD-nFOG, PD-FOG showed increased functional connectivity between the HDP and the cerebellum and the middle occipital gyrus, which was associated with motor impairment in the contralateral limbs. These data extend neuroimaging evidence on that compensatory increased functional connectivity in HDP in FOG patients may indicate a failure compensate for clinical manifestations of limb akinesia, and may represent a loss of low-level automatic control of gait regulation by the basal ganglia.
{"title":"Alterations of functional connectivity between hyperdirect pathway regions and outside regions in Parkinson’s disease patients with freezing of gait","authors":"Yuting Li , Shuwen Bo , Jian-Feng Qu , Xiuhang Ruan , Bin Chen , Mengyan Li , Yujian Zou , Changzheng Shi , Xinhua Wei","doi":"10.1016/j.neuroscience.2025.12.058","DOIUrl":"10.1016/j.neuroscience.2025.12.058","url":null,"abstract":"<div><div>Emerging neuroimaging evidence has propelled the formulation of the hypothesis that freezing of gait (FOG) in Parkinson’s disease (PD) arises from dysfunction within the locomotor network. However, to date, there has been a lack of functional connectivity analyses targeting the hyperdirect pathway (HDP) to explore this hypothesis. In this study, we investigate impaired communication within the HDP neural circuitry in FOG patients. Fifty-nine PD patients (33 PD-nFOG and 26 PD-FOG) and thirty matched healthy controls underwent resting-state functional magnetic resonance imaging. Both ROI-wise and voxel-wise based resting-state functional connectivity were calculated in this study. No group differences were observed in the ROI-wise functional connectivity among the regions within the HDP. However, significant reduced functional connectivity based on voxel-wise analysis were observed between the HDP and several brain regions, including the default mode network (DMN), sensorimotor cortex, limbic system and cerebellum in PD, which were associated with psychiatric symptoms, emotional decline, and motor dysfunction. Of note, compared to PD-nFOG, PD-FOG showed increased functional connectivity between the HDP and the cerebellum and the middle occipital gyrus, which was associated with motor impairment in the contralateral limbs. These data extend neuroimaging evidence on that compensatory increased functional connectivity in HDP in FOG patients may indicate a failure compensate for clinical manifestations of limb akinesia, and may represent a loss of low-level automatic control of gait regulation by the basal ganglia.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"595 ","pages":"Pages 220-228"},"PeriodicalIF":2.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.neuroscience.2025.12.059
Victor Manuel Ruiz-Rodríguez, Ares Orlando Cuellar-Santoyo, Ana María Estrada-Sánchez
The human body consists of various organs composed of many cells that form complex systems. The brain and immune system are especially interesting because they were once thought to operate independently, with little communication between them. However, the exact pathways connecting the brain and peripheral immune system, as well as their roles in maintaining brain balance or triggering neuropathologies, remain unclear. This review outlines the components of the immune system within the brain. Next, we elaborate on new evidence demonstrating that, in the brain, mast cells serve as neuroimmune sentinels, and that perivascular spaces, the skull’s bone marrow, and meningeal lymphatic innervation coordinate brain immunity. This evidence uncovers a close interaction between the brain and the peripheral immune system. Additionally, recent findings on neurotransmitter-immune crosstalk and the role of miRNA-loaded exosomes in long-range peripheral signaling may outline potential regulatory pathways between the peripheral immune system and the brain. Finally, we highlight that changes in the mechanisms of interaction between the brain and the immune system are linked to the development and progression of various diseases. A deeper understanding of the connection between the immune and nervous systems could yield new insights into the causes of neuropathologies, neurodegenerative diseases, and immune-related disorders, potentially opening new avenues for treatment.
{"title":"Advances in how the peripheral immune system interacts with the brain in health and disease","authors":"Victor Manuel Ruiz-Rodríguez, Ares Orlando Cuellar-Santoyo, Ana María Estrada-Sánchez","doi":"10.1016/j.neuroscience.2025.12.059","DOIUrl":"10.1016/j.neuroscience.2025.12.059","url":null,"abstract":"<div><div>The human body consists of various organs composed of many cells that form complex systems. The brain and immune system are especially interesting because they were once thought to operate independently, with little communication between them. However, the exact pathways connecting the brain and peripheral immune system, as well as their roles in maintaining brain balance or triggering neuropathologies, remain unclear. This review outlines the components of the immune system within the brain. Next, we elaborate on new evidence demonstrating that, in the brain, mast cells serve as neuroimmune sentinels, and that perivascular spaces, the skull’s bone marrow, and meningeal lymphatic innervation coordinate brain immunity. This evidence uncovers a close interaction between the brain and the peripheral immune system. Additionally, recent findings on neurotransmitter-immune crosstalk and the role of miRNA-loaded exosomes in long-range peripheral signaling may outline potential regulatory pathways between the peripheral immune system and the brain. Finally, we highlight that changes in the mechanisms of interaction between the brain and the immune system are linked to the development and progression of various diseases. A deeper understanding of the connection between the immune and nervous systems could yield new insights into the causes of neuropathologies, neurodegenerative diseases, and immune-related disorders, potentially opening new avenues for treatment.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"596 ","pages":"Pages 24-35"},"PeriodicalIF":2.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.neuroscience.2025.12.057
Sean D. Carey , Allison J. Gibbons , John A. Craig , Hryhoriy Zhoba , Jessica A. Babb , Gary B. Kaplan , Mark R. Zielinski
Traumatic brain injuries (TBI) induce persistent sleep dysregulation. We aimed to determine if a dual orexin receptor antagonist (DORA) could improve sleep dysregulation acutely in mice after TBI across multiple timepoints after an injury to mimic as needed clinical interventions. Male and female C57BL/6J mice (N = 5–8 per treatment group) received a TBI by controlled cortical impact or sham surgery (SHAM). Sleep architecture was assessed at baseline and after vehicle (VEH) or DORA (Lemborexant) given by gavage 24 hours (H), 2 weeks (W), 1 month (M), or 2 M post-TBI. TBI produced increases in non-rapid eye movement sleep (NREMS) amounts and waking EEG delta, theta, and alpha power 24 H post-injury compared to baseline measures and reductions in these measures 1–2 months post-injury. TBI-DORA condition had no effect on acute TBI sleep amount and EEG power effects. However, increased waking frequencies were observed at 1 M in the TBI-VEH group during the light period and were not significantly different from baseline at 1 M in the TBI-DORA group, suggesting an effect on sleep fragmentation. A return to baseline NREMS was also observed in TBI-DORA groups at 1 M looking at average NREMS duration across Zeitgeber Time (ZT) during the light period. DORA treatment reduced sleep latency during the multiple sleep latency test (MSLT) in all groups. Overall, these data suggest that acute interventional DORA treatment can inhibit persistent sleep fragmentation and reverse increased wakefulness after TBI.
{"title":"Acute administration of a dual orexin receptor antagonist attenuates sleep fragmentation in a mouse model of traumatic brain injury","authors":"Sean D. Carey , Allison J. Gibbons , John A. Craig , Hryhoriy Zhoba , Jessica A. Babb , Gary B. Kaplan , Mark R. Zielinski","doi":"10.1016/j.neuroscience.2025.12.057","DOIUrl":"10.1016/j.neuroscience.2025.12.057","url":null,"abstract":"<div><div>Traumatic brain injuries (TBI) induce persistent sleep dysregulation. We aimed to determine if a dual orexin receptor antagonist (DORA) could improve sleep dysregulation acutely in mice after TBI across multiple timepoints after an injury to mimic as needed clinical interventions. Male and female C57BL/6J mice (N = 5–8 per treatment group) received a TBI by controlled cortical impact or sham surgery (SHAM). Sleep architecture was assessed at baseline and after vehicle (VEH) or DORA (Lemborexant) given by gavage 24 hours (H), 2 weeks (W), 1 month (M), or 2 M post-TBI. TBI produced increases in non-rapid eye movement sleep (NREMS) amounts and waking EEG delta, theta, and alpha power 24 H post-injury compared to baseline measures and reductions in these measures 1–2 months post-injury. TBI-DORA condition had no effect on acute TBI sleep amount and EEG power effects. However, increased waking frequencies were observed at 1 M in the TBI-VEH group during the light period and were not significantly different from baseline at 1 M in the TBI-DORA group, suggesting an effect on sleep fragmentation. A return to baseline NREMS was also observed in TBI-DORA groups at 1 M looking at average NREMS duration across Zeitgeber Time (ZT) during the light period. DORA treatment reduced sleep latency during the multiple sleep latency test (MSLT) in all groups. Overall, these data suggest that acute interventional DORA treatment can inhibit persistent sleep fragmentation and reverse increased wakefulness after TBI.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"594 ","pages":"Pages 190-202"},"PeriodicalIF":2.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.neuroscience.2025.12.055
R. Gutierrez , M. Fibla , E. Skorupska , M.M. Santafe
Neuromuscular transmission plays a crucial role in muscle function, with differences in neurotransmitter release potentially influenced by sex and aging. While hormonal effects on neurotransmission have been studied, their impact on acetylcholine (ACh) release at the neuromuscular junction remains largely unexplored. Understanding these differences could provide insights into age-related muscle function decline and sex-specific variations in neuromuscular disorders. This study aims to investigate sex- and age-related differences in spontaneous ACh release at the neuromuscular junction in mammals, focusing on variations in electromyographic (EMG) activity. Experiments were conducted on young (2 months) and old (15 months) Swiss male and female mice. EMG recordings were taken from the gastrocnemius muscle, analyzing the percentage of sites with endplate noise, noise frequency, and spike frequency. Estrous cycle stages in female mice were identified to account for hormonal fluctuations. Males exhibited a higher percentage of sites with endplate noise than females. Old females had the highest frequency of endplate noise, while old males had the largest amplitude. Spike frequency was higher in females and increased with age. These results suggest sex and age differences in neuromuscular activity, potentially influenced by hormonal and autonomic regulation. In conclusion, neuromuscular transmission differs between sexes and across aging. Estrogens may modulate cholinergic receptor function, and autonomic nervous system activity likely contributes to observed differences. These findings highlight distinct aging patterns in neuromuscular function between males and females.
{"title":"Electromyography of spontaneous neuromuscular release of ACh: variations according to sex and age","authors":"R. Gutierrez , M. Fibla , E. Skorupska , M.M. Santafe","doi":"10.1016/j.neuroscience.2025.12.055","DOIUrl":"10.1016/j.neuroscience.2025.12.055","url":null,"abstract":"<div><div>Neuromuscular transmission plays a crucial role in muscle function, with differences in neurotransmitter release potentially influenced by sex and aging. While hormonal effects on neurotransmission have been studied, their impact on acetylcholine (ACh) release at the neuromuscular junction remains largely unexplored. Understanding these differences could provide insights into age-related muscle function decline and sex-specific variations in neuromuscular disorders. This study aims to investigate sex- and age-related differences in spontaneous ACh release at the neuromuscular junction in mammals, focusing on variations in electromyographic (EMG) activity. Experiments were conducted on young (2 months) and old (15 months) Swiss male and female mice. EMG recordings were taken from the gastrocnemius muscle, analyzing the percentage of sites with endplate noise, noise frequency, and spike frequency. Estrous cycle stages in female mice were identified to account for hormonal fluctuations. Males exhibited a higher percentage of sites with endplate noise than females. Old females had the highest frequency of endplate noise, while old males had the largest amplitude. Spike frequency was higher in females and increased with age. These results suggest sex and age differences in neuromuscular activity, potentially influenced by hormonal and autonomic regulation<strong>.</strong> In conclusion, neuromuscular transmission differs between sexes and across aging. Estrogens may modulate cholinergic receptor function, and autonomic nervous system activity likely contributes to observed differences. These findings highlight distinct aging patterns in neuromuscular function between males and females.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"594 ","pages":"Pages 113-119"},"PeriodicalIF":2.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.neuroscience.2025.12.054
Hao Yang , Jianping Jia
Background
Apremilast, a novel inhibitor of phosphodiesterase-4 (PDE4), has demonstrated anti-inflammatory, immunomodulatory, neuroprotective, and senolytic properties. Given these characteristics, Apremilast, similar to other PDE4 inhibitors, holds potential as a therapeutic candidate for Alzheimer’s disease (AD).
Objective
This study aims to investigate whether Apremilast can mitigate neurotoxicity induced by amyloid β (Aβ) in BV2 microglial and HT-22 hippocampal mouse cell lines, while also exploring its neuroprotective effects and the underlying molecular mechanisms.
Methods
To begin, network pharmacology was employed to identify potential shared targets between Apremilast and AD. Molecular docking was subsequently used to assess the binding affinity of Apremilast to key targets. At the cellular level, the Cell Counting Kit-8 (CCK-8) assay was conducted to evaluate Apremilast’s protective effects against Aβ-induced cytotoxicity in BV2 and HT-22 cells. Finally, Western blot (WB) analysis was performed to examine the expression of proteins in the PI3K/Akt signaling pathway, offering insights into the molecular mechanisms underlying Apremilast’s neuroprotective role.
Results
Target enrichment analysis identified several potential pathways, among which the PI3K/Akt pathway was chosen for further examination. The results showed that Apremilast effectively counteracted Aβ-induced cytotoxicity in both BV2 and HT-22 cells, leading to a significant improvement in cell viability. Moreover, Western blot analysis demonstrated an upregulation of phosphorylated Akt (p-Akt/Akt) and PI3K protein levels.
Conclusion
In conclusion, this study provides evidence that Apremilast may exert protective effects against Aβ-induced cytotoxicity in BV2 and HT-22 cells by modulating the PI3K/Akt signaling pathway. However, further validation of its dosage and efficacy in vivo is required.
背景：Apremilast是一种新型磷酸二酯酶-4 （PDE4）抑制剂，具有抗炎、免疫调节、神经保护和抗衰老的特性。鉴于这些特点，Apremilast与其他PDE4抑制剂类似，具有作为阿尔茨海默病（AD）治疗候选药物的潜力。目的：研究阿普雷米司特是否能减轻β淀粉样蛋白（Aβ）对小鼠BV2小胶质细胞和HT-22海马细胞系的神经毒性，并探讨其神经保护作用及其分子机制。方法：首先，采用网络药理学方法识别阿普拉米司特和AD之间潜在的共享靶点。随后使用分子对接来评估Apremilast与关键靶点的结合亲和力。在细胞水平上，通过细胞计数试剂盒-8 （CCK-8）检测来评估阿普雷米司特对a β诱导的BV2和HT-22细胞毒性的保护作用。最后，采用Western blot （WB）分析检测PI3K/Akt信号通路中蛋白的表达，从而深入了解Apremilast神经保护作用的分子机制。结果：通过靶富集分析发现了几种潜在通路，我们选择了PI3K/Akt通路进行进一步研究。结果表明，阿普雷米司特能有效抵消a β诱导的BV2和HT-22细胞毒性，显著提高细胞活力。此外，Western blot分析显示磷酸化Akt （p-Akt/Akt）和PI3K蛋白水平上调。结论：本研究提示阿普雷米司特可能通过调节PI3K/Akt信号通路，对a β诱导的BV2和HT-22细胞毒性发挥保护作用。然而，需要进一步验证其剂量和体内疗效。
{"title":"Apremilast-mediated protection against Aβ-induced cytotoxicity correlates with PI3K/Akt pathway activation","authors":"Hao Yang , Jianping Jia","doi":"10.1016/j.neuroscience.2025.12.054","DOIUrl":"10.1016/j.neuroscience.2025.12.054","url":null,"abstract":"<div><h3>Background</h3><div>Apremilast, a novel inhibitor of phosphodiesterase-4 (PDE4), has demonstrated anti-inflammatory, immunomodulatory, neuroprotective, and senolytic properties. Given these characteristics, Apremilast, similar to other PDE4 inhibitors, holds potential as a therapeutic candidate for Alzheimer’s disease (AD).</div></div><div><h3>Objective</h3><div>This study aims to investigate whether Apremilast can mitigate neurotoxicity induced by amyloid β (Aβ) in BV2 microglial and HT-22 hippocampal mouse cell lines, while also exploring its neuroprotective effects and the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>To begin, network pharmacology was employed to identify potential shared targets between Apremilast and AD. Molecular docking was subsequently used to assess the binding affinity of Apremilast to key targets. At the cellular level, the Cell Counting Kit-8 (CCK-8) assay was conducted to evaluate Apremilast’s protective effects against Aβ-induced cytotoxicity in BV2 and HT-22 cells. Finally, Western blot (WB) analysis was performed to examine the expression of proteins in the PI3K/Akt signaling pathway, offering insights into the molecular mechanisms underlying Apremilast’s neuroprotective role.</div></div><div><h3>Results</h3><div>Target enrichment analysis identified several potential pathways, among which the PI3K/Akt pathway was chosen for further examination. The results showed that Apremilast effectively counteracted Aβ-induced cytotoxicity in both BV2 and HT-22 cells, leading to a significant improvement in cell viability. Moreover, Western blot analysis demonstrated an upregulation of phosphorylated Akt (p-Akt/Akt) and PI3K protein levels.</div></div><div><h3>Conclusion</h3><div>In conclusion, this study provides evidence that Apremilast may exert protective effects against Aβ-induced cytotoxicity in BV2 and HT-22 cells by modulating the PI3K/Akt signaling pathway. However, further validation of its dosage and efficacy in vivo is required.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"595 ","pages":"Pages 20-27"},"PeriodicalIF":2.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.neuroscience.2025.12.053
Mandana AmeliMojarad, Melika AmeliMojarad
Antibody–drug conjugates (ADCs) are emerging as a targeted therapeutic strategy for Alzheimer’s disease (AD), offering precise delivery of disease modifying agents with reduced systemic toxicity. By linking monoclonal antibodies to small-molecule payloads, ADCs hold promise in overcoming key challenges in AD treatment, including poor blood–brain barrier (BBB) penetration and off-target effects. This review provides a critical synthesis of ADC strategies in neurodegeneration, with emphasis on molecular design, payload selection, and delivery mechanisms. Distinctively, we integrate lessons from oncology-based ADC development into the neurodegenerative context, highlighting how these cross disciplinary insights open new avenues for tackling multifactorial AD pathology, including amyloid-beta (Aβ) and tau-related mechanisms. By outlining translational progress, ongoing clinical efforts, and future directions, this review positions ADCs not only as a promising precision medicine approach but also as a novel framework for advancing therapeutic innovation in complex neurodegenerative disorders.
{"title":"Antibody drug conjugates in Alzheimer’s disease: emerging strategies and future directions","authors":"Mandana AmeliMojarad, Melika AmeliMojarad","doi":"10.1016/j.neuroscience.2025.12.053","DOIUrl":"10.1016/j.neuroscience.2025.12.053","url":null,"abstract":"<div><div>Antibody–drug conjugates (ADCs) are emerging as a targeted therapeutic strategy for Alzheimer’s disease (AD), offering precise delivery of disease modifying agents with reduced systemic toxicity. By linking monoclonal antibodies to small-molecule payloads, ADCs hold promise in overcoming key challenges in AD treatment, including poor blood–brain barrier (BBB) penetration and off-target effects. This review provides a critical synthesis of ADC strategies in neurodegeneration, with emphasis on molecular design, payload selection, and delivery mechanisms. Distinctively, we integrate lessons from oncology-based ADC development into the neurodegenerative context, highlighting how these cross disciplinary insights open new avenues for tackling multifactorial AD pathology, including amyloid-beta (Aβ) and tau-related mechanisms. By outlining translational progress, ongoing clinical efforts, and future directions, this review positions ADCs not only as a promising precision medicine approach but also as a novel framework for advancing therapeutic innovation in complex neurodegenerative disorders.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"596 ","pages":"Pages 45-53"},"PeriodicalIF":2.8,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.neuroscience.2025.12.050
Zeyi Wang , Sungchil Yang , Jianping Lu , Qiang Zhou
Understanding the excitation/inhibition (E/I) balance is fundamental to deciphering cortical circuit dynamics, supporting cognition, and elucidating the pathophysiology of brain disorders, yet methods for assessing E/I balance in vivo remain limited. While recent studies have proposed the aperiodic component (1/f slope) of the local field potentials (LFPs) power spectrum as a potential indicator of E/I balance, this hypothesis has lacked systematic, multi-level in vivo validation. Here, we systematically tested the hypothesis that the aperiodic 1/f slope can serve as a reliable proxy for dynamically monitoring change in E/I balance. In freely moving male mice, we first optimized the analytical parameters for the 1/f slope. We then demonstrated that the slope quantitatively tracks shifts in inhibition induced by pharmacological manipulations in a dose-dependent manner, captures the rapid dynamic shift to inhibition induced by cell-type-specific optogenetic manipulation, and shows generality across drugs altering E/I with diverse mechanisms. On an applied level, we show that the 1/f slope tracks performance-related neural dynamics during a working memory task and indicates the direction of E/I balance in mouse models of epilepsy and depression. Collectively, our findings establish the 1/f slope as a reliable, rapid and sensitive proxy for monitoring E/I balance shift, offering a potential, practical tool for monitoring brain dynamics and as a biomarker for translational research.
{"title":"Reliable and dynamic monitoring changes in cortical excitation and inhibition balance using aperiodic 1/f slope: functions, diseases and drug effects","authors":"Zeyi Wang , Sungchil Yang , Jianping Lu , Qiang Zhou","doi":"10.1016/j.neuroscience.2025.12.050","DOIUrl":"10.1016/j.neuroscience.2025.12.050","url":null,"abstract":"<div><div>Understanding the excitation/inhibition (E/I) balance is fundamental to deciphering cortical circuit dynamics, supporting cognition, and elucidating the pathophysiology of brain disorders, yet methods for assessing E/I balance <em>in vivo</em> remain limited. While recent studies have proposed the aperiodic component (1/f slope) of the local field potentials (LFPs) power spectrum as a potential indicator of E/I balance, this hypothesis has lacked systematic, multi-level <em>in vivo</em> validation. Here, we systematically tested the hypothesis that the aperiodic 1/f slope can serve as a reliable proxy for dynamically monitoring change in E/I balance. In freely moving male mice, we first optimized the analytical parameters for the 1/f slope. We then demonstrated that the slope quantitatively tracks shifts in inhibition induced by pharmacological manipulations in a dose-dependent manner, captures the rapid dynamic shift to inhibition induced by cell-type-specific optogenetic manipulation, and shows generality across drugs altering E/I with diverse mechanisms. On an applied level, we show that the 1/f slope tracks performance-related neural dynamics during a working memory task and indicates the direction of E/I balance in mouse models of epilepsy and depression. Collectively, our findings establish the 1/f slope as a reliable, rapid and sensitive proxy for monitoring E/I balance shift, offering a potential, practical tool for monitoring brain dynamics and as a biomarker for translational research.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"595 ","pages":"Pages 9-19"},"PeriodicalIF":2.8,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.neuroscience.2025.12.049
Justin Joseph , Simi V.R. , Rashmi K.M. , Rashmi R.
Olfactory impairment is an early symptom of Alzheimer’s disease (AD). However, currently used olfactory task-based functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS), and electroencephalogram features are not powerful enough to detect the impairment. To address this issue, we propose an explainable Artificial Intelligence (XAI) framework that comprises discriminant analysis/naive Bayes/thresholding classifiers driven by the sample entropy (SE) of olfactory event-related potentials (OERPs) at the Fz/Pz electrodes. The proposed XAI framework exhibits a higher accuracy (92.14%) than methods in the literature, namely, support vector machine (88.20%), logistic regression (67.42%), thresholding (82.5%), and light gradient boosting (80.68%) classifiers fed respectively by inter-electrode β-γ magnitude squared coherence of OERPs, P2 latency of OERPs, fMRI activation pattern of primary olfactory cortex, and NIRS oxygenation difference in the orbito-frontal cortex. Reduction in SE in AD patients is caused by low dynamicity of OERPs as a consequence of diminished sensitivity to the olfactory stimulus.
{"title":"Complexity of olfactory-evoked EEG as an evidence-based marker of Alzheimer’s disease","authors":"Justin Joseph , Simi V.R. , Rashmi K.M. , Rashmi R.","doi":"10.1016/j.neuroscience.2025.12.049","DOIUrl":"10.1016/j.neuroscience.2025.12.049","url":null,"abstract":"<div><div>Olfactory impairment is an early symptom of Alzheimer’s disease (AD). However, currently used olfactory task-based functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS), and electroencephalogram features are not powerful enough to detect the impairment. To address this issue, we propose an explainable Artificial Intelligence (XAI) framework that comprises discriminant analysis/naive Bayes/thresholding classifiers driven by the sample entropy (SE) of olfactory event-related potentials (OERPs) at the Fz/Pz electrodes. The proposed XAI framework exhibits a higher accuracy (92.14%) than methods in the literature, namely, support vector machine (88.20%), logistic regression (67.42%), thresholding (82.5%), and light gradient boosting (80.68%) classifiers fed respectively by inter-electrode β-γ magnitude squared coherence of OERPs, P2 latency of OERPs, fMRI activation pattern of primary olfactory cortex, and NIRS oxygenation difference in the orbito-frontal cortex. Reduction in SE in AD patients is caused by low dynamicity of OERPs as a consequence of diminished sensitivity to the olfactory stimulus.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"594 ","pages":"Pages 224-239"},"PeriodicalIF":2.8,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to evaluate the neuroprotective effects of aegeline on lipopolysaccharide (LPS) −induced cognitive dysfunction in rats.
Background
The global rise in neuroinflammatory and cognitive disorders demands safe and effective plant-based neuroprotective agents. LPS is a potent endotoxin that triggers inflammation and tissue damage. Aegeline, a hydroxyamide derived from Aegle marmelos, exhibits anti-inflammatory and antioxidant properties. However, its ability to modulate hippocampal cholinergic and proinflammatory cytokine receptors, as well as to protect against LPS-induced memory impairment, remains unexplored.
Methods
Aegeline was administered at doses of 5 and 10 mg/kg for seven days to Wistar rats. Behavioral tests included the Y-maze and the Morris water maze (MWM). Biochemical analyses measured acetylcholinesterase (AChE), choline acetyltransferase (ChAT), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), nitric oxide (NO), and inflammatory cytokines: tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6. Furthermore, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and caspase-3 markers were evaluated. Additionally, in silico molecular docking and molecular dynamics simulations (MDS) were conducted.
Results
Aegeline treatment improved performance in the Y-maze and MWM tests. It reduced AChE, proinflammatory cytokine, NF-κB, oxidative stress marker, and caspase-3 levels. Antioxidant enzymes and ChAT levels were increased. In silico, aegeline showed strong binding to protein 7JRA with a binding energy of −9.289 kcal/mol, respectively. MDS confirmed the stable interactions with key therapeutic targets.
Conclusion
Aegeline improved cognition, reduced inflammation and oxidative stress, and enhanced antioxidant and cholinergic activity. Its strong molecular binding supports its potential as a neuroprotective agent against memory impairment.
{"title":"Neuroprotective effects of aegeline against LPS-induced memory dysfunction: involvement of hippocampal cholinergic/proinflammatory cytokines receptor modulation and insilico insight","authors":"Khalid Saad Alharbi , Sattam Khulaif Alenezi , Tariq G Alsahli , Reem ALQahtani , Muhammad Afzal , Imran Kazmi , Nadeem Sayyed","doi":"10.1016/j.neuroscience.2025.12.048","DOIUrl":"10.1016/j.neuroscience.2025.12.048","url":null,"abstract":"<div><h3>Aims</h3><div>This study aimed to evaluate the neuroprotective effects of aegeline on lipopolysaccharide (LPS) −induced cognitive dysfunction in rats.</div></div><div><h3>Background</h3><div>The global rise in neuroinflammatory and cognitive disorders demands safe and effective plant-based neuroprotective agents. LPS is a potent endotoxin that triggers inflammation and tissue damage. Aegeline, a hydroxyamide derived from <em>Aegle marmelos</em>, exhibits anti-inflammatory and antioxidant properties. However, its ability to modulate hippocampal cholinergic and proinflammatory cytokine receptors, as well as to protect against LPS-induced memory impairment, remains unexplored.</div></div><div><h3>Methods</h3><div>Aegeline was administered at doses of 5 and 10 mg/kg for seven days to Wistar rats. Behavioral tests included the Y-maze and the Morris water maze (MWM). Biochemical analyses measured acetylcholinesterase (AChE), choline acetyltransferase (ChAT), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), nitric oxide (NO), and inflammatory cytokines: tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6. Furthermore, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and caspase-3 markers were evaluated. Additionally, in silico molecular docking and molecular dynamics simulations (MDS) were conducted.</div></div><div><h3>Results</h3><div>Aegeline treatment improved performance in the Y-maze and MWM tests. It reduced AChE, proinflammatory cytokine, NF-κB, oxidative stress marker, and caspase-3 levels. Antioxidant enzymes and ChAT levels were increased. In silico, aegeline showed strong binding to protein 7JRA with a binding energy of −9.289 kcal/mol, respectively. MDS confirmed the stable interactions with key therapeutic targets.</div></div><div><h3>Conclusion</h3><div>Aegeline improved cognition, reduced inflammation and oxidative stress, and enhanced antioxidant and cholinergic activity. Its strong molecular binding supports its potential as a neuroprotective agent against memory impairment.</div></div>","PeriodicalId":19142,"journal":{"name":"Neuroscience","volume":"595 ","pages":"Pages 112-129"},"PeriodicalIF":2.8,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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