Pub Date : 2026-01-22DOI: 10.1016/j.bbr.2026.116055
Alixandria T. Mascarin , Srinivasu Kallakuri , Justin L. Carthage , Ali Gheidi , Alana C. Conti , Shane A. Perrine
Individuals using cocaine, particularly those with Cocaine Use Disorder, experience long-lasting neurobiological alterations that contribute to high rates of relapse and increased morbidity and mortality. Rodent models suggest that neuronal activation, as represented by Fos expression, in the nucleus accumbens (NAc) is crucial for cocaine-related behaviors. However, the role of biological sex in NAc activation in these behaviors remains unclear. Therefore, the present study examined the impact of sex on cocaine-induced locomotor activity (LMA), cocaine self-administration, cocaine seeking, and associated NAc Fos expression. We hypothesized that, relative to males, female rats would display heightened behavioral responses in the tested models and greater numbers of Fos+ cells in the NAc, and that Fos expression would correlate with the outcome measures of the assessed behaviors (i.e., locomotor activity and cocaine seeking). In this study, females displayed greater cocaine-induced locomotor activity, cocaine self-administration, and cocaine seeking than males. However, neither sex nor cocaine treatment impacted NAc Fos expression in the LMA study, and NAc Fos levels did not correlate with LMA in either sex. Following cocaine seeking, NAc Fos expression was not sex-dependent, though it correlated with cocaine seeking in males, but not in females. Taken together, these results suggest that the number of Fos+ cells in the NAc do not underlie sex differences in cocaine use or relapse-like behaviors. Future work should characterize the proteomic or electrophysiologic profiles in specific cell types of Fos+ cells in the NAc following cocaine use to determine how these behaviors differ by sex.
{"title":"The role of nucleus accumbens Fos expression in sex-dependent cocaine-induced locomotion, cocaine self-administration, and primed cocaine seeking in rats","authors":"Alixandria T. Mascarin , Srinivasu Kallakuri , Justin L. Carthage , Ali Gheidi , Alana C. Conti , Shane A. Perrine","doi":"10.1016/j.bbr.2026.116055","DOIUrl":"10.1016/j.bbr.2026.116055","url":null,"abstract":"<div><div>Individuals using cocaine, particularly those with Cocaine Use Disorder, experience long-lasting neurobiological alterations that contribute to high rates of relapse and increased morbidity and mortality. Rodent models suggest that neuronal activation, as represented by Fos expression, in the nucleus accumbens (NAc) is crucial for cocaine-related behaviors. However, the role of biological sex in NAc activation in these behaviors remains unclear. Therefore, the present study examined the impact of sex on cocaine-induced locomotor activity (LMA), cocaine self-administration, cocaine seeking, and associated NAc Fos expression. We hypothesized that, relative to males, female rats would display heightened behavioral responses in the tested models and greater numbers of Fos+ cells in the NAc, and that Fos expression would correlate with the outcome measures of the assessed behaviors (i.e., locomotor activity and cocaine seeking). In this study, females displayed greater cocaine-induced locomotor activity, cocaine self-administration, and cocaine seeking than males. However, neither sex nor cocaine treatment impacted NAc Fos expression in the LMA study, and NAc Fos levels did not correlate with LMA in either sex. Following cocaine seeking, NAc Fos expression was not sex-dependent, though it correlated with cocaine seeking in males, but not in females. Taken together, these results suggest that the number of Fos+ cells in the NAc do not underlie sex differences in cocaine use or relapse-like behaviors. Future work should characterize the proteomic or electrophysiologic profiles in specific cell types of Fos+ cells in the NAc following cocaine use to determine how these behaviors differ by sex.</div></div>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"503 ","pages":"Article 116055"},"PeriodicalIF":2.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The presence of metabolic syndrome (MetS) constitutes a significant risk factor for the development of cognitive dysfunction and dementia. MetS can result in damage to the integrity and microstructure of white matter (WM). There may exist certain distinctions in WM between MetS patients with mild cognitive impairment (MCI) and MetS patients with preserved cognitive function. Using diffusion tensor imaging (DTI), we aim to investigate the alterations of the WM in MetS patients with and without MCI.
Methods
36 MetS patients with MCI (MetS-MCI group), 30 age-, gender-, and education-matched MetS patients with normal cognition (MetS-NC group), and 36 healthy controls (HC) were included in the study. Diffusion data was analyzed using Tract-Based Spatial Statistics (TBSS) analysis and Region of Interest (ROI) quantitative analysis to investigate the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ1), and radial diffusivity (λ23) among these groups. Analyses on WM fiber tracts showed FA reduction or MD elevation in regions related to cognitive functions. Relationship between DTI metrics in these regions and neuropsychological assessments was characterized.
Results
In the whole-brain TBSS analysis, compared to HC group, MetS-MCI group primarily exhibited an increase in MD, λ1 and λ23. MetS-NC group primarily exhibited an increase in MD and λ1 compared to HC group. Furthermore, compared to MetS-NC group, MetS-MCI group demonstrated significantly elevated MD and λ23. In the ROI quantitative analysis, increased MD values in right posterior thalamic radiation (PTR.R), left external capsule (EC.L), right inferior fronto-occipital fasciculus (IFO.R), left inferior fronto-occipital fasciculus (IFO.L), and right uncinate fasciculus (UF.R), along with decreased FA values in EC.L, right external capsule (EC.R) and left superior corona radiata (SCR.L), were associated with overall cognitive decline. Elevated MD values in EC.L and IFO.L, as well as reduced FA values in EC.L, were linked to poorer executive function. Similarly, higher MD values in EC.L, IFO.L, and UF.R, combined with lower FA values in EC.L, were associated with worse memory performance.
Conclusions
Our study showed that MetS patients with MCI exhibited more severe WM damage compared to MetS patients without cognitive impairment, and loss of myelin sheath integrity may contribute to the cognitive decline in patients with MetS. Furthermore, our study clarified the association between different cognitive functions and specific WM fiber bundles in MetS patients.
{"title":"White matter abnormalities in metabolic syndrome patients with and without mild cognitive impairment: A diffusion tensor imaging study","authors":"Wen Shao , TianTian Zhu , Xiaoxiao Xiong , Ying Xiong , Qiang Zhang","doi":"10.1016/j.bbr.2026.116057","DOIUrl":"10.1016/j.bbr.2026.116057","url":null,"abstract":"<div><h3>Background</h3><div>The presence of metabolic syndrome (MetS) constitutes a significant risk factor for the development of cognitive dysfunction and dementia. MetS can result in damage to the integrity and microstructure of white matter (WM). There may exist certain distinctions in WM between MetS patients with mild cognitive impairment (MCI) and MetS patients with preserved cognitive function. Using diffusion tensor imaging (DTI), we aim to investigate the alterations of the WM in MetS patients with and without MCI.</div></div><div><h3>Methods</h3><div>36 MetS patients with MCI (MetS-MCI group), 30 age-, gender-, and education-matched MetS patients with normal cognition (MetS-NC group), and 36 healthy controls (HC) were included in the study. Diffusion data was analyzed using Tract-Based Spatial Statistics (TBSS) analysis and Region of Interest (ROI) quantitative analysis to investigate the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ<sub>1</sub>), and radial diffusivity (λ<sub>23</sub>) among these groups. Analyses on WM fiber tracts showed FA reduction or MD elevation in regions related to cognitive functions. Relationship between DTI metrics in these regions and neuropsychological assessments was characterized.</div></div><div><h3>Results</h3><div>In the whole-brain TBSS analysis, compared to HC group, MetS-MCI group primarily exhibited an increase in MD, λ<sub>1</sub> and λ<sub>23.</sub> MetS-NC group primarily exhibited an increase in MD and λ<sub>1</sub> compared to HC group. Furthermore, compared to MetS-NC group, MetS-MCI group demonstrated significantly elevated MD and λ<sub>23</sub>. In the ROI quantitative analysis, increased MD values in right posterior thalamic radiation (PTR.R), left external capsule (EC.L), right inferior fronto-occipital fasciculus (IFO.R), left inferior fronto-occipital fasciculus (IFO.L), and right uncinate fasciculus (UF.R), along with decreased FA values in EC.L, right external capsule (EC.R) and left superior corona radiata (SCR.L), were associated with overall cognitive decline. Elevated MD values in EC.L and IFO.L, as well as reduced FA values in EC.L, were linked to poorer executive function. Similarly, higher MD values in EC.L, IFO.L, and UF.R, combined with lower FA values in EC.L, were associated with worse memory performance.</div></div><div><h3>Conclusions</h3><div>Our study showed that MetS patients with MCI exhibited more severe WM damage compared to MetS patients without cognitive impairment, and loss of myelin sheath integrity may contribute to the cognitive decline in patients with MetS. Furthermore, our study clarified the association between different cognitive functions and specific WM fiber bundles in MetS patients.</div></div>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"503 ","pages":"Article 116057"},"PeriodicalIF":2.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parkinson's disease (PD) is a common neurodegenerative disorder. It has motor symptoms and non motor symptoms, like cognitive impairment, sleep disturbance. Studies show PD patient with sleep disorders show more severe cognitive impairment. To investigate the underlying mechanisms, we used a PD zebrafish model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and simulated insomnia by sleep deprivation (SD). Behavioral tests showed that SD exacerbated cognitive impairment. SD aggravated vascular loss and dopaminergic neuron damage. RT-qPCR analysis revealed the highest expression levels of Toll Like Receptor 4 (tlr-4), Myeloid Differentiation Primary Response 88 (myd88), Nuclear Factor Kappa B (nfκb), Caspase 3 (casp3), BCL2 Associated X, Apoptosis Regulator (bax) in the SD co-treatment group, indicating maximal Toll Like Receptor 4 (TLR4)/Myeloid Differentiation Primary Response 88 (MyD88)/Nuclear Factor Kappa B (NF-κB) pathway activation and apoptosis levels, while Autophagy Related 5 (atg5) expression was lowest, indicating severe autophagy dysfunction. ELISA detected the highest levels of IL-6 and TNF-α, indicating maximal neuroinflammation. This study clarified the mechanism of SD exacerbating PD cognitive impairment: SD upregulates the TLR4/MyD88/NF-κB pathway, which intensifies neuroinflammation and apoptosis and led to autophagy dysfunction. This study revealed the potential mechanism between sleep disturbance and cognitive impairment in PD patients, provided a theoretical basis for the therapies targeting the TLR4/MyD88/NF-κB pathway, holds significant clinical significance for enhancing the quality of life of PD patients.
{"title":"Sleep deprivation-induced TLR4/MyD88/NF-κB pathway dysregulation worsens cognitive impairment in Parkinson's Disease.","authors":"Tianhao Liu, Yanqing Zhang, Xinjia Li, Siyu Liu, Xiaoran Zhu, Yanhong Ren, Rundong Han, Kechun Liu, Chen Sun, Xiuna Ji, Xiuhua Li","doi":"10.1016/j.bbr.2026.116058","DOIUrl":"10.1016/j.bbr.2026.116058","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a common neurodegenerative disorder. It has motor symptoms and non motor symptoms, like cognitive impairment, sleep disturbance. Studies show PD patient with sleep disorders show more severe cognitive impairment. To investigate the underlying mechanisms, we used a PD zebrafish model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and simulated insomnia by sleep deprivation (SD). Behavioral tests showed that SD exacerbated cognitive impairment. SD aggravated vascular loss and dopaminergic neuron damage. RT-qPCR analysis revealed the highest expression levels of Toll Like Receptor 4 (tlr-4), Myeloid Differentiation Primary Response 88 (myd88), Nuclear Factor Kappa B (nfκb), Caspase 3 (casp3), BCL2 Associated X, Apoptosis Regulator (bax) in the SD co-treatment group, indicating maximal Toll Like Receptor 4 (TLR4)/Myeloid Differentiation Primary Response 88 (MyD88)/Nuclear Factor Kappa B (NF-κB) pathway activation and apoptosis levels, while Autophagy Related 5 (atg5) expression was lowest, indicating severe autophagy dysfunction. ELISA detected the highest levels of IL-6 and TNF-α, indicating maximal neuroinflammation. This study clarified the mechanism of SD exacerbating PD cognitive impairment: SD upregulates the TLR4/MyD88/NF-κB pathway, which intensifies neuroinflammation and apoptosis and led to autophagy dysfunction. This study revealed the potential mechanism between sleep disturbance and cognitive impairment in PD patients, provided a theoretical basis for the therapies targeting the TLR4/MyD88/NF-κB pathway, holds significant clinical significance for enhancing the quality of life of PD patients.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"116058"},"PeriodicalIF":2.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.bbr.2026.116050
Daniela A. Avalos-Moreno , Sergio G. Cuevas-Carbonell , Metzli E. Ramírez-Vargas , Luis Castro-Sánchez , Adolfo Virgen-Ortiz , Enrique Sánchez-Pastor , José L. Góngora-Alfaro , Ricardo A. Navarro-Polanco , Eloy G. Moreno-Galindo , Javier Alamilla
Depression is a distressing mental disorder that affects millions of people worldwide. Current treatments include both psychological and pharmacological approaches. However, delays in clinical improvement and high percentage of patients unresponsive to conventional antidepressants highlight the need to identify novel compounds or strategies with optimal antidepressant actions. We have previously shown the antidepressant-like effects of the intraperitoneal (i.p.) administration of the TRPV1 agonist capsaicin (Cap). Moreover, accumulating evidence indicates that the endocannabinoid system plays a key role in the regulation of mood. To explore the role of cerebral cannabinoid receptor type 1 (CB1) in the antidepressant-like effects of Cap, we assessed the impact of separated and combined administration of Cap (i.p.) and the CB1 agonist ACEA (intracerebroventricularly) on rat’s immobility time in the forced swim test. Alike to Cap, we found that ACEA significantly reduced this parameter. Importantly, when combining these compounds, synergistic effects were observed. Contrarily, no impact on the general locomotor activity was detected in the open field test, and no changes in anxiety-related behaviors were noted in the elevated plus maze, for either ACEA alone or its combination with Cap. The present findings suggest that Cap acts through activation of gastrointestinal TRPV1 vagal fibers, while ACEA acts by stimulation of cerebral CB1 receptors. However, more studies are required to elucidate the implied mechanisms of action.
{"title":"Combined administration of intracerebroventricular CB1 agonist ACEA and systemic TRPV1 agonist capsaicin induces synergistic antidepressant-like effects in rats","authors":"Daniela A. Avalos-Moreno , Sergio G. Cuevas-Carbonell , Metzli E. Ramírez-Vargas , Luis Castro-Sánchez , Adolfo Virgen-Ortiz , Enrique Sánchez-Pastor , José L. Góngora-Alfaro , Ricardo A. Navarro-Polanco , Eloy G. Moreno-Galindo , Javier Alamilla","doi":"10.1016/j.bbr.2026.116050","DOIUrl":"10.1016/j.bbr.2026.116050","url":null,"abstract":"<div><div>Depression is a distressing mental disorder that affects millions of people worldwide. Current treatments include both psychological and pharmacological approaches. However, delays in clinical improvement and high percentage of patients unresponsive to conventional antidepressants highlight the need to identify novel compounds or strategies with optimal antidepressant actions. We have previously shown the antidepressant-like effects of the intraperitoneal (i.p.) administration of the TRPV1 agonist capsaicin (Cap). Moreover, accumulating evidence indicates that the endocannabinoid system plays a key role in the regulation of mood. To explore the role of cerebral cannabinoid receptor type 1 (CB1) in the antidepressant-like effects of Cap, we assessed the impact of separated and combined administration of Cap (i.p.) and the CB1 agonist ACEA (intracerebroventricularly) on rat’s immobility time in the forced swim test. Alike to Cap, we found that ACEA significantly reduced this parameter. Importantly, when combining these compounds, synergistic effects were observed. Contrarily, no impact on the general locomotor activity was detected in the open field test, and no changes in anxiety-related behaviors were noted in the elevated plus maze, for either ACEA alone or its combination with Cap. The present findings suggest that Cap acts through activation of gastrointestinal TRPV1 vagal fibers, while ACEA acts by stimulation of cerebral CB1 receptors. However, more studies are required to elucidate the implied mechanisms of action.</div></div>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"503 ","pages":"Article 116050"},"PeriodicalIF":2.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer’s disease (AD), a neurodegenerative disorder characterized by progressive cognitive impairment, involves pathological mechanisms including β-amyloid protein deposition, hyperphosphorylation of Tau proteins, and neuronal damage mediated by ferroptosis. As a traditional Chinese medicine, anti-aging tablets have potential neuroprotective effects, but their active ingredients and mechanisms have not been fully elucidated.
Methods
We screened active ingredients and AD-related targets in anti-aging tablets using liquid chromatography-mass spectrometry combined with network pharmacology analysis. A protein-protein interaction network was established, and GO/KEGG enrichment analyses were performed. The binding of choline to PTGS2 was verified through molecular thermal shift assay. qPCR was utilized to detect PTGS2 expression. An AD model was constructed, with cellular injury levels evaluated through CCK-8, LDH assays, and WB detection by examining the expression of apoptosis-related biomarkers. The expression of ferroptosis-related proteins (FSP1, SLC7A11, GPX4) was examined through Western blot analysis. MDA and GSH/GSSG analyses determined lipid peroxidation and antioxidant capacity. DCFH-DA detected ROS levels.
Results
The combined use of UPLC-MS/MS with network pharmacology led to the identification and characterization of choline as the key active ingredient in anti-aging tablets. PTGS2 was determined as its primary target. The direct binding of choline to PTGS2 was verified through molecular thermal shift assay. In vitro experiments revealed that choline significantly repressed cell damage in the AD model, as indicated by enhanced cell viability, reduced release of LDH, lowered levels of reactive oxygen species (ROS), and downregulated expression of caspase-3 and Bax. Additional studies uncovered that overexpression of PTGS2 exacerbated ferroptosis-related parameters (upregulation of MDA, decrease in GSH/GSSG ratio, downregulation of FSP1, SLC7A11, and GPX4 expression), whereas Fer-1 treatment reversed these changes.
Conclusion
This study revealed that choline targets PTGS2 to depress ferroptosis, thus alleviating AD-related neuronal injury. This study provides a theoretical basis for the pharmacodynamic effects of anti-aging tablets as well as new therapeutic strategies for AD.
{"title":"Choline serves as the primary active compound of anti-aging tablets and targets PTGS2 to alleviate neuronal damage in Alzheimer’s disease by modulating ferroptosis and apoptosis in nerve cells","authors":"Xueping Zhang , Wenwen Ding , Chunxia Guo , Xiuhong Chen , Binhua Chen","doi":"10.1016/j.bbr.2026.116040","DOIUrl":"10.1016/j.bbr.2026.116040","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer’s disease (AD), a neurodegenerative disorder characterized by progressive cognitive impairment, involves pathological mechanisms including β-amyloid protein deposition, hyperphosphorylation of Tau proteins, and neuronal damage mediated by ferroptosis. As a traditional Chinese medicine, anti-aging tablets have potential neuroprotective effects, but their active ingredients and mechanisms have not been fully elucidated.</div></div><div><h3>Methods</h3><div>We screened active ingredients and AD-related targets in anti-aging tablets using liquid chromatography-mass spectrometry combined with network pharmacology analysis. A protein-protein interaction network was established, and GO/KEGG enrichment analyses were performed. The binding of choline to PTGS2 was verified through molecular thermal shift assay. qPCR was utilized to detect PTGS2 expression. An AD model was constructed, with cellular injury levels evaluated through CCK-8, LDH assays, and WB detection by examining the expression of apoptosis-related biomarkers. The expression of ferroptosis-related proteins (FSP1, SLC7A11, GPX4) was examined through Western blot analysis. MDA and GSH/GSSG analyses determined lipid peroxidation and antioxidant capacity. DCFH-DA detected ROS levels.</div></div><div><h3>Results</h3><div>The combined use of UPLC-MS/MS with network pharmacology led to the identification and characterization of choline as the key active ingredient in anti-aging tablets. PTGS2 was determined as its primary target. The direct binding of choline to PTGS2 was verified through molecular thermal shift assay. <em>In vitro</em> experiments revealed that choline significantly repressed cell damage in the AD model, as indicated by enhanced cell viability, reduced release of LDH, lowered levels of reactive oxygen species (ROS), and downregulated expression of caspase-3 and Bax. Additional studies uncovered that overexpression of PTGS2 exacerbated ferroptosis-related parameters (upregulation of MDA, decrease in GSH/GSSG ratio, downregulation of FSP1, SLC7A11, and GPX4 expression), whereas Fer-1 treatment reversed these changes.</div></div><div><h3>Conclusion</h3><div>This study revealed that choline targets PTGS2 to depress ferroptosis, thus alleviating AD-related neuronal injury. This study provides a theoretical basis for the pharmacodynamic effects of anti-aging tablets as well as new therapeutic strategies for AD.</div></div>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"503 ","pages":"Article 116040"},"PeriodicalIF":2.3,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.bbr.2026.116051
Wasim Akhtar , Mohd Muazzam Khan , Mohd Khalid Raza , Sarita Maurya , Sanjay Kumar , Usama Ahmad
Ischemic stroke (IS) stands as a major global health burden, often resulting in death or lasting disability. Beyond the initial deprivation of blood flow, the subsequent cerebral ischemia-reperfusion injury significantly amplifies neural damage through complex inflammatory mechanisms. When blood supply is restored after vascular blockage, the sudden influx of oxygen and immune cells intensifies oxidative stress and triggers a cascade involving glial cell activation, blood–brain barrier (BBB) disruption, and infiltration of peripheral leukocytes. Although this immune response begins as a protective effort, it frequently becomes dysregulated, leading to neuronal degeneration, cerebral edema, and worsened clinical outcomes. In light of this, recent studies have turned toward modulating neuroinflammation as a therapeutic avenue, with plant-derived compounds gaining traction due to their broad-spectrum activity and favourable safety profiles. Bioactive phytochemicals such as flavonoids, polyphenols, and terpenoids have shown potential in preclinical models by attenuating pro-inflammatory cytokine production, inhibiting NF-κB and NLRP3 inflammasome signaling, promoting microglial transition to neuroprotective phenotypes, and reinforcing BBB stability. Enhancing stroke therapy choices requires the creation of natural medications that are highly effective, low in toxicity, and reasonably priced. This review covers 40 phytoconstituents studied between 1996 and 2024, along with their experimental models, tested doses, and observed outcomes. These natural compounds show promise in reducing injury after ischemic stroke. However, their clinical use still requires more research, including detailed pharmacokinetic studies, improved delivery methods, and well-designed human trials to confirm their effectiveness and safety.
{"title":"Targeting neuroinflammation in ischemic stroke: The promise of phytoconstituents","authors":"Wasim Akhtar , Mohd Muazzam Khan , Mohd Khalid Raza , Sarita Maurya , Sanjay Kumar , Usama Ahmad","doi":"10.1016/j.bbr.2026.116051","DOIUrl":"10.1016/j.bbr.2026.116051","url":null,"abstract":"<div><div>Ischemic stroke (IS) stands as a major global health burden, often resulting in death or lasting disability. Beyond the initial deprivation of blood flow, the subsequent cerebral ischemia-reperfusion injury significantly amplifies neural damage through complex inflammatory mechanisms. When blood supply is restored after vascular blockage, the sudden influx of oxygen and immune cells intensifies oxidative stress and triggers a cascade involving glial cell activation, blood–brain barrier (BBB) disruption, and infiltration of peripheral leukocytes. Although this immune response begins as a protective effort, it frequently becomes dysregulated, leading to neuronal degeneration, cerebral edema, and worsened clinical outcomes. In light of this, recent studies have turned toward modulating neuroinflammation as a therapeutic avenue, with plant-derived compounds gaining traction due to their broad-spectrum activity and favourable safety profiles. Bioactive phytochemicals such as flavonoids, polyphenols, and terpenoids have shown potential in preclinical models by attenuating pro-inflammatory cytokine production, inhibiting NF-κB and NLRP3 inflammasome signaling, promoting microglial transition to neuroprotective phenotypes, and reinforcing BBB stability. Enhancing stroke therapy choices requires the creation of natural medications that are highly effective, low in toxicity, and reasonably priced. This review covers 40 phytoconstituents studied between 1996 and 2024, along with their experimental models, tested doses, and observed outcomes. These natural compounds show promise in reducing injury after ischemic stroke. However, their clinical use still requires more research, including detailed pharmacokinetic studies, improved delivery methods, and well-designed human trials to confirm their effectiveness and safety.</div></div>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"503 ","pages":"Article 116051"},"PeriodicalIF":2.3,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.bbr.2026.116052
Wu Zhou , Bo Hei , Zhixin Liu , Shuai Chen , Yifei Fan , Haifeng Zhang , Bingkai Ren , Yong Fu , Jiacong Tan
<div><h3>Background</h3><div>Spinal cord injury (SCI) induces neuroinflammation and brain alterations that contribute to depression-like behaviors. Ferroptosis plays a critical role in neuronal injury following SCI. HMGB1 regulates ferroptosis, while SIRT1 inhibits HMGB1 activity. Electroacupuncture (EA) has demonstrated neuroprotective and antidepressant effects, but its mechanisms in SCI remain unclear. This study investigated whether EA alleviates post-SCI depression by activating SIRT1, retaining HMGB1 in the nucleus, and limiting ferroptosis in the prefrontal cortex (PFC).</div></div><div><h3>Methods</h3><div>A moderate SCI model was established in male Sprague-Dawley rats to assess the neuroprotective effects of EA. Behavioral assessments for depression, histopathological analysis of cortical neurons, and quantification of ferroptosis biomarkers—including malondialdehyde (MDA), Fe<sup>2 +</sup> , glutathione (GSH), and mitochondrial integrity—were conducted. Western blotting and immunofluorescence staining were used to analyze protein expression levels of SIRT1, HMGB1, acetylated HMGB1 (Ace-HMGB1), GPX4, and other oxidative stress markers. To assess the role of SIRT1 activation in mediating EA's effects, the SIRT1 inhibitor EX-527 was co-administered with EA. Additionally, HMGB1 overexpression (OE-HMGB1) and pharmacological inhibition with glycyrrhizic acid (GA) were employed to validate the specificity of the SIRT1/HMGB1 pathway in EA’s neuroprotective action.</div></div><div><h3>Results</h3><div>EA significantly improved depression-like behaviors in SCI rats, as evidenced by increased sucrose preference, reduced immobility, and enhanced social interaction. EA also mitigated neuronal damage, preserved mitochondrial structure, and alleviated oxidative stress by reducing ROS and Fe<sup>2+</sup> levels while increasing GPX4 and GSH expression. Western blot and immunofluorescence analysis showed that EA activated SIRT1 and inhibited HMGB1 translocation to the cytoplasm, reducing HMGB1 acetylation. HMGB1 overexpression (OE-HMGB1) reversed these protective effects, promoting HMGB1 translocation and acetylation. Furthermore, co-treatment with EX-527 (SIRT1 inhibitor) and GA (HMGB1 inhibitor) diminished EA’s neuroprotective effects, confirming the pivotal roles of SIRT1 activation and HMGB1 modulation in EA’s neuroprotection and improvement of depression-like behaviors.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate that EA protects against SCI-induced depression by inhibiting ferroptosis through activation of the SIRT1/HMGB1 signaling axis. This study unveils a novel mechanism underlying EA's neuroprotective effects in SCI-related depression and highlights ferroptosis modulation as a potential therapeutic strategy. By integrating traditional Chinese medicine with modern molecular pathophysiology, this work offers new insights into EA's mechanisms in treating SCI-induced depression and proposes a promising avenue for future the
{"title":"Electroacupuncture alleviates depression-like behavior after spinal cord injury via SIRT1/HMGB1 signaling axis mediated ferroptosis","authors":"Wu Zhou , Bo Hei , Zhixin Liu , Shuai Chen , Yifei Fan , Haifeng Zhang , Bingkai Ren , Yong Fu , Jiacong Tan","doi":"10.1016/j.bbr.2026.116052","DOIUrl":"10.1016/j.bbr.2026.116052","url":null,"abstract":"<div><h3>Background</h3><div>Spinal cord injury (SCI) induces neuroinflammation and brain alterations that contribute to depression-like behaviors. Ferroptosis plays a critical role in neuronal injury following SCI. HMGB1 regulates ferroptosis, while SIRT1 inhibits HMGB1 activity. Electroacupuncture (EA) has demonstrated neuroprotective and antidepressant effects, but its mechanisms in SCI remain unclear. This study investigated whether EA alleviates post-SCI depression by activating SIRT1, retaining HMGB1 in the nucleus, and limiting ferroptosis in the prefrontal cortex (PFC).</div></div><div><h3>Methods</h3><div>A moderate SCI model was established in male Sprague-Dawley rats to assess the neuroprotective effects of EA. Behavioral assessments for depression, histopathological analysis of cortical neurons, and quantification of ferroptosis biomarkers—including malondialdehyde (MDA), Fe<sup>2 +</sup> , glutathione (GSH), and mitochondrial integrity—were conducted. Western blotting and immunofluorescence staining were used to analyze protein expression levels of SIRT1, HMGB1, acetylated HMGB1 (Ace-HMGB1), GPX4, and other oxidative stress markers. To assess the role of SIRT1 activation in mediating EA's effects, the SIRT1 inhibitor EX-527 was co-administered with EA. Additionally, HMGB1 overexpression (OE-HMGB1) and pharmacological inhibition with glycyrrhizic acid (GA) were employed to validate the specificity of the SIRT1/HMGB1 pathway in EA’s neuroprotective action.</div></div><div><h3>Results</h3><div>EA significantly improved depression-like behaviors in SCI rats, as evidenced by increased sucrose preference, reduced immobility, and enhanced social interaction. EA also mitigated neuronal damage, preserved mitochondrial structure, and alleviated oxidative stress by reducing ROS and Fe<sup>2+</sup> levels while increasing GPX4 and GSH expression. Western blot and immunofluorescence analysis showed that EA activated SIRT1 and inhibited HMGB1 translocation to the cytoplasm, reducing HMGB1 acetylation. HMGB1 overexpression (OE-HMGB1) reversed these protective effects, promoting HMGB1 translocation and acetylation. Furthermore, co-treatment with EX-527 (SIRT1 inhibitor) and GA (HMGB1 inhibitor) diminished EA’s neuroprotective effects, confirming the pivotal roles of SIRT1 activation and HMGB1 modulation in EA’s neuroprotection and improvement of depression-like behaviors.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate that EA protects against SCI-induced depression by inhibiting ferroptosis through activation of the SIRT1/HMGB1 signaling axis. This study unveils a novel mechanism underlying EA's neuroprotective effects in SCI-related depression and highlights ferroptosis modulation as a potential therapeutic strategy. By integrating traditional Chinese medicine with modern molecular pathophysiology, this work offers new insights into EA's mechanisms in treating SCI-induced depression and proposes a promising avenue for future the","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"503 ","pages":"Article 116052"},"PeriodicalIF":2.3,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146001702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1016/j.bbr.2026.116048
Lucas Villar Pedrosa da Silva Pantoja , Luiza Fernanda Ramos Soares , Brenda Costa da Conceição , Taiana Cristina Carvalheiro-Simas , Diandra Araújo da Luz , Rui Daniel Prediger , Geanne Matos de Andrade , Enéas Andrade Fontes-Junior , Bruno Gonçalves Pinheiro , Sabrina de Carvalho Cartágenes , Cristiane Socorro Ferraz Maia
Adolescence is a period of profound behavioral changes associated with high brain vulnerability to negative stimuli including psychotropic drugs misuse which may contribute to the development of psychiatric disorders. Ketamine, an NMDA receptor antagonist, is an anesthetic agent used in a recreational manner in night clubs and raves, especially by intranasal route. The psychedelic effects of ketamine include euphoria, reward and mood swings, leading to an altered state of consciousness. Ketamine use has increased among adolescents and young adults, becoming a relevant global public health concern. At these events, drug consumption is often episodic but intense, which may disrupt diverse neuromodulation processes leading to behavioral impairments. Here, we investigated the mnemonic consequences of ketamine withdrawal following recreational exposure in adolescent female rats. To mimic weekend recreational use, adolescent female Wistar rats (n = 8 animals per group) received intranasal ketamine or saline (10 mg/kg/day) for three consecutive days. Twenty-four hours after the last ketamine administration, animals were submitted to a battery of behavioral tasks including novel object recognition, social recognition and Y-maze paradigms to assess episodic, social and working memories. Hippocampal and prefrontal cortex samples were collected for neurochemical analysis. Early ketamine withdrawal following acute exposure impaired all memory types evaluated in the current study. Additionally, a significant reduction in serotonin and norepinephrine levels were observed in the hippocampus and prefrontal cortex of ketamine exposure rats. These findings indicated cognitive and monoaminergic impairments in adolescent female rats at early ketamine withdrawal periods following acute exposure.
{"title":"Acute ketamine withdrawal disrupts memory and monoaminergic neurotransmission in adolescent female rats","authors":"Lucas Villar Pedrosa da Silva Pantoja , Luiza Fernanda Ramos Soares , Brenda Costa da Conceição , Taiana Cristina Carvalheiro-Simas , Diandra Araújo da Luz , Rui Daniel Prediger , Geanne Matos de Andrade , Enéas Andrade Fontes-Junior , Bruno Gonçalves Pinheiro , Sabrina de Carvalho Cartágenes , Cristiane Socorro Ferraz Maia","doi":"10.1016/j.bbr.2026.116048","DOIUrl":"10.1016/j.bbr.2026.116048","url":null,"abstract":"<div><div>Adolescence is a period of profound behavioral changes associated with high brain vulnerability to negative stimuli including psychotropic drugs misuse which may contribute to the development of psychiatric disorders. Ketamine, an NMDA receptor antagonist, is an anesthetic agent used in a recreational manner in night clubs and raves, especially by intranasal route. The psychedelic effects of ketamine include euphoria, reward and mood swings, leading to an altered state of consciousness. Ketamine use has increased among adolescents and young adults, becoming a relevant global public health concern. At these events, drug consumption is often episodic but intense, which may disrupt diverse neuromodulation processes leading to behavioral impairments. Here, we investigated the mnemonic consequences of ketamine withdrawal following recreational exposure in adolescent female rats. To mimic weekend recreational use, adolescent female Wistar rats (n = 8 animals per group) received intranasal ketamine or saline (10 mg/kg/day) for three consecutive days. Twenty-four hours after the last ketamine administration, animals were submitted to a battery of behavioral tasks including novel object recognition, social recognition and Y-maze paradigms to assess episodic, social and working memories. Hippocampal and prefrontal cortex samples were collected for neurochemical analysis. Early ketamine withdrawal following acute exposure impaired all memory types evaluated in the current study. Additionally, a significant reduction in serotonin and norepinephrine levels were observed in the hippocampus and prefrontal cortex of ketamine exposure rats. These findings indicated cognitive and monoaminergic impairments in adolescent female rats at early ketamine withdrawal periods following acute exposure.</div></div>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"502 ","pages":"Article 116048"},"PeriodicalIF":2.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1016/j.bbr.2026.116049
Mariana Rodrigues Alves , Anaelli Aparecida Nogueira-Campos , Adriana Ribeiro de Macedo , Angela Nogueira Neves , Talita P. Pinto , Fabio Vieira dos Anjos , Claudia Domingues Vargas , Luis Aureliano Imbiriba
Postural and autonomic adjustments are commonly described during the observation of emotional stimuli. Thus, this study investigated the physiological impact of emotional images viewing revealed by whole-body expressions. Body sway and cardiorespiratory signals were recorded in thirty-nine healthy young people who maintained an upright stance while observing 20 neutral, 20 happiness (positive) or 20 anger (negative) images from the Bodily Expressive Action Stimulus Test (BEAST) database. Participants rated each image considering their valence and arousal dimensions with the Self-Assessment Manikin. Additionally, emotional recognition level was rated using a three alternative-forced-choice task (happiness, anger, and neutral). A repeated-measures one-way analysis of variance (ANOVA) was used to compare the main physiological variables among emotionally-laden blocks. Valence statistically differed among blocks. The emotional recognition rate was above 70 % for all blocks. There was a significant decrease in body sway area during the observation of anger whole-body expressions compared to the neutral and happiness ones. The mean power frequency in the medial-lateral axis showed a significant increase during viewing anger images compared to the neutral one. Further, there was a significant increase in the heart rate variability during observation of anger whole-body expressions compared to the happiness one. These findings revealed physiological adjustments in the observer while viewing whole-body expressions consistent with the emotional processing experience. Therefore, the observation of images depicting anger whole-body expressions led to postural and autonomic changes in agreement with defensive responses (”postural immobility”).
{"title":"Postural and cardiorespiratory responses to emotionally-laden whole-body expressions","authors":"Mariana Rodrigues Alves , Anaelli Aparecida Nogueira-Campos , Adriana Ribeiro de Macedo , Angela Nogueira Neves , Talita P. Pinto , Fabio Vieira dos Anjos , Claudia Domingues Vargas , Luis Aureliano Imbiriba","doi":"10.1016/j.bbr.2026.116049","DOIUrl":"10.1016/j.bbr.2026.116049","url":null,"abstract":"<div><div>Postural and autonomic adjustments are commonly described during the observation of emotional stimuli. Thus, this study investigated the physiological impact of emotional images viewing revealed by whole-body expressions. Body sway and cardiorespiratory signals were recorded in thirty-nine healthy young people who maintained an upright stance while observing 20 neutral, 20 happiness (positive) or 20 anger (negative) images from the Bodily Expressive Action Stimulus Test (BEAST) database. Participants rated each image considering their valence and arousal dimensions with the Self-Assessment Manikin. Additionally, emotional recognition level was rated using a three alternative-forced-choice task (happiness, anger, and neutral). A repeated-measures one-way analysis of variance (ANOVA) was used to compare the main physiological variables among emotionally-laden blocks. Valence statistically differed among blocks. The emotional recognition rate was above 70 % for all blocks. There was a significant decrease in body sway area during the observation of anger whole-body expressions compared to the neutral and happiness ones. The mean power frequency in the medial-lateral axis showed a significant increase during viewing anger images compared to the neutral one. Further, there was a significant increase in the heart rate variability during observation of anger whole-body expressions compared to the happiness one. These findings revealed physiological adjustments in the observer while viewing whole-body expressions consistent with the emotional processing experience. Therefore, the observation of images depicting anger whole-body expressions led to postural and autonomic changes in agreement with defensive responses (”postural immobility”).</div></div>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"503 ","pages":"Article 116049"},"PeriodicalIF":2.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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