Frontiers in Behavioral Neuroscience最新文献

{"title":"Sexually dimorphic effects of single prolonged stress on conditioned suppression behavior in Long Evans rats with no detection of altered mRNA expression of VGLUT1, GAD1, and Arc in the ventral hippocampus.","authors":"Stacy R Pitcairn, Andrew E Tapp, Ryan M Drenan, Jeffrey L Weiner","doi":"10.3389/fnbeh.2026.1771722","DOIUrl":"10.3389/fnbeh.2026.1771722","url":null,"abstract":"<p><strong>Introduction: </strong>Women are especially vulnerable to stress-related disorders such as posttraumatic stress disorder (PTSD), yet most preclinical studies have focused on males. Rodents often exhibit sexually-dimorphic coping strategies in fear behaviors, thus complicating neurobiological interpretations. To facilitate comparisons, an operant conditioned suppression paradigm was implemented where the measure of fear is not dependent on the coping strategy. The effect of single prolonged stress (SPS) on fear behavior was assessed. Since stress has been linked to excitatory phenotypes, mRNA expression of vesicular glutamate transporter 1 (VGLUT1) and glutamate decarboxylase (GAD1) was measured to assess excitation and inhibition-related markers in the ventral hippocampus (vHip), a stress-sensitive brain region. Activity-regulated cytoskeleton associated protein (Arc/Arg3.1) was used to identify neurons activated during fear extinction. The goal of this study was to determine whether SPS produces sex differences in conditioned-suppression fear behavior and to identify accompanying molecular changes in the vHip.</p><p><strong>Methods: </strong>Thirty-two adult male and female Long Evans rats (<i>n</i> = 16/sex) were trained to lever press for sucrose on variable-interval (VI) schedules. After stable responding, a subset (8/sex) underwent single prolonged stress (SPS). All rats received fear conditioning with five presentations of a conditioned stimulus (CS)-shock pairing. Extinction sessions included baseline VI-60 responding followed by CS presentations. Fear was defined as the suppression of lever pressing during CS. Tissue containing the vHip was collected following the last session for RNA <i>in situ</i> hybridization (RNA-ISH) to examine mRNA expression of molecular markers of excitation/inhibition (VGLUT1, GAD1) and neuronal activation (Arc).</p><p><strong>Results: </strong>SPS impaired extinction in males on day 1 but had no effect in females. On day 2, males showed greater fear than females regardless of SPS. No significant effects were observed on day 3 or the recall session. No significant effects of sex or stress were observed on vHip mRNA expression of VGLUT1, GAD1, or Arc under the experimental conditions.</p><p><strong>Discussion: </strong>These findings demonstrate sex-specific effects of SPS on fear extinction measured by conditioned suppression. Future studies should explore earlier time points, additional regions (e.g., amygdala and medial prefrontal cortex) hormonal modulation, and interventions that may mitigate SPS effects in males and females.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1771722"},"PeriodicalIF":3.4,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13253521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in compulsive sexual behavior disorder.","authors":"Aviv M Weinstein","doi":"10.3389/fnbeh.2026.1821534","DOIUrl":"10.3389/fnbeh.2026.1821534","url":null,"abstract":"<p><strong>Background: </strong>Compulsive sexual behavior is a failure to control intense, repetitive sexual impulses or urges, resulting in sexual behavior that causes marked distress or impairment. Studies on compulsive sexual behavior report a higher prevalence of CSBD among men. There are sex differences in the symptoms and behaviors associated with CSB, like sexual arousal and motivation.</p><p><strong>Methods: </strong>A systematic search in PubMed/Medline and Scopus databases between January 2000 and January 2026, using search terms related to compulsive sexual behavior.</p><p><strong>Results: </strong>While CSBD is more common in men, neuroticism and stress vulnerability contribute importantly to CSBD symptoms in women. Human sexuality is associated with neurotransmitters, hormones, and genes, in particular genes responsible for dopamine, which is associated with novelty seeking, impulsivity, and may influence sexual activity. Neuroimaging studies outlined sex differences in neural responses to sexual stimuli in men in fMRI. Men with CSBD showed an activation of reward areas in the brain in response to sexually explicit stimuli. Their higher sensitivity to the rewarding value of sexual cues may contribute to their increased risk of addictive or compulsive sexual behaviors. Studies on CSBD indicate that impulsivity and psychiatric comorbidity are common across both genders. Finally, childhood trauma and abuse are often reported in individuals seeking treatment for sex addiction, particularly among women.</p><p><strong>Implications: </strong>Little is known about sex differences in CSBD. Although childhood adversities may contribute to the development of CSB in both women and men, further research is needed to determine whether the groups respond differently.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1821534"},"PeriodicalIF":3.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13246655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IntelliCage protocols using incentive-disincentive dual motivation work with male as well as female mice and reveal sex differences in motivated behavior.","authors":"Laurine Roos, Gian Rieder, Irmgard Amrein, David P Wolfer","doi":"10.3389/fnbeh.2026.1833013","DOIUrl":"10.3389/fnbeh.2026.1833013","url":null,"abstract":"<p><strong>Introduction: </strong>In the IntelliCage system, spontaneous behavior and cognitive abilities of mice can be assessed automatically in a social homecage context and without handling by human experimenters. We have recently shown that female mice can be motivated to learn complex spatial tasks with refined IntelliCage protocols that lack water restriction and thereby eliminate the risk of water deprivation in poor learners. These protocols create a dual motivation by combining incentive and disincentive taste stimuli. The mice learn to gain access to saccharin sweetened water while water rendered bitter by quinine remains permanently available.</p><p><strong>Methods: </strong>Here, we used a total of 64 C57BL/6J mice to assess males and females in dual motivation protocols versus single motivation protocols using only saccharin as incentive stimulus.</p><p><strong>Results: </strong>We found that in dual motivation protocols male mice learned at least as well as females provided that the location of target corners was stable over time. When targets shifted frequently and in response to the choices of the animals, male mice lost motivation and learned poorly. Based on lick counts, we did not find evidence of impaired liquid intake despite the addition of a disincentive stimulus.</p><p><strong>Discussion: </strong>Our study demonstrates that by using dual motivation protocols, it is possible to create spatial learning tasks for IntelliCage which do not enforce learning by water restriction and which can be learned by mice of both sexes. Furthermore, our results reveal an interesting sex difference in motivated behavior which is not apparent in protocols that enforce learning by water restriction. We hypothesize that this sex difference may be related to the socio-spatial organization of male mouse groups in the IntelliCage.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1833013"},"PeriodicalIF":3.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13246642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tube-plugging test: a simple assay that reveals offspring-centered defensive behavior in postpartum mice.","authors":"Noriko Horii-Hayashi, Shoma Miki, Hanano Takashima, Koshiro Akaki, Koichi Inoue","doi":"10.3389/fnbeh.2026.1767805","DOIUrl":"10.3389/fnbeh.2026.1767805","url":null,"abstract":"<p><p>Perinatal mental health is a major public health concern. Epidemiological studies indicate that approximately 10-20% of women in the postpartum period experience clinically significant depressive or obsessive-compulsive symptoms. Many postpartum symptoms involve heightened vigilance and behaviors aimed at protecting the infant from possible harm, suggesting the presence of offspring-centered defensive processes. One offspring-centered defensive behavior described in wild rats is entrance-sealing, in which lactating females plug the entrance of their burrow to limit access by potential intruders. Although laboratory mice rarely exhibit such behavior spontaneously, similar bedding-plugging behavior has been occasionally observed, suggesting that mice retain the capacity for this response. However, no method has existed for reliably quantifying such behavior under controlled laboratory conditions. To address this gap, we developed the Tube-Plugging Test (TPT), an assay that measures bedding accumulated at tube-like openings attached to the home cage and enables repeated, non-invasive quantification of plugging behavior. Using this approach, we found that tube plugging occurred rarely in males, intermittently in virgin females, and most robustly in postpartum females. Notably, plugging behavior exhibited substantial inter-individual variability, but was more temporally stable across days in postpartum females than in virgin females. In postpartum females, exposure to a male intruder altered plugging behavior at the tube through which the intruder was introduced, suggesting that plugging is modulated by direct social context. Together, these findings establish the TPT as a simple and reproducible method for quantifying plugging behavior and identify tube plugging as a measurable component of offspring-centered defensive behavior.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1767805"},"PeriodicalIF":3.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13246676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction.","authors":"Gergely Jocsak, David S Kiss, Daiana Alymbaeva, Anna Diebald, Attila Zsarnovszky, Andrea Heinzlmann, Tibor Bartha","doi":"10.3389/fnbeh.2026.1821381","DOIUrl":"10.3389/fnbeh.2026.1821381","url":null,"abstract":"<p><p>Synaptic plasticity forms the basis for learning and memory processes, controlled by a finely tuned interaction of neurotransmitters, intracellular signaling pathways and hormonal modulators. Exogenous substances, especially endocrine disrupting chemicals (EDCs), can significantly disrupt these processes. EDCs such as bisphenols, phthalates, pesticides, PCBs/dioxins, heavy metals and flame retardants interfere with hormonal regulatory circuits, receptor systems and epigenetic programs. They alter glutamatergic transmission, disrupt calcium homeostasis, modulate signal transduction pathways and destabilize structural proteins. This results in functional disorders in long-term potentiation and depression, as well as morphological and functional changes in dendritic spines. In addition to functional deficits, EDCs lead to mitochondrial dysfunction, oxidative stress, inflammatory processes and impaired blood-brain barrier (BBB) integrity. These mechanisms manifest themselves in cognitive impairments, behavioral abnormalities and increased susceptibility to neuropsychiatric disorders. Exposure during sensitive developmental phases is particularly critical, as it can be passed on transgenerationally <i>via</i> epigenetic changes. Integrative analysis shows that heterogenous EDCs undermine neural plasticity <i>via</i> convergent molecular mechanisms. They, therefore, pose a significant challenge to public health and prevention. A better understanding of these processes is essential to strengthen regulatory measures and minimize long-term risks to cognitive function and behavior.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1821381"},"PeriodicalIF":3.4,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13236926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantum-entangled feature selection and spiking graph transformer networks for early detection of childhood behavioral markers.","authors":"Karthiga M, Emerson Raja Joseph, Subhash Patil, Saranya K","doi":"10.3389/fnbeh.2026.1797210","DOIUrl":"10.3389/fnbeh.2026.1797210","url":null,"abstract":"<p><strong>Introduction: </strong>Early identification of childhood behavioural markers using wearable sensing is important for timely intervention in developmental and sleep-related disorders. Wrist-worn accelerometer data provide objective measures of behavioural regulation by capturing actigraphy-derived states such as Sleep, Wake, and Transitional periods. However, existing deep learning methods for behavioural state detection often face challenges related to redundant features, sensitivity to sensor noise, limited robustness in long-term wearable deployment, and high energy consumption.</p><p><strong>Methods: </strong>This study proposes a Quantum Variational Feature Selection-Spiking Graph Transformer Network (QVFS-SGTN), a hybrid quantum-neuromorphic framework for robust and energy-efficient behavioural state classification. The prediction task was defined as a three-class classification problem involving Sleep, Wake, and Transitional behavioural states from high-frequency wrist-worn accelerometer data. The proposed model integrates a parameterized quantum circuit-based feature selector to identify non-linear and entangled sensor correlations. Selected features are then processed by a spiking graph transformer network, which models temporal dependencies through event-driven self-attention and neuromorphic neuron dynamics. Experiments were conducted using the Child Mind Institute wearable dataset, with additional cross-dataset validation performed on the external Multi-Ethnic Study of Atherosclerosis sleep dataset.</p><p><strong>Results: </strong>The proposed QVFS-SGTN framework achieved state-of-the-art performance on the Child Mind Institute wearable dataset, with an accuracy of 0.968, an F1-score of 0.968, and an AUC of 0.991. Robustness evaluation demonstrated stable performance under significant Gaussian noise, maintaining accuracy above 92%. Energy analysis showed a 40-55% reduction in computational cost compared with conventional deep learning models. In cross-dataset evaluation using the MESA sleep dataset, the model achieved an accuracy of 0.931 without fine-tuning, indicating strong generalization capability.</p><p><strong>Discussion: </strong>The findings demonstrate that combining quantum-enhanced feature selection with spiking graph-based temporal modelling can improve the robustness, accuracy, and energy efficiency of wearable behavioural state detection. The QVFS-SGTN framework effectively addresses key limitations of existing deep learning approaches, including feature redundancy, sensor noise sensitivity, and computational cost. These results support the potential of the proposed hybrid quantum-neuromorphic model for scalable, long-term, real-world paediatric behavioural monitoring.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1797210"},"PeriodicalIF":3.4,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13236668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EEG-based monitoring of mental fatigue during virtual-reality motor imagery tasks.","authors":"Nina Evetović, Roman Rosipal, Arina Polyanskaya, Zuzana Rošťáková, Katarina Dvornák, Martin Vankó, Štefan Korečko, Leonardo Jose Trejo","doi":"10.3389/fnbeh.2026.1810723","DOIUrl":"10.3389/fnbeh.2026.1810723","url":null,"abstract":"<p><p>Prolonged motor-imagery training in immersive virtual-reality environments can induce mental fatigue, reducing engagement and potentially limiting the effectiveness of neurorehabilitation. This study investigated neural markers of mental fatigue by recording electroencephalography (EEG) from healthy participants during extended motor-imagery and control sessions in a head-mounted display setup. Multidimensional analysis was applied to extract spectral, spatial, and temporal features while using a novel deflation step for removing task-related motor components to isolate fatigue-specific activity. Evidence of mental fatigue was consistently seen in parieto-occipital alpha-band modulation, with increases in alpha power corresponding to subjective reports and EEG-based measures of mental fatigue. The derived models were robust to common EEG artifacts and demonstrated consistent fatigue estimation across tasks and sessions. These findings suggest that individualized neural markers can enable real-time monitoring of fatigue (with an accuracy of 83.49 ± 6.34%), allowing adaptive adjustments of task difficulty or pacing in brain-computer interface systems. This work advances understanding of the neurophysiological dynamics of mental fatigue during immersive motor-imagery tasks and provides a foundation for designing more effective, personalized neurorehabilitation protocols.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1810723"},"PeriodicalIF":3.4,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13233495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of metabolic syndrome with minimal hepatic encephalopathy in patients with cirrhosis and portal hypertension: a retrospective cohort study.","authors":"Xinyi Ding, Lingna Jing, Lei Li, Chao Zhao, Long Gao, Rong Wang, Chunjuan Zhao, Lijun Yang, Duiping Feng, Jinyu Li","doi":"10.3389/fnbeh.2026.1779609","DOIUrl":"10.3389/fnbeh.2026.1779609","url":null,"abstract":"<p><strong>Background and purpose: </strong>Metabolic syndrome and minimal hepatic encephalopathy are both associated with impaired hepatic metabolic function. This study aimed to investigate their relationship in patients with cirrhosis and portal hypertension.</p><p><strong>Methods: </strong>This retrospective cohort study enrolled 127 patients. Minimal hepatic encephalopathy was diagnosed using the Psychometric Hepatic Encephalopathy Score. Restricted cubic spline and threshold analyses were used to assess dose-response relationships. Multivariable logistic and modified Poisson regression analyses were performed to identify independent predictors.</p><p><strong>Results: </strong>The prevalence of minimal hepatic encephalopathy was 17.3% (22/127). Patients with MHE had significantly higher fasting blood glucose (8.17 ± 4.36 vs. 5.33 ± 0.98 mmoL/L), and higher prevalence of metabolic syndrome and diabetes. Fasting blood glucose was an independent risk factor for MHE (<i>P</i> < 0.05), and diabetes showed a similar association in a separate model. A nonlinear relationship was observed between FBG and MHE risk (P for overall = 0.006, P for nonlinear = 0.078), with an exploratory inflection point at 8.36 mmol/L. Below this threshold, each 1 mmol/L increase in glucose corresponded to a 92.1% higher risk of MHE. Spearman correlation analysis showed that higher FBG levels were associated with poorer performance on DST and SDT subtests of PHES. Multivariate regression identified older age (OR = 1.103, <i>P</i> = 0.007), higher Child-Pugh grade (OR = 5.869, <i>P</i> = 0.008), and higher FBG (OR = 1.750, <i>P</i> = 0.007) as independent risk factors for MHE.</p><p><strong>Conclusion: </strong>Metabolic disorders, especially hyperglycemia is closely associated with the occurrence of MHE in cirrhotic patients. Blood glucose control and comprehensive metabolic management may help reduce the risk of MHE.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1779609"},"PeriodicalIF":3.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13230085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148162472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinoids in Alzheimer's disease: animal-human evidence and clinical pharmacology challenges.","authors":"Maria Komedera, Urszula Wojda, Anna Kiryk","doi":"10.3389/fnbeh.2026.1833021","DOIUrl":"10.3389/fnbeh.2026.1833021","url":null,"abstract":"<p><p>Cannabinoids have emerged as potential modulators of pathological processes in Alzheimer's disease (AD), including neuroinflammation, synaptic dysfunction, and protein aggregation. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the main phytocannabinoids from <i>Cannabis sativa</i>, interact with the endocannabinoid system and may influence neuronal and glial signaling pathways relevant to AD pathology. This mini review summarizes evidence from transgenic animal models and clinical studies evaluating CBD, THC, and their combination in AD. Preclinical studies show that CBD and THC reduce <i>β</i>-amyloid accumulation, attenuate tau phosphorylation, and regulate neuroinflammatory responses, often associated with improvements in learning and memory. Cognitive outcomes appear to depend on cannabinoid composition, with CBD or THC administered individually showing more consistent effects, while combined CBD + THC effects appear dose- and ratio-dependent. Clinical evidence in AD patients remains limited and primarily reports improvements in neuropsychiatric symptoms, such as reductions in agitation, nighttime activity, and behavioral disturbances, whereas cognitive improvements are modest. Cannabinoid-based treatments are generally well tolerated, with mild sedation, somnolence, or disorientation as the most reported adverse effects. Overall, current data support the biological plausibility of cannabinoids as modulators of neuroinflammatory and synaptic processes in AD. However, heterogeneity in formulations, dosing, and study design limits firm conclusions. Future research should focus on dose optimization, biomarker-guided clinical trials, and long-term safety assessments to better define their therapeutic potential in AD.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1833021"},"PeriodicalIF":3.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13212195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gardenoside restores blood-brain barrier integrity following ischemic stroke via AMPK-dependent ZO-1 preservation.","authors":"Rongze Jia","doi":"10.3389/fnbeh.2026.1768582","DOIUrl":"10.3389/fnbeh.2026.1768582","url":null,"abstract":"<p><strong>Background: </strong>Blood-brain barrier (BBB) disruption is a critical pathological feature of ischemic stroke, yet effective therapies targeting BBB repair remain limited. Gardenoside, an iridoid glycoside from <i>Gardenia jasminoides</i> Ellis, has shown neuroprotective properties, but its role in post-stroke BBB restoration is unclear. This study investigated whether Gardenoside preserves BBB integrity after ischemic stroke via AMPK-dependent regulation of the tight junction protein ZO-1.</p><p><strong>Methods: </strong>Male and female C57BL/6 mice (8-10 weeks) underwent transient middle cerebral artery occlusion (MCAO; 60 min ischemia, 24 h reperfusion). Gardenoside (20 mg/kg/day, i.p.) was administered for 21 days pre-MCAO and continued post-reperfusion. Neurological deficits, BBB permeability (sodium fluorescein, Evans blue), infarct volume (TTC), endothelial activation markers (ICAM-1, VCAM-1), ZO-1 expression (qPCR, western blot, immunofluorescence), and AMPK phosphorylation were assessed. In parallel, human brain microvascular endothelial cells (HBMVECs) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R; 6 h OGD, 24 h reoxygenation) with Gardenoside (5-10 μM) ± the AMPK inhibitor compound C. Outcomes included cell viability (CCK-8), LDH release, permeability (FITC-dextran, TEER), and ZO-1/AMPK signaling.</p><p><strong>Results: </strong>In MCAO mice, Gardenoside significantly reduced neurological deficit scores (by ~50%), BBB permeability (28-32% reduction), and infarct volume (45% reduction) compared to vehicle-treated controls. It suppressed ICAM-1 and VCAM-1 expression (mRNA: 43-52%; protein: 30-34%) and restored ZO-1 levels to near-sham values. Gardenoside increased AMPK phosphorylation (p-AMPK/AMPK ratio: 2.1-fold). Co-administration of compound C (10 mg/kg) abolished these protective effects, reversing infarct volume, BBB leakage, neurological scores, and ZO-1 restoration. <i>In vitro</i>, Gardenoside (5-10 μM) dose-dependently improved HBMVEC viability (from 42% to 68-88% of control), reduced LDH release (27-47%), decreased permeability (25-40%), and restored TEER (40-66%) and ZO-1 expression (50-98%) following OGD/R. These effects were associated with enhanced AMPK phosphorylation and were completely reversed by compound C (10 μM). Comparable efficacy was observed in female mice.</p><p><strong>Conclusion: </strong>Gardenoside preserves BBB integrity and improves neurological outcomes after ischemic stroke through AMPK-dependent restoration of ZO-1. These findings identify AMPK-mediated tight junction preservation as a previously unrecognized mechanism of Gardenoside, supporting its potential as a vascular-targeted therapy for ischemic stroke.</p>","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":"20 ","pages":"1768582"},"PeriodicalIF":3.4,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13201230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148041560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}