Physiology & Behavior最新文献

{"title":"Blue light exposure mitigates vibration noise-induced anxiety by enhancing serotonin levels","authors":"Longfei Huo ,&nbsp;Xiaojing Miao ,&nbsp;Yi Ren ,&nbsp;Xuran Zhang ,&nbsp;Qiqi Fu ,&nbsp;Jiali Yang ,&nbsp;Muqing Liu","doi":"10.1016/j.physbeh.2025.115187","DOIUrl":"10.1016/j.physbeh.2025.115187","url":null,"abstract":"<div><div>Prolonged exposure to vibration and noisy environments has been shown to contribute to the development of anxiety disorders. Pharmacological interventions are typically not administered during the early stages, which may lead to the uncontrolled progression of anxiety symptoms. In this study, we found that daily exposure to low-frequency vibration for 1 hour significantly increased anxiety-like behavior in zebrafish, with the most pronounced effects observed at 100 Hz. Behavioral analyses demonstrated that exposure to blue light significantly alleviated vibration-induced anxiety. Further physiological measurements showed that vibration and noise exposure markedly elevated cortisol and norepinephrine levels in zebrafish. In contrast, prolonged exposure to 455 nm blue light significantly increased serotonin levels and decreased norepinephrine concentrations, thereby counteracting the anxiety-like state. These findings suggest that 455 nm blue light may serve as an effective, simple, adaptable, and relatively safe strategy for preventing or alleviating anxiety induced by long-term exposure to vibration and noise.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"304 ","pages":"Article 115187"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621419","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}

{"title":"Evoking flavor memories through real food sounds: A preliminary study on crossmodal compensation in taste and smell disorders","authors":"Huan Ding ,&nbsp;Xizhi Zhang","doi":"10.1016/j.physbeh.2025.115171","DOIUrl":"10.1016/j.physbeh.2025.115171","url":null,"abstract":"<div><div>Taste and olfactory dysfunctions significantly impair flavor perception, reduce eating pleasure, and affect emotional well-being. Existing interventions primarily focus on restoring sensory function, with limited attention to the potential of sound as a cross-modal pathway for flavor reconstruction. As a multimodal stimulus, food-related sound shows compensatory potential in evoking flavor associations and triggering emotional memory. This study investigates whether real-world food sounds can effectively elicit flavor-related associations and memories, and aims to establish a symbolic mapping model between auditory cues and flavor perception. Forty participants (including 20 clinically diagnosed with taste or smell disorders) were exposed to 15 real food sound clips. They rated each clip across dimensions including flavor association strength, emotional arousal, image clarity, and memory activation. Open-ended responses were also collected for semantic analysis. Results showed that participants with sensory impairments scored significantly higher across all perceptual dimensions compared to controls (<em>p</em>&lt; 0.01), indicating a stronger compensatory response to sound. Specific sounds, such as stir-frying and hotpot boiling, exhibited particularly strong evocative effects. Semantic analysis revealed that auditory associations were closely linked to specific foods and culturally familiar scenarios, highlighting the emotional embeddedness of these cues. This study suggests that real food sounds may serve as effective substitutes for flavor perception, offering a context-rich and emotionally resonant compensatory pathway. The findings provide theoretical support for the development of “sound–flavor training sets,” with potential applications in inclusive eating design and sensory rehabilitation.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"304 ","pages":"Article 115171"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524268","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}

{"title":"Evaluation of the role of CRFergic neurotransmission in anxiety and BNST neuronal activity in male and female mice exposed to psychosocial stress","authors":"Felipe Forero-Castillo ,&nbsp;Daniel Enrique Gonzalez-Escobar ,&nbsp;Julian Humberto Avalo-Zuluaga ,&nbsp;Daniela Baptista-de-Souza ,&nbsp;Lucas Canto-de-Souza ,&nbsp;Carlos C. Crestani ,&nbsp;Javier Leonardo Rico ,&nbsp;Ricardo Luiz Nunes-de-Souza","doi":"10.1016/j.physbeh.2025.115160","DOIUrl":"10.1016/j.physbeh.2025.115160","url":null,"abstract":"<div><div>Anxiety disorders are increasingly prevalent, and the exposure to psychosocial stress is an important influencing factor; however, the underlying neurobiological mechanisms in female populations remain largely unexplored in animal models. This study investigated the role of the corticotropin-releasing factor type 1 receptor (CRF1R) in the bed nucleus of the stria terminalis (BNST) in anxiety-like behaviors induced by vicarious social defeat stress in female and male mice. Swiss-Webster mice underwent 10 sessions of witnessing social defeat stress (WSDS) or witnessing non-aggressive interactions (WNAI). Subsequently, their behaviors were evaluated in the social interaction test (SIT). Twenty-four hours later, each mouse received treatment with the CRF1R antagonist, CP376395, and after 1 h, was exposed to the elevated plus maze (EPM). Immunofluorescence for c-Fos was employed to assess BNST activation. WSDS female mice exhibited anxiety-like behavior, which was effectively reversed by CP3763995. Additionally, these stressed females exhibited greater c-Fos expression in the ventral BNST, a response attenuated by CRF1 receptor blockade. Notably, no significant behavioral or neural activation changes were observed in males under identical conditions. These findings underscore a sex-specific role for CRF1R signaling in the BNST in mediating anxiety-like responses to vicarious stress, highlighting the relevance of this neurobiological mechanism as a potential target for female-focused therapeutic strategies.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"304 ","pages":"Article 115160"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471625","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}

{"title":"TurkerPat: EEG-Based detection of hunger, thirst, and nicotine withdrawal","authors":"Suheda Kaya ,&nbsp;Serkan Kirik ,&nbsp;Suat Tas ,&nbsp;Dahiru Tanko ,&nbsp;Tugce Keles ,&nbsp;Irem Tasci ,&nbsp;Sengul Dogan ,&nbsp;Mehmet Baygin ,&nbsp;Turker Tuncer","doi":"10.1016/j.physbeh.2025.115156","DOIUrl":"10.1016/j.physbeh.2025.115156","url":null,"abstract":"<div><h3>Background</h3><div>One of the primary objectives of neuroscience is to gather information from the brain. Therefore, brain data are crucial for understanding its secrets, and one of the most affordable methods for collecting such data is electroencephalography (EEG). To capture meaningful information, machine learning models have been applied to EEG signals. In this research, our main goal is to investigate an innovative feature-extraction method on a new EEG dataset to obtain both accurate classification and interpretable results.</div></div><div><h3>Material and Methods</h3><div>First, we curated a novel EEG signal dataset comprising four classes: (i) hungry, (ii) thirsty, (iii) cigarette-addicted, and (iv) control. Using this dataset, we defined four cases: (1) hunger detection, (2) thirst detection, (3) nicotine-withdrawal detection, and (4) abnormality (hunger + thirst + nicotine-withdrawal) detection. To automatically detect these cases, we introduced a specialized transformer-based feature-extraction method. This transformer, called the Moon Star Transformer (MST), was deployed alongside a Transition Table Feature Extractor (TTFE) to form the Turker Pattern (TurkerPat). Feature selection, ensemble and iterative classification, and an interpretable results generator were then integrated into the TurkerPat-centric XFE framework to achieve both classification accuracy and interpretability.</div></div><div><h3>Results</h3><div>The proposed TurkerPat-centric XFE framework attained over 85 % classification accuracy using leave-one-subject-out cross-validation (LOSO CV). By applying Directed Lobish (DLob) for interpretable result generation, we obtained connectome diagrams for each defined case.</div></div><div><h3>Conclusion</h3><div>The classification and explainable results clearly demonstrate that the TurkerPat-centric XFE framework makes a significant contribution to both neuroscience and feature engineering.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"304 ","pages":"Article 115156"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471650","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}

{"title":"Voluntary wheel running improves cognitive deficits and abnormal agonistic behavior induced by social isolation stress in mice","authors":"Kana Umamichi ,&nbsp;Tomonori Furukawa ,&nbsp;Chihiro Sato ,&nbsp;Hiroyuki Miura ,&nbsp;Kai Hatakenaka ,&nbsp;Tomohito Nunomura ,&nbsp;Misaki Mikami ,&nbsp;Shuhei Koeda ,&nbsp;Junko Yamada","doi":"10.1016/j.physbeh.2025.115176","DOIUrl":"10.1016/j.physbeh.2025.115176","url":null,"abstract":"<div><div>Reduced social interactions negatively impact adolescents. However, underlying mechanisms of social isolation (SI) stress and interventions remain unclear. Therefore, we investigated the effects of an exercise intervention on SI stress-induced behavioral abnormalities and the underlying mechanisms. We used male mice: Ctrl (<em>N</em> = 32), SI (<em>N</em> = 33), SI + voluntary wheel running (VWR) (<em>N</em> = 14), and SI + lurasidone (<em>N</em> = 7), and assessed emotion, anxiety, depression, social interactions, and cognitive functions using behavioral tests. In addition, we measured plasma corticosterone and performed immunohistochemical staining for ΔFosB, a marker of repeatedly activated neurons, to assess the stress response and identify brain regions associated with SI stress. Interventions lasted for 3 weeks, and behavioral assessments were initiated 2 weeks after the intervention initiation. The SI mice exhibited significant hyperactivity, reduced self-care and motivation, impaired recognition, excessive sniffing toward strangers and aggressive but avoidant social behaviors. We observed significant improvements in recognition impairments and excessive sniffing behavior after VWR. In addition, there was a trend toward reduced flight behavior. However, VWR did not induce a significant change in the number of attacks and the ΔFosB expression in the ventral tegmental area (VTA). Lurasidone administration significantly reduced sniffing and aggressive behavior and increased ΔFosB-positive cells in VTA. Our results suggest that, while VWR and lurasidone both mitigate some aspects of SI-induced behavioral deficits, they likely act independent or only partially overlapping neurobiological pathways. Thus, VWR may act through broader neuroadaptive processes, potentially involving serotonergic modulation, neurotrophic factors, or stress regulatory circuits.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"304 ","pages":"Article 115176"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534734","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}

{"title":"Sex-specific effects of GnIH on lipid metabolism in SD rats","authors":"Jiaming Zheng ,&nbsp;Xin Zhang ,&nbsp;Xingxing Song,&nbsp;Dongyang Han,&nbsp;Kaiou Han,&nbsp;Chengcheng Liu,&nbsp;Changlin Xu,&nbsp;Zixin Li,&nbsp;Qiang Ge,&nbsp;Wenhao Xu,&nbsp;Lei Chen,&nbsp;Xun Li","doi":"10.1016/j.physbeh.2025.115183","DOIUrl":"10.1016/j.physbeh.2025.115183","url":null,"abstract":"<div><div>Gonadotropin-inhibitory hormone (GnIH) is a neuropeptide pivotal in reproduction, which has recently been implicated in appetite-driven obesity among mammals. Yet, its functions in metabolic homeostasis and sex-specific lipid regulation remain largely underexplored. In this study, we found that GnIH administration initially caused weight gain and increased food intake in both male and female rats within 2 weeks. However, at week 6, male rats receiving high-dose (10 μg/100 μL) GnIH gained weight, while female rats receiving low-dose (1 μg/100 μL) GnIH lost weight. In addition, high-dose GnIH increased organ weight and glucose levels in male rats, while reduced white adipose tissues (WAT) and raised triglycerides in females. Histologically, GnIH dose-dependently increased hepatic lipid vacuoles in male rats, while female rats exhibited nuclear swelling and cellular damage. Mechanistically, GnIH exhibited sex-specific effects on hepatic lipid metabolism. In male rats, it enhanced lipogenesis through the upregulation of microsomal triglyceride transfer protein (MTP) and CCAAT/enhancer binding protein (c/EBP), while inhibiting lipolysis via reduced peroxisome proliferator-activated receptor γ (PPARγ), Adiponectin (ADPN), and AMP-activated protein kinase α (AMPKα) phosphorylation. Conversely, female rats treated with GnIH displayed diminished MTP expression alongside elevated lipolysis. In WAT, GnIH promoted lipogenesis in male rats, evidenced by increased fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD), and c/EBP levels. However, it suppressed this process in females even though lipolytic markers such as ADPN and PPARγ were elevated in both sexes. Overall, GnIH exerts distinct sex-specific effects on lipid metabolism, promoting anabolic pathways in males while triggering catabolic responses in females. These findings highlight the complex role of GnIH in energy homeostasis and underscore its potential as a target for sex-specific therapeutic interventions in metabolic disorders.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"304 ","pages":"Article 115183"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573713","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}

{"title":"Analysis of the nonclinical safety and antinociceptive potential of amentoflavone (AMT) on corneal pain in adult zebrafish (Danio rerio)","authors":"Lucas Soares Frota ,&nbsp;Francisco Ernani Alves Magalhães ,&nbsp;Daniela Braga de Sousa ,&nbsp;Francisco Lucas Alves Batista ,&nbsp;Francisco Bastos Cavalcante Sobrinho ,&nbsp;Djane Ventura de Azevedo ,&nbsp;Franciglauber Silva Bezerra ,&nbsp;Sacha Aubrey Alves Rodrigues Santos ,&nbsp;Gabriela Alves do Nascimento ,&nbsp;Lia Gomes Crisóstomo Sabóia ,&nbsp;Hamilton Mitsugu Ishiki ,&nbsp;Adriana Rolim Campos ,&nbsp;Selene Maia de Morais","doi":"10.1016/j.physbeh.2025.115121","DOIUrl":"10.1016/j.physbeh.2025.115121","url":null,"abstract":"<div><div>Corneal pain affects the outer layer of the eye and can result from injuries, infections, autoimmune diseases, or dry eye syndrome. Amentoflavone (AMT), a natural biflavonoid used in traditional Chinese medicine, is known for its anti-inflammatory and neuroprotective properties. This study investigated the effects of AMT on the inhibition of corneal pain in adult zebrafish. Acute nociception was induced using formalin (cutaneous model) and hypertonic saline solution (corneal model). In a separate set of experiments, animals were pre-treated with naloxone, camphor, ruthenium red, capsazepine, <span>l</span>-NAME, methylene blue, ketamine, or amiloride to explore the mechanisms underlying AMT’s antinociceptive effects. The results demonstrated that AMT exhibits corneal analgesic activity comparable to morphine, without causing sedation or motor impairment in zebrafish. AMT modulated antinociceptive responses through the TRPV1, ASIC, opioid, and nitrergic systems. In the <em>in silico</em> analysis, AMT showed lower binding energies compared to the antagonists naloxone and <span>l</span>-NAME, suggesting greater stability and potential efficacy. These findings support the potential of AMT as a candidate for the development of new treatments for corneal pain.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"303 ","pages":"Article 115121"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233270","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}

{"title":"Sex differences in cortisol levels and their relationship with memory and negative affectivity in patients with drug-resistant epilepsy","authors":"Paula Tormos-Pons ,&nbsp;Irene Cano-López ,&nbsp;Judit Catalán-Aguilar ,&nbsp;Alejandro Lozano-García ,&nbsp;Kevin G. Hampel ,&nbsp;Vanesa Hidalgo ,&nbsp;Alicia Salvador ,&nbsp;Vicente Villanueva ,&nbsp;Esperanza González-Bono","doi":"10.1016/j.physbeh.2025.115118","DOIUrl":"10.1016/j.physbeh.2025.115118","url":null,"abstract":"<div><div>Drug-resistant epilepsy can be considered a chronic stress condition characterized by uncontrollable seizures together with cognitive and affective alterations. Epilepsy and its treatments affect men and women differently, potentially due to interactions with sexual hormones that influence how they experience the condition. This study examines potential sex differences in cortisol levels (as the product of stress processes), affectivity, and memory in patients with drug-resistant epilepsy, and the relationships among these variables. The sample was composed of 96 adult patients with drug-resistant epilepsy (<em>M</em> = 38.01 ± 11.12 years; 47 men and 49 women). Results show that men had higher evening cortisol levels and cortisol area under the curve (AUC_i) than women (for both, <em>p</em> &lt; .05), especially in those with a left hemisphere focus. Men also showed higher trait anxiety, higher DDD and poorer memory than women. In the total sample, trait anxiety and the DDD significantly predicted poor immediate and delayed memory, controlling for the side of seizure focus and effects of epilepsy type (<em>p</em> &lt; .001). When analyses were stratified by sex, cortisol AUC_i predicted poorer delayed memory in men but not in women, while DDD predicted memory performance only in women. These findings suggest that cortisol, trait anxiety and the DDD are reliable predictors of memory impairment in patients with drug-resistant epilepsy, with a sex-differential pattern of relationships. Our results highlight the importance of considering sex differences and clinical variables when developing tailored treatment approaches for this population.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"303 ","pages":"Article 115118"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228598","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}

{"title":"Boredom, interoceptive ability, and emotional eating: An experimental study","authors":"Erica Ahlich ,&nbsp;Kendall Poovey ,&nbsp;Allison Cunning ,&nbsp;Laura Boyajian ,&nbsp;Diana Rancourt","doi":"10.1016/j.physbeh.2025.115137","DOIUrl":"10.1016/j.physbeh.2025.115137","url":null,"abstract":"<div><div>Growing evidence underscores the importance of examining specific emotions to better understand emotional eating. Boredom is one such underexplored emotion, and little is known about individual differences that may increase vulnerability to “bored eating.” Given the relevance of interoception—awareness of internal bodily signals—to other forms of dysregulated eating, the current study investigated whether interoceptive ability moderates the relationship between boredom and food consumption. In a controlled laboratory experiment, 187 participants consumed a water preload and were randomly assigned to a 30-minute boredom or neutral condition. Snack foods (chocolate, crackers, chips) were available ad libitum, and consumption was covertly measured. Interoception was assessed via general interoceptive sensibility, hunger/satiety-specific sensibility, and gastric interoceptive sensitivity using the two-step Water Load Test. Analyses of covariance tested main and interaction effects of condition and interoceptive measures on food consumption. Contrary to hypotheses, neither boredom nor any interoceptive measure predicted total or food-type-specific consumption. Additionally, interoception did not moderate the relationship between boredom and eating. These findings contribute to a growing body of research questioning the predictive validity of self-reported emotional eating and highlight the importance of distinguishing between self-reported tendencies and observable behavior. Future research using ecologically valid, longitudinal methods may help clarify when and for whom boredom contributes to dysregulated eating and whether physiological awareness influences this pathway.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"303 ","pages":"Article 115137"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355643","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}

{"title":"Gut microbiota mediates the protective effects of SGLT-2 inhibitors on bipolar disorder: An intermediary Mendelian randomization study","authors":"Yunchang Yang,&nbsp;Yunqin Sun,&nbsp;Yaofeng Wang","doi":"10.1016/j.physbeh.2025.115120","DOIUrl":"10.1016/j.physbeh.2025.115120","url":null,"abstract":"<div><h3>Background</h3><div>Bipolar disorder (BD), with a global prevalence of approximately 1%, is characterized by mood swings and social impairment, and involves factors such as genetics, brain structure abnormalities, and gut-brain axis dysregulation</div></div><div><h3>Objectives</h3><div>The influence of SGLT-2 inhibitors and gut microbiota on BD remains unclear. We Investigate causal links between SGLT-2 inhibitors, gut microbiota, and BD risk using Mendelian randomization (MR). Identify mediating microbiota and elucidate connecting molecular pathways.</div></div><div><h3>Methods</h3><div>Two-sample MR utilized European GWAS data. Instrumental variables (<em>p</em> &lt; 5 × 10⁻⁵ for microbiota/BD) were analyzed primarily via inverse-variance weighted regression, with sensitivity analyses. Mediation analysis assessed SGLT-2 effects via microbiota. Functional enrichment (GO/KEGG), gene expression (GSE5388), and PPI network analyses identified pathways and hub genes.</div></div><div><h3>Results</h3><div>SGLT-2 inhibitors showed a significant negative causal effect on BD risk (OR = 0.104, 95% CI: 0.048–0.228, <em>p</em> &lt; 0.001), partially mediated by <em>Clostridium sporosphaeroides</em> abundance (proportion mediated = 4.1%; statistically significant at a nominal p-value threshold, though not after multiple testing correction. 368 of the 473 gut microbiota <strong>taxa showed evidence of a</strong> causal association with BD. Enrichment implicated calcium signaling (<em>p</em> &lt; 0.001) and neuroactive ligand-receptor pathways. Differential expression identified dysregulated GANC (<em>p</em> = 0.048) in BD frontal cortices. PPI networks revealed hub genes (COQ2, PKM) involved in mitochondrial function and GPCR activity.</div></div><div><h3>Conclusions</h3><div>This study provides genetic evidence that SGLT-2 inhibitors may reduce BD risk, partly modulated by Clostridium sporosphaeroides. Identified pathways (e.g., calcium signaling) and dysregulated genes highlight mecolic-immune interplay in BD. Findings support evaluating SGLT-2 inhibitors and microbiota therapies in BD, though European-centric data requires broader validation.</div></div>","PeriodicalId":20201,"journal":{"name":"Physiology & Behavior","volume":"303 ","pages":"Article 115120"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233240","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}