Pub Date : 2026-02-02DOI: 10.1016/j.bbr.2026.116078
Shu Xing, Yuan Yuan, Ping Ren, Zhuangfei Chen, Yu Fu
Cognitive impairment is a serious pathological feature of neuropsychiatric disorders, making the exploration of effective treatments urgent. Recent research shows that combined transcranial electrical stimulation (tES) and cognitive training (CT) can reduce cognitive deficits. This review summarizes studies on neurological disorders that use both clinical patients and rodent models to highlight the underlying neural mechanisms. In patients, this combined approach improves cognitive domains such as attention, working memory, and executive function. Improvements have been observed in patients with mild cognitive impairment (MCI), dementia (e.g., Alzheimer's disease (AD)), Parkinson's disease (PD), stroke, traumatic brain injury (TBI), multiple sclerosis, schizophrenia, attention deficit hyperactivity disorder (ADHD) and depression, as well as in healthy populations. In contrast, studies on the combined intervention are lacking in rodent models of disease. However, tES and CT separately improve spatial learning and memory in AD, TBI, schizophrenia, ADHD, and healthy animals, as well as in models of vascular dementia and cerebral ischemia. The combined intervention regulates and remodels functional connectivity in brain networks, and improves cerebrovascular microcirculation and glutamatergic neurotransmission. Importantly, tES and CT may enhance each other through cooperative and complementary effects. In addition, some studies have reported the limited efficacy or negative outcomes of combined and single interventions, which may be due to suboptimal parameters or techniques that fail to target key pathologies. Future clinical trials should explore tES-CT combination strategies targeting disease-specific brain regions. Furthermore, animal studies must be strengthened to elucidate the potential mechanisms and interactions of tES and CT.
{"title":"Combined transcranial electrical stimulation (tES) and cognitive training (CT) for cognitive impairment: Evidence from clinical applications and basic research.","authors":"Shu Xing, Yuan Yuan, Ping Ren, Zhuangfei Chen, Yu Fu","doi":"10.1016/j.bbr.2026.116078","DOIUrl":"https://doi.org/10.1016/j.bbr.2026.116078","url":null,"abstract":"<p><p>Cognitive impairment is a serious pathological feature of neuropsychiatric disorders, making the exploration of effective treatments urgent. Recent research shows that combined transcranial electrical stimulation (tES) and cognitive training (CT) can reduce cognitive deficits. This review summarizes studies on neurological disorders that use both clinical patients and rodent models to highlight the underlying neural mechanisms. In patients, this combined approach improves cognitive domains such as attention, working memory, and executive function. Improvements have been observed in patients with mild cognitive impairment (MCI), dementia (e.g., Alzheimer's disease (AD)), Parkinson's disease (PD), stroke, traumatic brain injury (TBI), multiple sclerosis, schizophrenia, attention deficit hyperactivity disorder (ADHD) and depression, as well as in healthy populations. In contrast, studies on the combined intervention are lacking in rodent models of disease. However, tES and CT separately improve spatial learning and memory in AD, TBI, schizophrenia, ADHD, and healthy animals, as well as in models of vascular dementia and cerebral ischemia. The combined intervention regulates and remodels functional connectivity in brain networks, and improves cerebrovascular microcirculation and glutamatergic neurotransmission. Importantly, tES and CT may enhance each other through cooperative and complementary effects. In addition, some studies have reported the limited efficacy or negative outcomes of combined and single interventions, which may be due to suboptimal parameters or techniques that fail to target key pathologies. Future clinical trials should explore tES-CT combination strategies targeting disease-specific brain regions. Furthermore, animal studies must be strengthened to elucidate the potential mechanisms and interactions of tES and CT.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"116078"},"PeriodicalIF":2.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117571","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}
In certain individuals, disgust experience is abnormally high. This heightened sensitivity serves as a cognitive component that can lead to dysfunction in neural circuits related to emotion processing and psychological disorders such as contamination-based obsessive-compulsive disorder. In this single-blind study, 36 individuals with high disgust sensitivity were randomly assigned to three groups: online, offline, and sham. The online group received intensified and repetitive transcranial direct current stimulation (tDCS) while performing a disgust image watching task, whereas the offline and sham groups performed the task at two time points: immediately before (pre-test) and immediately after (post-test) the stimulation session. The offline group received active tDCS, whereas the sham group received placebo tDCS to control for the interval duration. Anodal and cathodal stimulation was applied to the left dorsolateral prefrontal cortex (l-DLPFC; F3) and pre-supplementary motor area (pre-SMA; FC2), respectively. The intervention consisted of 10 sessions of tDCS (2 sessions per day) over 5 days, with a stimulation intensity of 2mA for 20minutes and a 20-minute interval between sessions. The results showed a significant decrease in disgust experience in the online group compared to the offline group, while there was no significant difference between the online and sham groups. Although these findings suggest potential effects of tDCS combined with a task, further studies are necessary to confirm its efficacy.
{"title":"Targeting the prefrontal-supplementary motor network with online and offline tDCS to modulate disgust: A single-blind and sham-controlled study.","authors":"Parastoo Soltani, Zekrollah Morovati, Majid Yousefi Afrashteh, Jakob Fink-Lamotte, Jaber Alizadehgoradel","doi":"10.1016/j.bbr.2026.116077","DOIUrl":"https://doi.org/10.1016/j.bbr.2026.116077","url":null,"abstract":"<p><p>In certain individuals, disgust experience is abnormally high. This heightened sensitivity serves as a cognitive component that can lead to dysfunction in neural circuits related to emotion processing and psychological disorders such as contamination-based obsessive-compulsive disorder. In this single-blind study, 36 individuals with high disgust sensitivity were randomly assigned to three groups: online, offline, and sham. The online group received intensified and repetitive transcranial direct current stimulation (tDCS) while performing a disgust image watching task, whereas the offline and sham groups performed the task at two time points: immediately before (pre-test) and immediately after (post-test) the stimulation session. The offline group received active tDCS, whereas the sham group received placebo tDCS to control for the interval duration. Anodal and cathodal stimulation was applied to the left dorsolateral prefrontal cortex (l-DLPFC; F3) and pre-supplementary motor area (pre-SMA; FC2), respectively. The intervention consisted of 10 sessions of tDCS (2 sessions per day) over 5 days, with a stimulation intensity of 2mA for 20minutes and a 20-minute interval between sessions. The results showed a significant decrease in disgust experience in the online group compared to the offline group, while there was no significant difference between the online and sham groups. Although these findings suggest potential effects of tDCS combined with a task, further studies are necessary to confirm its efficacy.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"116077"},"PeriodicalIF":2.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117579","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 : 2026-02-02DOI: 10.1016/j.bbr.2026.116072
Yao Xiao , Min Yang , Yuling Huang , Han Li , Na Zhao , Chenjin Qiao , Pingyuan Gong
Decoy effect and compromise effect are context-dependent choice biases in which adding an option shift preference without changing the original alternatives. The decoy effect increases a preference for a target by introducing an inferior comparison, whereas the compromise effect reflects a tendency to choose intermediate options. Given the established roles of dopaminergic and serotonergic pathways in reward motivation and behavioral inhibition, this study investigated whether polygenic risk scores (PRSs) within these neurotransmitter pathways could predict these two effects. Two independent samples of Chinese university students were recruited from Luoyang (Sample 1: N = 647) and Xi’an (Sample 2: N = 569), providing demographically homogeneous populations for assessing genetic contributions to decision biases. In the serotonergic system, the PRS significantly predicted compromise effect in both samples (Sample 1: β = 0.093, p = 0.017; Sample 2: β = 0.094, p = 0.026) and decoy effect in Sample 2 (β = 0.122, p = 0.003). In the dopaminergic system, the PRS only significantly predicted compromise effect in Sample 2 (β = 0.132, p = 0.002), while it significantly predicted decoy effect in both samples (Sample 1: β = 0.132, p = 0.001; Sample 2: β = 0.126, p = 0.003). Combined-sample analyses confirmed a unique contribution of dopaminergic PRS to the compromise effect and showed that the decoy effect was jointly influenced by dopaminergic and serotonergic pathways. These results show that the decoy and compromise effects arise from distinct genetic mechanisms: dopamine amplifies relative reward signals driving the decoy choices, whereas serotonin promotes safer, intermediate preferences underlying the compromise decisions.
诱饵效应和妥协效应是一种情境依赖的选择偏差,即在不改变原有选择的情况下,增加一个选项会改变人们的偏好。诱饵效应通过引入劣势比较来增加对目标的偏好,而妥协效应则反映了选择中间选项的倾向。鉴于多巴胺能和血清素能通路在奖励动机和行为抑制中的作用,本研究探讨了这些神经递质通路中的多基因风险评分(PRSs)是否可以预测这两种作用。从洛阳(样本1:N = 647)和西安(样本2:N = 569)招募了两个独立的中国大学生样本,为评估遗传对决策偏差的影响提供了人口统计学上同质的群体。在血清素能系统中,PRS显著预测了两个样本的妥协效应(样本1:β = 0.093, p = 0.017;样本2:β = 0.094, p = 0.026)和诱饵效应(样本2:β = 0.122, p = 0.003)。在多巴胺能系统中,PRS仅在样本2中显著预测妥协效应(β = 0.132, p = 0.002),而在两个样本中显著预测诱饵效应(样本1:β = 0.132, p = 0.001;样本2:β = 0.126, p = 0.003)。联合样本分析证实了多巴胺能PRS对妥协效应的独特贡献,并表明诱饵效应受多巴胺能和血清素能途径的共同影响。这些结果表明,诱饵效应和妥协效应来自不同的遗传机制:多巴胺放大了驱动诱饵选择的相对奖励信号,而血清素促进了妥协决定背后更安全的中间偏好。
{"title":"Polygenic modulations of decoy and compromise effects by dopaminergic and serotonergic systems","authors":"Yao Xiao , Min Yang , Yuling Huang , Han Li , Na Zhao , Chenjin Qiao , Pingyuan Gong","doi":"10.1016/j.bbr.2026.116072","DOIUrl":"10.1016/j.bbr.2026.116072","url":null,"abstract":"<div><div>Decoy effect and compromise effect are context-dependent choice biases in which adding an option shift preference without changing the original alternatives. The decoy effect increases a preference for a target by introducing an inferior comparison, whereas the compromise effect reflects a tendency to choose intermediate options. Given the established roles of dopaminergic and serotonergic pathways in reward motivation and behavioral inhibition, this study investigated whether polygenic risk scores (PRSs) within these neurotransmitter pathways could predict these two effects. Two independent samples of Chinese university students were recruited from Luoyang (Sample 1: <em>N</em> = 647) and Xi’an (Sample 2: <em>N</em> = 569), providing demographically homogeneous populations for assessing genetic contributions to decision biases. In the serotonergic system, the PRS significantly predicted compromise effect in both samples (Sample 1: <em>β</em> = 0.093, <em>p</em> = 0.017; Sample 2: <em>β</em> = 0.094, <em>p</em> = 0.026) and decoy effect in Sample 2 (<em>β</em> = 0.122, <em>p</em> = 0.003). In the dopaminergic system, the PRS only significantly predicted compromise effect in Sample 2 (<em>β</em> = 0.132, <em>p</em> = 0.002), while it significantly predicted decoy effect in both samples (Sample 1: <em>β</em> = 0.132, <em>p</em> = 0.001; Sample 2: <em>β</em> = 0.126, <em>p</em> = 0.003). Combined-sample analyses confirmed a unique contribution of dopaminergic PRS to the compromise effect and showed that the decoy effect was jointly influenced by dopaminergic and serotonergic pathways. These results show that the decoy and compromise effects arise from distinct genetic mechanisms: dopamine amplifies relative reward signals driving the decoy choices, whereas serotonin promotes safer, intermediate preferences underlying the compromise decisions.</div></div>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"504 ","pages":"Article 116072"},"PeriodicalIF":2.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102577","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 : 2026-01-31DOI: 10.1016/j.bbr.2026.116075
Danna F Masri, William J Frazier, Melanie G Kimball, Christine R Lattin
Behavioural syndromes are suites of correlated behaviours at the population or species level that can affect how wild animals respond to their environments, including potentially stressful situations such as captivity. In this study, we assessed whether beak wiping, a stereotyped anxiety-linked behaviour where birds wipe their beaks on a perch in a "windshield wiper" motion, was correlated with another anxiety-linked behaviour, neophobia towards novel objects presented with food, in captive house sparrows (Passer domesticus). We predicted that more neophobic sparrows would also exhibit more beak-wiping stereotypies. We analyzed 1 h long control videos (when sparrows were presented with a normal food dish only; n = 54) from three previous neophobia studies to assess beak wiping frequency, mean beak wiping bout duration, and total bout duration. Sparrows' reluctance to feed in the presence of novel objects was significantly correlated with the mean duration of beak wiping bouts during control trials. We also found that simple enrichment (rubber perches, manzanita branch perches, and/or artificial pine branches) decreased both the frequency and duration of beak wiping. These findings suggest that high neophobia and high levels of stereotypy may arise due to similar neuroendocrine mechanisms and reflect a "high anxiety" behavioural syndrome. This work also highlights the importance of providing species-appropriate environmental enrichment to decrease the prevalence of stereotypic behaviours in captive songbirds.
{"title":"Beak wiping stereotypies are correlated with neophobia and lack of enrichment in captive house sparrows (Passer domesticus).","authors":"Danna F Masri, William J Frazier, Melanie G Kimball, Christine R Lattin","doi":"10.1016/j.bbr.2026.116075","DOIUrl":"10.1016/j.bbr.2026.116075","url":null,"abstract":"<p><p>Behavioural syndromes are suites of correlated behaviours at the population or species level that can affect how wild animals respond to their environments, including potentially stressful situations such as captivity. In this study, we assessed whether beak wiping, a stereotyped anxiety-linked behaviour where birds wipe their beaks on a perch in a \"windshield wiper\" motion, was correlated with another anxiety-linked behaviour, neophobia towards novel objects presented with food, in captive house sparrows (Passer domesticus). We predicted that more neophobic sparrows would also exhibit more beak-wiping stereotypies. We analyzed 1 h long control videos (when sparrows were presented with a normal food dish only; n = 54) from three previous neophobia studies to assess beak wiping frequency, mean beak wiping bout duration, and total bout duration. Sparrows' reluctance to feed in the presence of novel objects was significantly correlated with the mean duration of beak wiping bouts during control trials. We also found that simple enrichment (rubber perches, manzanita branch perches, and/or artificial pine branches) decreased both the frequency and duration of beak wiping. These findings suggest that high neophobia and high levels of stereotypy may arise due to similar neuroendocrine mechanisms and reflect a \"high anxiety\" behavioural syndrome. This work also highlights the importance of providing species-appropriate environmental enrichment to decrease the prevalence of stereotypic behaviours in captive songbirds.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"116075"},"PeriodicalIF":2.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103705","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}
Adolescent stress not only exerts enduring effects on individual behavior and physiology, but also shapes offspring phenotypes through mechanisms of transgenerational inheritance. However, the transgenerational effects of predation risk, an important ecological factor, remain poorly characterized in wild, social rodents. Using male Brandt's voles (Lasiopodomys brandtii) as a model, this study systematically investigated the transgenerational effect of adolescent exposure to cat urine, rabbit urine (as a non-predator stimulus), and distilled water (as a control) for 60min daily over 18 consecutive days on the behavioral and physiological traits of future offspring. Our data showed that while male paternal adolescent cat odor (CO) exposure did not significantly alter overall parental investment by either parent, it induced significant phenotypic changes in offspring. These included an increased female ratio at weaning and reduced post-weaning weight gain. Furthermore, adolescent offspring exhibited decreased locomotor activity in the open field test, while adult offspring displayed heightened vigilant rearing and reduced head-out behavior when confronted with CO exposure. These behavioral and developmental alterations were accompanied by elevated serum levels of adrenocorticotropic hormone and corticosterone, suggesting enhanced basal activity of the hypothalamic-pituitary-adrenal axis. These findings demonstrate that male paternal experience with predation risk during adolescence can transgenerationally regulate the sex ratio, growth and development, stress response, and antipredator strategies of future offspring, independent of alterations in parental investment in wild, social rodents. This study elucidates the unique role of the paternal lineage in the transgenerational inheritance of early adversity and provides further experimental evidence for understanding how environmental stress drives adaptive phenotypic transmission across generations.
{"title":"Male paternal exposure to predatory risk during adolescence alters offspring antipredator behavior and basal HPA axis activity in Brandt's voles.","authors":"Ping Wang, Taoxiu Zhou, Yinyue Gu, Xinyi Lan, Wanhong Wei, Ruiyong Wu","doi":"10.1016/j.bbr.2026.116073","DOIUrl":"https://doi.org/10.1016/j.bbr.2026.116073","url":null,"abstract":"<p><p>Adolescent stress not only exerts enduring effects on individual behavior and physiology, but also shapes offspring phenotypes through mechanisms of transgenerational inheritance. However, the transgenerational effects of predation risk, an important ecological factor, remain poorly characterized in wild, social rodents. Using male Brandt's voles (Lasiopodomys brandtii) as a model, this study systematically investigated the transgenerational effect of adolescent exposure to cat urine, rabbit urine (as a non-predator stimulus), and distilled water (as a control) for 60min daily over 18 consecutive days on the behavioral and physiological traits of future offspring. Our data showed that while male paternal adolescent cat odor (CO) exposure did not significantly alter overall parental investment by either parent, it induced significant phenotypic changes in offspring. These included an increased female ratio at weaning and reduced post-weaning weight gain. Furthermore, adolescent offspring exhibited decreased locomotor activity in the open field test, while adult offspring displayed heightened vigilant rearing and reduced head-out behavior when confronted with CO exposure. These behavioral and developmental alterations were accompanied by elevated serum levels of adrenocorticotropic hormone and corticosterone, suggesting enhanced basal activity of the hypothalamic-pituitary-adrenal axis. These findings demonstrate that male paternal experience with predation risk during adolescence can transgenerationally regulate the sex ratio, growth and development, stress response, and antipredator strategies of future offspring, independent of alterations in parental investment in wild, social rodents. This study elucidates the unique role of the paternal lineage in the transgenerational inheritance of early adversity and provides further experimental evidence for understanding how environmental stress drives adaptive phenotypic transmission across generations.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"116073"},"PeriodicalIF":2.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103648","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 : 2026-01-31DOI: 10.1016/j.bbr.2026.116076
Ali Rahimi Saryazdi, Farnaz Ghassemi, Golnaz Baghdadi
Deception is one of the most enigmatic human behaviors, and understanding its neural mechanisms remains a central challenge in neuroscience. Investigating brain dynamics during deception provides insights into cognitive control and social processing. In this study, we analyzed the architecture of brain region connections, focusing on rich, feeder, and local links, using EEG signals from 22 participants performing a visual task under instructed deception. Functional connectivity matrices were computed with phase lag index, and binary networks were constructed across multiple thresholds. Results showed that brain networks are organized around stable hub regions, which remain largely unchanged during deception. However, deceptive behavior disrupted peripheral connections, with feeder and local links showing reductions relative to truthful responding, suggesting reallocation of cognitive resources. Although hub regions were consistent, hubs in the truthful condition exhibited higher connectivity than during deception in both binary and weighted networks across all percentages of rich nodes (p < 10-6), indicating more efficient hub-to-hub integration during truthful processing. Analysis of link deviations across thresholds and rich-node percentages revealed a dynamic pattern. At low percentages, rich links were stable while local links varied most. As percentages increased, rich links showed the largest deviations, local links the smallest, and feeder links maintained intermediate variability. These results indicate that deception initially disrupts local processing, while communication among core hubs is affected as network engagement grows. These findings highlight the importance of investigating the architecture of brain region connections during complex social behaviors, showing how stable hubs and flexible peripheral links support cognitive processing.
{"title":"Resilient Hubs, Shifting Links: The Brain's Network Architecture During Deceptive Behavior.","authors":"Ali Rahimi Saryazdi, Farnaz Ghassemi, Golnaz Baghdadi","doi":"10.1016/j.bbr.2026.116076","DOIUrl":"https://doi.org/10.1016/j.bbr.2026.116076","url":null,"abstract":"<p><p>Deception is one of the most enigmatic human behaviors, and understanding its neural mechanisms remains a central challenge in neuroscience. Investigating brain dynamics during deception provides insights into cognitive control and social processing. In this study, we analyzed the architecture of brain region connections, focusing on rich, feeder, and local links, using EEG signals from 22 participants performing a visual task under instructed deception. Functional connectivity matrices were computed with phase lag index, and binary networks were constructed across multiple thresholds. Results showed that brain networks are organized around stable hub regions, which remain largely unchanged during deception. However, deceptive behavior disrupted peripheral connections, with feeder and local links showing reductions relative to truthful responding, suggesting reallocation of cognitive resources. Although hub regions were consistent, hubs in the truthful condition exhibited higher connectivity than during deception in both binary and weighted networks across all percentages of rich nodes (p < 10<sup>-6</sup>), indicating more efficient hub-to-hub integration during truthful processing. Analysis of link deviations across thresholds and rich-node percentages revealed a dynamic pattern. At low percentages, rich links were stable while local links varied most. As percentages increased, rich links showed the largest deviations, local links the smallest, and feeder links maintained intermediate variability. These results indicate that deception initially disrupts local processing, while communication among core hubs is affected as network engagement grows. These findings highlight the importance of investigating the architecture of brain region connections during complex social behaviors, showing how stable hubs and flexible peripheral links support cognitive processing.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"116076"},"PeriodicalIF":2.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103695","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 : 2026-01-31DOI: 10.1016/j.bbr.2026.116074
Xiaohong Wang, Lu Sun, Zhongyu Zhang, Haowei Shen, Lei Chen, Jianmei Huang, Haifeng Zhai
Homovanillic acid (HVA), the principal terminal metabolite of dopamine, has long been considered an inactive byproduct of dopaminergic signaling. However, its potential neuromodulatory role in emotional regulation remains largely unexplored. This study investigated the neuromodulatory capacity of HVA within the medial prefrontal cortex (mPFC) and its implications for anxiety-like behavior. We employed an integrated approach in rodents, combining neurochemical profiling, stereotaxic microinfusion, and whole-cell patch-clamp electrophysiology. Rats were phenotyped for anxiety-like behavior using the elevated plus-maze (EPM), revealing a distinct neurochemical signature in the mPFC of high-anxiety individuals: significantly elevated HVA alongside reduced 3-methoxytyramine (3-MT), without alterations in dopamine, norepinephrine, serotonin, or their major metabolites. Crucially, bilateral microinjection of HVA (0.5 or 1.5 μg/side) into the mPFC of naïve rats induced dose-dependent anxiogenic effects, evidenced by reduced open-arm exploration and entries in the EPM. Electrophysiological recordings from deep-layer pyramidal neurons in mouse mPFC slices demonstrated that HVA (80 μM) suppresses calcium channel-mediated plateau potentials. Our findings reveal HVA as an active neuromodulator in the mPFC that shapes anxiety-like behaviors through inhibition of calcium channels, challenging its traditional status as a metabolic waste product.
{"title":"The emerging neuromodulatory role of Homovanillic acid in the medial prefrontal cortex: Implications for anxiety.","authors":"Xiaohong Wang, Lu Sun, Zhongyu Zhang, Haowei Shen, Lei Chen, Jianmei Huang, Haifeng Zhai","doi":"10.1016/j.bbr.2026.116074","DOIUrl":"10.1016/j.bbr.2026.116074","url":null,"abstract":"<p><p>Homovanillic acid (HVA), the principal terminal metabolite of dopamine, has long been considered an inactive byproduct of dopaminergic signaling. However, its potential neuromodulatory role in emotional regulation remains largely unexplored. This study investigated the neuromodulatory capacity of HVA within the medial prefrontal cortex (mPFC) and its implications for anxiety-like behavior. We employed an integrated approach in rodents, combining neurochemical profiling, stereotaxic microinfusion, and whole-cell patch-clamp electrophysiology. Rats were phenotyped for anxiety-like behavior using the elevated plus-maze (EPM), revealing a distinct neurochemical signature in the mPFC of high-anxiety individuals: significantly elevated HVA alongside reduced 3-methoxytyramine (3-MT), without alterations in dopamine, norepinephrine, serotonin, or their major metabolites. Crucially, bilateral microinjection of HVA (0.5 or 1.5 μg/side) into the mPFC of naïve rats induced dose-dependent anxiogenic effects, evidenced by reduced open-arm exploration and entries in the EPM. Electrophysiological recordings from deep-layer pyramidal neurons in mouse mPFC slices demonstrated that HVA (80 μM) suppresses calcium channel-mediated plateau potentials. Our findings reveal HVA as an active neuromodulator in the mPFC that shapes anxiety-like behaviors through inhibition of calcium channels, challenging its traditional status as a metabolic waste product.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"116074"},"PeriodicalIF":2.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099823","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 : 2026-01-31DOI: 10.1016/j.bbr.2026.116059
Daniel B K Gabriel, Kaitlin R Crilow, Susan Sangha
Stimuli can acquire meaning and significance indirectly by being paired with other stimuli that already have known outcomes. When a stimulus has a well-established association with either aversive or rewarding consequences, other neutral stimuli can take on similar properties simply by occurring alongside it - even if the original outcome is not presented. This process is known as second-order conditioning. Relatively few studies have examined second-order conditioning of inhibitory safety memories. Here, we examined second-order conditioning of safety in adult male and female Long-Evans rats by adapting our well-established first-order safety conditioning paradigm to include novel stimuli paired with the established safety cue. Our findings demonstrate that a second-order safety cue can attenuate fear responses to a degree comparable to that of a first-order safety cue. In contrast, a novel cue that had never been paired with a safety signal failed to produce an equivalent reduction in defensive behavior during fear cue presentation, demonstrating that the reduced fear to the second-order safety cue was a product of conditioning and not external inhibition. Developing methods to generalize safety to novel stimuli that have not been explicitly conditioned for safety holds significant promise for advancing innovative strategies aimed at mitigating maladaptive fear responses.
{"title":"Second-Order Conditioning of Safety in Male and Female Rats.","authors":"Daniel B K Gabriel, Kaitlin R Crilow, Susan Sangha","doi":"10.1016/j.bbr.2026.116059","DOIUrl":"https://doi.org/10.1016/j.bbr.2026.116059","url":null,"abstract":"<p><p>Stimuli can acquire meaning and significance indirectly by being paired with other stimuli that already have known outcomes. When a stimulus has a well-established association with either aversive or rewarding consequences, other neutral stimuli can take on similar properties simply by occurring alongside it - even if the original outcome is not presented. This process is known as second-order conditioning. Relatively few studies have examined second-order conditioning of inhibitory safety memories. Here, we examined second-order conditioning of safety in adult male and female Long-Evans rats by adapting our well-established first-order safety conditioning paradigm to include novel stimuli paired with the established safety cue. Our findings demonstrate that a second-order safety cue can attenuate fear responses to a degree comparable to that of a first-order safety cue. In contrast, a novel cue that had never been paired with a safety signal failed to produce an equivalent reduction in defensive behavior during fear cue presentation, demonstrating that the reduced fear to the second-order safety cue was a product of conditioning and not external inhibition. Developing methods to generalize safety to novel stimuli that have not been explicitly conditioned for safety holds significant promise for advancing innovative strategies aimed at mitigating maladaptive fear responses.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"116059"},"PeriodicalIF":2.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103639","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}
<p><strong>Background: </strong>Schizophrenia (SCZ) is increasingly recognized as a complex, systemic disorder involving interactions between the central nervous system and peripheral biological processes. Growing evidence implicates dysregulation of the gut-brain axis in SCZ pathophysiology; however, the genetic mechanisms linking schizophrenia susceptibility to gut-related biological pathways remain poorly understood, particularly with respect to causal gene prioritization across tissues.</p><p><strong>Methods: </strong>To address this gap, we conducted a cross-tissue transcriptome-wide association study (TWAS) using FUSION across five tissues relevant to brain-gut interactions, including the hippocampus, frontal cortex (BA9), transverse colon, sigmoid colon, and whole blood. Candidate genes were further prioritized using MAGMA gene-based analysis based on schizophrenia genome-wide association study (GWAS) summary statistics from the Psychiatric Genomics Consortium and the IEU Open GWAS project. Integrative analyses combining summary-data-based Mendelian randomization (SMR) and Bayesian colocalization (PP.H4 > 0.75) were applied to refine candidate gene selection. Expression of the top candidate gene was examined by RT-qPCR in peripheral blood samples from 19 patients with SCZ and 21 healthy controls. Finally, two-sample Mendelian randomization (MR) analyses were performed to explore potential associations between the prioritized gene and 205 gut microbial metabolic pathways.</p><p><strong>Results: </strong>Cross-tissue integration of TWAS, MAGMA, and SMR identified five convergent schizophrenia susceptibility genes: TVP23B, NSUN2, RPL12, FOXN2, and THAP5. Bayesian colocalization analysis highlighted FOXN2 as the most robust candidate (PP.H4 =0.995). RT-qPCR analysis demonstrated significantly lower FOXN2 expression in peripheral blood from patients with schizophrenia compared with healthy controls (mean ± SD: 0.72±0.64 vs.1.13±0.42; t = 2.34, P = 0.02). In two-sample MR analyses, genetically proxied FOXN2 expression was modestly but significantly associated with 10 gut microbial metabolic pathways after false discovery rate correction, suggesting potential links between schizophrenia risk genes and gut microbial metabolic processes.</p><p><strong>Limitations: </strong>This study relies on cis-eQTL-based transcriptomic integration and assumes a single causal variant in colocalization analyses. The number of available MR instruments was limited, and the clinical validation sample size was modest, with residual confounding not fully excluded. In addition, the GWAS and eQTL datasets were predominantly derived from populations of European ancestry, which may limit generalizability. The observed associations between FOXN2 and gut microbial metabolic pathways should therefore be considered exploratory and require further functional validation.</p><p><strong>Conclusion: </strong>Our findings suggest that FOXN2 may contribute to the genetic architectur
{"title":"Transcriptomic integration nominates FOXN2 as a candidate schizophrenia risk gene.","authors":"Ling Yu, Jian Chen, Shanshan Du, Qing Long, Zeyi Guo, Yilin Liu, Fuyi Qin, Mengxue Wang, Raoxiang Luo, Yunqiao Zhang, Yong Zeng, Zhaowei Teng","doi":"10.1016/j.bbr.2026.116068","DOIUrl":"https://doi.org/10.1016/j.bbr.2026.116068","url":null,"abstract":"<p><strong>Background: </strong>Schizophrenia (SCZ) is increasingly recognized as a complex, systemic disorder involving interactions between the central nervous system and peripheral biological processes. Growing evidence implicates dysregulation of the gut-brain axis in SCZ pathophysiology; however, the genetic mechanisms linking schizophrenia susceptibility to gut-related biological pathways remain poorly understood, particularly with respect to causal gene prioritization across tissues.</p><p><strong>Methods: </strong>To address this gap, we conducted a cross-tissue transcriptome-wide association study (TWAS) using FUSION across five tissues relevant to brain-gut interactions, including the hippocampus, frontal cortex (BA9), transverse colon, sigmoid colon, and whole blood. Candidate genes were further prioritized using MAGMA gene-based analysis based on schizophrenia genome-wide association study (GWAS) summary statistics from the Psychiatric Genomics Consortium and the IEU Open GWAS project. Integrative analyses combining summary-data-based Mendelian randomization (SMR) and Bayesian colocalization (PP.H4 > 0.75) were applied to refine candidate gene selection. Expression of the top candidate gene was examined by RT-qPCR in peripheral blood samples from 19 patients with SCZ and 21 healthy controls. Finally, two-sample Mendelian randomization (MR) analyses were performed to explore potential associations between the prioritized gene and 205 gut microbial metabolic pathways.</p><p><strong>Results: </strong>Cross-tissue integration of TWAS, MAGMA, and SMR identified five convergent schizophrenia susceptibility genes: TVP23B, NSUN2, RPL12, FOXN2, and THAP5. Bayesian colocalization analysis highlighted FOXN2 as the most robust candidate (PP.H4 =0.995). RT-qPCR analysis demonstrated significantly lower FOXN2 expression in peripheral blood from patients with schizophrenia compared with healthy controls (mean ± SD: 0.72±0.64 vs.1.13±0.42; t = 2.34, P = 0.02). In two-sample MR analyses, genetically proxied FOXN2 expression was modestly but significantly associated with 10 gut microbial metabolic pathways after false discovery rate correction, suggesting potential links between schizophrenia risk genes and gut microbial metabolic processes.</p><p><strong>Limitations: </strong>This study relies on cis-eQTL-based transcriptomic integration and assumes a single causal variant in colocalization analyses. The number of available MR instruments was limited, and the clinical validation sample size was modest, with residual confounding not fully excluded. In addition, the GWAS and eQTL datasets were predominantly derived from populations of European ancestry, which may limit generalizability. The observed associations between FOXN2 and gut microbial metabolic pathways should therefore be considered exploratory and require further functional validation.</p><p><strong>Conclusion: </strong>Our findings suggest that FOXN2 may contribute to the genetic architectur","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"116068"},"PeriodicalIF":2.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091742","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}
This review aimed to examine the role of the amygdala as a central hub in the pathophysiology of chronic pain, with a specific focus on fibromyalgia and migraine. We synthesize evidence on how structural, functional, and neurochemical alterations within amygdala-centered circuits contribute to pain amplification, emotional dysregulation, and central sensitization, and discuss their implications for circuit-based therapeutic strategies.
Methods
A comprehensive, theory-driven literature synthesis was conducted, integrating findings from neuroimaging, neuromodulation, molecular neuroscience, and clinical studies. We examined alterations in amygdala structure, function, and connectivity with cortical and brainstem regions involved in nociceptive processing, emotional regulation, and descending pain modulation. Pharmacological and non-pharmacological interventions targeting limbic–brainstem circuits were also analyzed.
Results
Converging evidence indicates that both fibromyalgia and migraine are associated with significant volumetric, functional, and connectivity-related alterations of the amygdala. These changes are characterized by limbic hyperexcitability and aberrant coupling with the prefrontal cortex, hypothalamus, periaqueductal gray (PAG), and rostral ventromedial medulla (RVM), biasing descending pain control toward facilitation rather than inhibition. This network reorganization amplifies both the sensory and affective dimensions of pain and promotes symptom persistence. Neurochemical dysregulation—encompassing glutamatergic, monoaminergic, GABAergic, and peptidergic systems—further sustains maladaptive plasticity within amygdala-centered circuits. Emerging therapeutic approaches, including cognitive-behavioral interventions, neuromodulation, pharmacological modulation, and immersive technologies, show potential to reshape dysfunctional limbic–cortical networks and attenuate pain amplification.
Conclusion
The amygdala emerges as a key integrative node linking nociceptive, emotional, and autonomic processes in fibromyalgia and migraine. Through its influence on descending pain modulatory systems, amygdala-centered circuits play a critical role in pain chronification and affective sensitization. These findings support a circuit-based framework for chronic pain, highlighting the amygdala as a promising target for individualized, multimodal therapeutic strategies aimed at restoring adaptive emotional–nociceptive integration.
{"title":"Amygdala-centered mechanisms of pain amplification and chronification in fibromyalgia and migraine: Narrative review","authors":"Nataliya Zharova , Yury Zharikov , Yane Pelicer-Marques , Vladimir Nikolenko , Vladislav Tarasenko , Elena Mikliaeva , Anastasia Mchenskaya , Sergey Ryagin , Sevak Antonyan , Denis Aniskin , André Pontes-Silva , Tatiana Zharikova","doi":"10.1016/j.bbr.2026.116071","DOIUrl":"10.1016/j.bbr.2026.116071","url":null,"abstract":"<div><h3>Objective</h3><div>This review aimed to examine the role of the amygdala as a central hub in the pathophysiology of chronic pain, with a specific focus on fibromyalgia and migraine. We synthesize evidence on how structural, functional, and neurochemical alterations within amygdala-centered circuits contribute to pain amplification, emotional dysregulation, and central sensitization, and discuss their implications for circuit-based therapeutic strategies.</div></div><div><h3>Methods</h3><div>A comprehensive, theory-driven literature synthesis was conducted, integrating findings from neuroimaging, neuromodulation, molecular neuroscience, and clinical studies. We examined alterations in amygdala structure, function, and connectivity with cortical and brainstem regions involved in nociceptive processing, emotional regulation, and descending pain modulation. Pharmacological and non-pharmacological interventions targeting limbic–brainstem circuits were also analyzed.</div></div><div><h3>Results</h3><div>Converging evidence indicates that both fibromyalgia and migraine are associated with significant volumetric, functional, and connectivity-related alterations of the amygdala. These changes are characterized by limbic hyperexcitability and aberrant coupling with the prefrontal cortex, hypothalamus, periaqueductal gray (PAG), and rostral ventromedial medulla (RVM), biasing descending pain control toward facilitation rather than inhibition. This network reorganization amplifies both the sensory and affective dimensions of pain and promotes symptom persistence. Neurochemical dysregulation—encompassing glutamatergic, monoaminergic, GABAergic, and peptidergic systems—further sustains maladaptive plasticity within amygdala-centered circuits. Emerging therapeutic approaches, including cognitive-behavioral interventions, neuromodulation, pharmacological modulation, and immersive technologies, show potential to reshape dysfunctional limbic–cortical networks and attenuate pain amplification.</div></div><div><h3>Conclusion</h3><div>The amygdala emerges as a key integrative node linking nociceptive, emotional, and autonomic processes in fibromyalgia and migraine. Through its influence on descending pain modulatory systems, amygdala-centered circuits play a critical role in pain chronification and affective sensitization. These findings support a circuit-based framework for chronic pain, highlighting the amygdala as a promising target for individualized, multimodal therapeutic strategies aimed at restoring adaptive emotional–nociceptive integration.</div></div>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":"503 ","pages":"Article 116071"},"PeriodicalIF":2.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075552","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}