Neuropsychopharmacology最新文献

{"title":"The prelimbic prefrontal cortex mediates the development of lasting social avoidance as a consequence of social threat conditioning.","authors":"Kelly Lozano-Ortiz, Ada C Felix-Ortiz, Jaelyn M Terrell, Carolina Gonzalez, Kamryn R Whitehorn, Addison E Kanke, Stephanie A Villalon, Angelica R Ramos, Ashley N Miller, Jose Rodriguez-Romaguera, Anthony Burgos-Robles","doi":"10.1038/s41386-025-02073-8","DOIUrl":"10.1038/s41386-025-02073-8","url":null,"abstract":"<p><p>Social avoidance is highly detrimental for natural behavior. Despite much research on this topic, the mechanisms underlying the development of social avoidance as a consequence of social-related traumatic experiences remain highly elusive. To investigate this issue, we adapted a mouse model of social threat conditioning in which mice received shock punishment during exploration of an unfamiliar conspecific. This resulted in prominent and lasting reductions in social behavior, effects that were not observed in mice that received shock punishment in the absence of a social stimulus. Furthermore, the effects of social threat conditioning were independent of contextual settings, sex variables, and particular identity of the unfamiliar conspecifics that predicted shock punishment. Shedding new light into the neurobiological bases for this phenomenon, we found that optogenetic silencing of the prelimbic (PL), but not infralimbic (IL), prefrontal cortex during social threat conditioning produced profound forgetting and restoration of social behavior during subsequent sociability tests. Significant forgetting and recovery of social behavior was also observed with prelimbic inhibition of NMDARs. Collectively, these findings are consistent with the notion that social-related trauma is a prominent risk factor for social avoidance, and that traumatic experiences that involve social elements engage learning-related mechanisms in corticolimbic networks to promote long-term representations of social threat.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal associations between white matter integrity, early life adversities, and treatment response following cognitive-behavioral therapy in depression","authors":"Kira Flinkenflügel,&nbsp;Tiana Borgers,&nbsp;Melissa Klug,&nbsp;Marie M. Mummendey,&nbsp;Elisabeth J. Leehr,&nbsp;Susanne Meinert,&nbsp;Marius Gruber,&nbsp;Jonathan Repple,&nbsp;Tilo Kircher,&nbsp;Nils Opel,&nbsp;Jochen Bauer,&nbsp;Esther Zwiky,&nbsp;Philine König,&nbsp;Antonia Küttner,&nbsp;Konrad Schöniger,&nbsp;Robin Kamrla,&nbsp;Udo Dannlowski,&nbsp;Verena Enneking,&nbsp;Ronny Redlich","doi":"10.1038/s41386-025-02070-x","DOIUrl":"10.1038/s41386-025-02070-x","url":null,"abstract":"Cognitive-behavioral therapy (CBT) is a primary treatment for depression. Although previous research has underscored the significant roles of white matter (WM) alterations and maladaptive parenting in depression risk, their associations with CBT response remain largely unknown. This longitudinal study investigated the interplay of WM integrity changes over time, treatment response, and parenting style in patients with depression. Diffusion-tensor-imaging and clinical data were assessed in n = 65 (55% female) patients with depression before and after 20 CBT sessions and n = 65 (68% female) healthy controls (HC) in a naturalistic design. Linear-mixed-effect models compared changes in fractional anisotropy (FA) between groups and tested associations between FA changes and symptom changes. It was investigated whether parenting style predicts depressive symptoms at follow-up and whether FA changes mediate this association. Patients showed differential FA changes over time in the corpus callosum and corona radiata compared to HC (ptfce-FWE = 0.008). Increases in FA in the corpus callosum, corona radiata and superior longitudinal fasciculus were linked to symptom improvement after CBT in patients (ptfce-FWE = 0.023). High parental care (pFDR = 0.010) and low maternal overprotection (pFDR = 0.001) predicted fewer depressive symptoms at follow-up. The association between maternal overprotection and depressive symptoms at follow-up was mediated by FA changes (pFDR = 0.044). Robustness checks—controlling for outliers, non-linear age effects, clinical characteristics, and patient subgroups—supported these results. Overall, patients with depression show changes in WM integrity following CBT, which are linked to treatment response. The results highlight the significance of early life adversities and related microstructural changes in the effectiveness of CBT for treating depression.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 6","pages":"1000-1007"},"PeriodicalIF":6.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02070-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein interacting with C-kinase 1 (PICK1) regulates synaptic function and reversal learning in a mouse model for schizophrenia.","authors":"James N Samsom, MengYi Xu, Ariel Ávila, Anastasios A Daskalakis, Jia Hong Dai, Xing Gao, John Georgiou, Graham L Collingridge, Fang Liu, Albert H C Wong","doi":"10.1038/s41386-025-02072-9","DOIUrl":"https://doi.org/10.1038/s41386-025-02072-9","url":null,"abstract":"<p><p>Protein interacting with C-kinase 1 (PICK1) is important for synaptic plasticity through directing transport of glutamate receptors and other proteins. PICK1 gene variants have been associated with schizophrenia. To examine the role of PICK1 in schizophrenia-related behaviors, mice with a mutation in the PICK1 lipid-interacting BAR domain were characterized. Male Pick1-S262T mice had disrupted AMPA receptor (AMPAR) subunit GluA1 and GluA2 protein expression in the hippocampus and prefrontal cortex (PFC). Young adult, but not juvenile (P21), Pick1-S262T mice showed decreased hippocampal synaptic transmission and deficits in long-term depression (LTD). Mutant males also had deficits in reversal learning in the Morris water maze (MWM). These observations suggest that the Pick1-S262T mutation affects AMPAR trafficking, disrupting synaptic transmission and plasticity, as well as cognitive flexibility, a core neuropsychological deficit in schizophrenia. This work suggests possible mechanisms by which a known schizophrenia susceptibility gene could contribute to clinical features of the disorder.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of alcohol intake patterns with olfactory and gustatory brain connectivity networks.","authors":"Khushbu Agarwal, Shefali Chaudhary, Dardo Tomasi, Nora D Volkow, Paule V Joseph","doi":"10.1038/s41386-025-02058-7","DOIUrl":"https://doi.org/10.1038/s41386-025-02058-7","url":null,"abstract":"<p><p>Craving in alcohol drinkers is often triggered by chemosensory cues, such as taste and smell, which are linked to brain network connectivity. This study aimed to investigate whether these brain connectivity patterns could predict alcohol intake in young adults. Resting-state fMRI data were obtained from the Human Connectome Project (HCP) Young Adult cohort, comprising 1003 participants. Functional connectomes generated from 100 independent components were analyzed, identifying significant connections correlated with taste and odor scores after applying a false discovery rate (FDR) correction using the Benjamini-Hochberg (BH) method. These significant connections were then utilized as predictors in general linear models for various alcohol intake metrics. The models were validated in an independent sample to assess their accuracy. The training sample (n = 702) and the validation sample (n = 117) showed no significant demographic differences. Out of 742 possible connections, 41 related to odor and 25 related to taste passed the significance threshold (P < 0.05) after FDR-BH correction. Notable predictors included visual-visual connectivity (node32-node13: β = 0.028, P = 0.02) for wine consumption and connectivity between the ventral attention network (VAN) and the frontal parietal/caudate nucleus (FP/CN) (node27-node9: β = -0.31, P = 0.04) for total alcohol intake in the past-week and maximum number of drinks per day in the past-year. The predictive models demonstrated strong accuracy, with root mean square error (RMSE) values of 5.15 for odor-related models and 5.14 for taste-related models. The F1 scores were 0.74 for the odor model and 0.71 for the taste model, indicating reliable performance. These findings suggest that specific patterns of brain connectivity associated with taste and olfactory perception may serve as predictors of alcohol consumption behaviors in young adults. Our study highlight the need for longitudinal research to evaluate the potential of taste- and smell-related brain connectivity patterns for early screening and targeted interventions, as well as their role in personalized treatment strategies for individuals at risk of AUD.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"REM density predicts rapid antidepressant response to ketamine in individuals with treatment-resistant depression","authors":"Mina Kheirkhah,&nbsp;Wallace C. Duncan Jr,&nbsp;Qiaoping Yuan,&nbsp;Philip R. Wang,&nbsp;Hamidreza Jamalabadi,&nbsp;Lutz Leistritz,&nbsp;Martin Walter,&nbsp;David Goldman,&nbsp;Carlos A. Zarate Jr,&nbsp;Nadia S. Hejazi","doi":"10.1038/s41386-025-02066-7","DOIUrl":"10.1038/s41386-025-02066-7","url":null,"abstract":"Abnormalities during rapid eye movement (REM) sleep contribute to the pathophysiology of major depressive disorder (MDD), but few studies have explored the relationship between REM sleep and treatment-resistant depression (TRD). In MDD, REM sleep abnormalities often manifest as alterations in total night REM Density (RD), RD in the first REM period (RD1), and REM Latency (RL). Among these, RD1 is notably considered a potential endophenotype of depression. This study compared REM sleep markers between 63 drug-free individuals with TRD (39 F/24 M) and 41 healthy volunteers (25 F/16 M). It also investigated the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, on these REM sleep variables. Specifically, the study investigated whether RD1 could predict antidepressant response to ketamine. TRD participants showed higher RD1 and shorter RL at baseline compared to HVs, as assessed via non-parametric tests, but Total Night RD did not differ between the two groups. Ketamine treatment decreased RD1 in TRD participants but did not affect Total Night RD or RL. As assessed via the Support Vector Machine (SVM) algorithm, baseline RD1 level moderately predicted antidepressant response to ketamine versus non-response (area under the receiver operating characteristic (ROC) curve (AUC) = 0.73, with a median accuracy of 0.75), wherein TRD participants with higher baseline RD1 were more likely to respond to ketamine. These results underscore the utility of RD1 for identifying individuals most likely to benefit from ketamine treatment, enabling more targeted and effective therapeutic strategies. Clinical Trials Identifier: NCT00088699, NCT01204918.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 6","pages":"941-946"},"PeriodicalIF":6.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02066-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of L-type calcium channel blocker amlodipine as a novel ADHD treatment through cross-species analysis, drug-target Mendelian randomization, and clinical evidence from medical records.","authors":"Haraldur Þorsteinsson, Hannes A Baukmann, Hildur S Sveinsdóttir, Dagmar Þ Halldórsdóttir, Bartosz Grzymala, Courtney Hillman, Jude Rolfe-Tarrant, Matthew O Parker, Justin L Cope, Charles N J Ravarani, Marco F Schmidt, Karl Æ Karlsson","doi":"10.1038/s41386-025-02062-x","DOIUrl":"https://doi.org/10.1038/s41386-025-02062-x","url":null,"abstract":"<p><p>ADHD is a chronic neurodevelopmental disorder that significantly affects life outcomes, and current treatments often have adverse side effects, high abuse potential, and a 25% non-response rate, highlighting the need for new therapeutics. This study investigates amlodipine, an L-type calcium channel blocker, as a potential foundation for developing a novel ADHD treatment by integrating findings from animal models and human genetic data. Amlodipine reduced hyperactivity in SHR rats and decreased both hyperactivity and impulsivity in adgrl3.1-/- zebrafish. It also crosses the blood-brain barrier, reducing telencephalic activation. Crucially, Mendelian Randomization analysis linked ADHD to genetic variations in L-type calcium channel subunits (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3) targeted by amlodipine, while polygenic risk score analysis showed symptom mitigation in individuals with high ADHD genetic liability. With its well-tolerated profile and efficacy across species, supported by genetic evidence, amlodipine shows potential to be refined and developed into a novel treatment for ADHD.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frontostriatal regulation of brain circuits contributes to flexible decision making.","authors":"Ying Duan, Zilu Ma, Pei-Jung Tsai, Hanbing Lu, Xiang Xiao, Danni Wang, Aslaan Siddiqi, Elliot A Stein, Michael Michaelides, Yihong Yang","doi":"10.1038/s41386-025-02065-8","DOIUrl":"https://doi.org/10.1038/s41386-025-02065-8","url":null,"abstract":"<p><p>Deficits in behavioral or cognitive flexibility that are linked to altered activity in both cortical and subcortical brain regions, are often observed across multiple neuropsychiatric disorders. The medial prefrontal cortex (mPFC)-nucleus accumbens (NAc) pathway in rats plays a critical role in flexible control of behavior. However, the modulation of this pathway on activity and functional connectivity with the rest of the brain remains unclear. In this study, we first confirmed the role of the mPFC-NAc pathway in behavioral flexibility using a set-shifting task in rats and then evaluated the causal effects of mPFC-NAc activation induced by chemogenetic stimulation of the terminal axons of the NAc with DREADD expression on whole-brain activity and functional connectivity measured by functional MRI. mPFC-NAc activation improved performance on the set-shifting task by reducing perseverative errors. Additionally, stimulation of this pathway increased activity in a set of brain regions within the basal ganglia-thalamus-cortical loop network including NAc, thalamus, hypothalamus and various connected cortical regions, while also decreased functional connectivity strength of NAc-mPFC, NAc-secondary motor cortex (M2), and various cortical circuits. Moreover, performance on the set-shifting task was related to the functional connectivity strength of the above frontostriatal and cortical circuits. These findings provide insights into the link between specific frontostriatal circuits on decision making flexibility, which may inform potential future interventions for behavioral flexibility deficits.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extended amygdala corticotropin-releasing hormone neurons regulate sexually dimorphic changes in pair bond formation following social defeat in prairie voles (Microtus ochrogaster)","authors":"Maria C. Tickerhoof,&nbsp;Lina K. Nerio Morales,&nbsp;Jeff Goff,&nbsp;Erika M. Vitale,&nbsp;Adam S. Smith","doi":"10.1038/s41386-025-02067-6","DOIUrl":"10.1038/s41386-025-02067-6","url":null,"abstract":"The neurobiological mechanisms underlying the connection between anxiety brought on by social stressors and the negative impact on relationship formation have remained elusive. In order to address this question, we used the social defeat model in the socially monogamous prairie vole to investigate the impact of this stress on pair bond formation. Social defeat experience inhibited partner preference formation in males but promoted preference in females. Furthermore, pair bonding increased corticotropin-releasing hormone (CRH) expression in the bed nucleus of the stria terminalis (BNST) in male prairie voles, while defeat experience increased BNST CRH expression in females. Chemogenetic excitation of BNST CRH neurons during a short cohabitation with a new partner promoted a partner preference in stress-naïve prairie voles. Interestingly, chemogenetic inhibition of BNST CRH neurons during cohabitation with a new partner blocked partner preference in stress-naïve males but promoted preference in defeated males. Inhibition of BNST CRH neurons also blocked partner preference in stress-naïve females but did not alter preference behavior in defeated females. This study revealed sexual dimorphism in not only the impact of social defeat on pair bond formation, but also in the role BNST CRHergic neurons play in regulating changes in pair bonding following social conflict.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 6","pages":"965-975"},"PeriodicalIF":6.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Absence of TAAR1 function increases methamphetamine-induced excitability of dorsal raphe serotonin neurons and drives binge-level methamphetamine intake.","authors":"Samantha M Rios, John R K Mootz, Tamara J Phillips, Susan L Ingram","doi":"10.1038/s41386-025-02063-w","DOIUrl":"10.1038/s41386-025-02063-w","url":null,"abstract":"<p><p>Methamphetamine (MA) is a potent psychostimulant capable of exerting both rewarding and aversive effects, the balance of which likely drives variation in voluntary MA intake. Understanding the genetic factors underlying sensitivity to these effects of MA is critical for developing effective treatments. The activity of dorsal raphe serotonin neurons is linked to reward processing. Here, we performed whole-cell patch-clamp electrophysiology in dorsal raphe serotonin neurons from mice with high or low MA intake corresponding with high or low MA reward sensitivity. The MA drinking (MADR) mice consist of the MA reward sensitive MA high drinking (MAHDR) and the MA reward insensitive MA low drinking (MALDR) lines. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and MAHDR mice are homozygous for a mutation in the Taar1 gene, Taar1^m1J, that encodes non-functional TAAR1, whereas MALDR mice possess at least one copy of the reference Taar1⁺ allele that encodes functional TAAR1. Our previous research using CRISPR-Cas9-generated MAHDR-Taar1^+/+ knock-in mice in which Taar1^m1J was replaced with Taar1⁺, and non-edited MAHDR-Taar1^m1J/m1J controls demonstrated that lack of TAAR1 function is critical for heightened MA consumption and MA reward sensitivity. Here, electrophysiological recordings in the MADR lines demonstrate a MA-induced decrease in dorsal raphe serotonin neuron activity from MALDR, but not MAHDR mice. However, in the presence of serotonin autoreceptor antagonists, MA potentiates dorsal raphe serotonin neuron activity of MAHDR, but not MALDR mice. Importantly, potentiation in the presence of the antagonists is abolished in knock-in mice expressing functional TAAR1. The knock-in mice did not display binge-level MA intake, consistent with the loss of MA-reward sensitivity previously reported in mice with functional TAAR1. Finally, because MA is a substrate of the serotonin transporter, we evaluated whether the serotonin transporter is necessary for MA-induced potentiation of dorsal raphe serotonin neuron activity in mice with non-functional TAAR1. The serotonin transporter antagonist fluoxetine blocks MA-induced potentiation for both MAHDR and MAHDR-Taar1^m1J/m1J mice. Thus, TAAR1 function directly impacts MA reward sensitivity and MA intake and serves as a critical regulator of MA-induced activity of dorsal raphe serotonin neurons through its interaction with the serotonin transporter.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A molecular mechanism mediating clozapine-enhanced sensorimotor gating","authors":"Ioannis Mantas,&nbsp;Ivana Flais,&nbsp;Niclas Branzell,&nbsp;Tudor M. Ionescu,&nbsp;Eugene Kim,&nbsp;Xiaoqun Zhang,&nbsp;Diana Cash,&nbsp;Bastian Hengerer,&nbsp;Per Svenningsson","doi":"10.1038/s41386-025-02060-z","DOIUrl":"10.1038/s41386-025-02060-z","url":null,"abstract":"The atypical antipsychotic clozapine targets multiple receptor systems beyond the dopaminergic pathway and influences prepulse inhibition (PPI), a critical translational measure of sensorimotor gating. Since PPI is modulated by atypical antipsychotics such as risperidone and clozapine, we hypothesized that p11—an adaptor protein associated with anxiety- and depressive-like behaviors and G-protein-coupled receptor function—might modulate these effects. In this study, we assessed the role of p11 in clozapine’s PPI-enhancing effect by testing wild-type and global p11 knockout (KO) mice in response to haloperidol, risperidone, and clozapine. We also performed structural and functional brain imaging. Contrary to our expectation that anxiety-like p11-KO mice would exhibit an augmented startle response and heightened sensitivity to clozapine, PPI tests showed that p11-KO mice were unresponsive to the PPI-enhancing effects of risperidone and clozapine. Imaging revealed distinct regional brain volume differences and reduced hippocampal connectivity in p11-KO mice, with significantly blunted clozapine-induced connectivity changes in the CA1 region. Our findings highlight a novel role for p11 in modulating clozapine’s effects on sensorimotor gating and hippocampal connectivity, offering new insight into its functional pathways.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 5","pages":"721-730"},"PeriodicalIF":6.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02060-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}