Biological Psychiatry最新文献

{"title":"Translational Relevance of the Methylazoxymethanol Acetate Model in Schizophrenia: A Systematic Review of Behavioral and Neurobiological Findings.","authors":"Taeyoung Lee, Kisang Eom, Jin Ju Kim, Yelin Lee, Jung Ho Hyun","doi":"10.1016/j.biopsych.2026.06.029","DOIUrl":"10.1016/j.biopsych.2026.06.029","url":null,"abstract":"<p><p>Schizophrenia is a neurodevelopmental psychiatric disorder whose circuit-level mechanisms remain incompletely understood. Among preclinical platforms, the methylazoxymethanol acetate (MAM) gestational model uniquely recapitulates the developmental, multidomain pathophysiology of schizophrenia, but the literature is fragmented, and prior systematic reviews have been limited to behavioral phenotypes. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) guidelines, we systematically searched PubMed, Embase, and Web of Science for original studies using the gestational MAM model in rats or mice. Findings were synthesized across 5 prespecified domains: behavioral, physiological, histological, genetic, and pharmacological. Of the 53 included studies, evidence converged on a single pathophysiological axis: gestational disruption of the ventral hippocampus (vHP) and medial prefrontal cortex produces parvalbumin interneuron loss, local excitatory/inhibitory imbalance, and vHP-nucleus accumbens-ventral tegmental area circuit hyperactivity, culminating in striatal dopamine excess. This axis maps bidirectionally to human postmortem, neuroimaging, and positron emission tomography evidence. Sex-stratified findings suggest that ovarian hormones modulate downstream circuit readout rather than the upstream cellular insult, accounting for attenuated behavioral phenotypes in female animals despite preserved cellular pathology. The MAM model recapitulates a convergent circuit-level pathophysiology of schizophrenia and is well positioned as a preclinical screening platform for next-generation non-D₂ therapeutics, including the muscarinic, TAAR1 (trace amine-associated receptor 1), and α5-GABA_AR (α5 subunit-containing gamma-aminobutyric acid type A receptor) approaches now entering clinical practice. Methodological harmonization, mixed-sex cohorts, and longitudinal designs will be critical to fully realize this translational potential.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410190","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":"Takeda G Protein-Coupled Receptor 5 Orchestrates Anxiolysis by Enhancing Anterior Paraventricular Thalamic Nucleus Glutamatergic Neuronal Activity to Engage Distinct Downstream Circuits.","authors":"Shanshan Hu, Shuyun Xing, Weijun Huang, Yueying Li, Xinru Tan, Ruizhe Nie, Qilu Zhang, Xinting Zhou, Xian Cao, Danhua Yuan, Hao Hong, Yan Long, Susu Tang","doi":"10.1016/j.biopsych.2026.06.024","DOIUrl":"10.1016/j.biopsych.2026.06.024","url":null,"abstract":"<p><strong>Background: </strong>The pathogenesis of anxiety disorders remains elusive, underscoring the urgent need for novel therapeutic targets. In this study, we investigated the role of TGR5 (Takeda G protein-coupled receptor 5) in anxiety and its underlying molecular and neural circuit mechanisms.</p><p><strong>Methods: </strong>Open field, elevated plus maze, and novelty suppressed feeding tests were used to assess anxiety-like behaviors. Immunofluorescence, Western blot, and RNAscope in situ hybridization were used to characterize TGR5 expression. Adeno-associated virus vectors carrying Cre-dependent double-floxed inverted open-reading frame (DIO) sequence were injected into the anterior paraventricular thalamic nucleus (aPVT) of vGlut2-Cre mice for TGR5 bidirectional modulation. Fiber photometry and chemogenetic manipulations were used to assess neuronal activity along with behaviors. In vitro electrophysiology recordings were used to assess neuronal excitability and I_Ca_v_3.1. Channelrhodopsin-2-assisted circuit mapping was used to explain neural circuits and synaptic mechanisms.</p><p><strong>Results: </strong>Chronic restraint stress (CRS) selectively downregulated TGR5 expression in aPVT glutamatergic neurons. TGR5 overexpression in aPVT glutamatergic neurons alleviated anxiety-like behaviors in CRS mice, while knockdown combined with subthreshold stress exacerbated anxiety phenotypes. Mechanistically, TGR5 activation enhanced aPVT glutamatergic neuronal excitability via the cAMP (cyclic adenosine monophosphate)/PKA (protein kinase A)/Ca_v3.1 pathway. TGR5 activation enhanced presynaptic glutamate release probability in the monosynaptic projection from the aPVT to the medial prefrontal cortex and restored the excitation-inhibition balance in the bed nucleus of the stria terminalis through direct efferent and indirect local circuit modulation under CRS, thereby contributing to emotional homeostasis.</p><p><strong>Conclusions: </strong>Our findings establish TGR5 as a pivotal regulator of anxiety, providing a crucial experimental foundation for novel therapeutics and a deeper understanding of anxiety disorders.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395785","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":"Functional Connectivity of the Orbitofrontal Cortex Predicts Cocaine Relapse: Protective and Risk Circuits, Individual Differences, and Neuromodulation Implications.","authors":"Tianye Zhai, Betty Jo Salmeron, Hong Gu, Sheng Zhang, Bryon Adinoff, Elliot A Stein, Chiang-Shan R Li, Yihong Yang","doi":"10.1016/j.biopsych.2026.06.026","DOIUrl":"10.1016/j.biopsych.2026.06.026","url":null,"abstract":"<p><strong>Background: </strong>Substance use disorder (SUD) remains a significant public health problem as it is highly refractory, with low treatment commitment and high relapse rates. The human orbitofrontal cortex (OFC), a brain region involved in decision making, valuation, and reward processing, has been implicated in multiple neuropsychiatric diseases and is considered one of the potential therapeutic targets for SUD treatment using noninvasive neuromodulation. However, the OFC is a large, heterogeneous brain area, and the precise location within the OFC that could serve as an efficacious stimulation target is unknown. Moreover, exploring all possible loci within the OFC with clinical trials is operationally not feasible.</p><p><strong>Methods: </strong>Using Cox regression-based prediction modeling, we examined resting-state functional connectivity across 20 OFC regions of interest (ROIs) of treated patients with cocaine use disorder. We aimed to identify loci and their functional circuits that predict cocaine relapse, quantified by area under the receiver operating characteristic curve (AUC) with cross-validation in a main cohort and external validation in an independent cohort.</p><p><strong>Results: </strong>We identified 2 left lateral OFC ROIs whose connectivity predicted relapse with high accuracy (cross-validated AUC of 0.896 and externally validated AUC of 0.780). Each ROI exhibited a pair of protective and risk circuits that contributed distinctively toward relapse.</p><p><strong>Conclusions: </strong>The predictive OFC ROIs and their functional circuits identified provide system-level insights into drug relapse, may help reveal specific disease subtypes, and offer potential neuromodulation targets to be tested in future clinical trials.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395756","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":"Distinct and Shared Molecular Mechanisms Underlie Morphological-Functional Overcoupling and Undercoupling in Major Depressive Disorder.","authors":"Huaijin Gao, Yihan Ma, Rui Qian, Tao Jin, Baorong Gu, Bowen Qiu, Shaoyong Ye, Manli Huang, Dan Wu, Zhiyong Zhao","doi":"10.1016/j.biopsych.2026.06.016","DOIUrl":"10.1016/j.biopsych.2026.06.016","url":null,"abstract":"<p><strong>Background: </strong>Major depressive disorder (MDD) exhibits significant heterogeneity in alterations of brain morphology and function; however, the potential neurobiological mechanisms remain elusive. In this study, we aimed to investigate MDD subtypes based on morphological-functional coupling (MFC) and their associations with clinical symptoms and molecular basis.</p><p><strong>Methods: </strong>We used a semisupervised machine learning approach on multicenter neuroimaging data (discovery: 828 patients with MDD/776 healthy control participants; validation: 236 patients with MDD/86 healthy control participants) to identify subtypes based on MFC. Subtypes were characterized clinically and linked to spatial gene expression, neurotransmitter maps, and cell type-specific density. Treatment response was assessed in a longitudinal cohort (n = 33) receiving escitalopram.</p><p><strong>Results: </strong>We identified 2 highly replicable MDD subtypes. Subtype I (overcoupling), with elevated MFC in association cortices, was associated with synaptic transmission pathways and more severe symptoms, especially psychomotor retardation, agitation, and hypochondriasis. In contrast, subtype II (undercoupling), with reduced MFC in primary cortices, was linked to cell cycle-related pathways. Crucially, both subtypes shared common enrichment for astrocyte and oligodendrocyte gene expression and convergent dysregulation in serotonergic and GABAergic (gamma-aminobutyric acidergic) receptor systems. Preliminary longitudinal data suggested that the undercoupling subtype showed a more favorable response to escitalopram, concomitant with a normalization of MFC.</p><p><strong>Conclusions: </strong>Our findings move beyond descriptive subtyping by showing that clinically distinct subtypes of MDD spatially correlate with divergent glial and synaptic molecular signatures. This MFC-based framework provides a neurobiologically informed classification of MDD, linking macroscale brain organization with microscale cellular and molecular features.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148326187","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":"The Role of Monoacylglycerol Lipase in Substance Use: A Systematic Review of Preclinical Studies.","authors":"Bertina Jebanesan, Khadija Brouillette, Caleb J Browne, Isabelle Boileau, Laura M Best","doi":"10.1016/j.biopsych.2026.06.011","DOIUrl":"10.1016/j.biopsych.2026.06.011","url":null,"abstract":"<p><p>Monoacylglycerol lipase (MAGL) is the primary enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), which is a key regulator of endocannabinoid system tone, thereby influencing synaptic function and neuroinflammation. These processes are central to the neurobiology of substance use disorders (SUDs), but the contribution of MAGL to addiction remains fragmented across studies. With growing interest in MAGL as a therapeutic and imaging target, a comprehensive synthesis is timely. In this systematic review, we aimed to evaluate whether exposure to substances of abuse alters MAGL expression or activity and whether manipulating MAGL function affects SUD-relevant outcomes. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, we screened preclinical studies that assessed MAGL directly in the context of substance exposure. A total of 42 studies met the inclusion criteria. Chronic substance exposure led to modest, region-specific changes in MAGL protein expression. In the hippocampus, alcohol increased MAGL levels. In the striatum, levels were largely unchanged across substances. In the prefrontal cortex, changes were only seen after repeated stimulant exposure. Findings for opioids and ketamine were mixed and inconsistent across regions. MAGL inhibition consistently reduced withdrawal-like behaviors across cannabis, opioid, and nicotine models, but effects on reward-related behaviors were more variable, reducing opioid-related reward while showing less consistent effects in other models. Collectively, these findings from preclinical models of SUDs suggest a more robust role for MAGL in withdrawal-like states than in reward. They highlight the need to better understand the dynamic endocannabinoid adaptations, including cannabinoid receptor function and 2-AG signaling, that shape addiction-related behaviors.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315480","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":"Enterochromaffin Cells Drive Anxiety-Like Behaviors in Sleep-Deprived Mice.","authors":"Yifang Zhai, Li Ma, Lixia Zhuo, Feidi Wang, Linjuan Zhang, Jiao Han, Yuhang Qin, Peiyu Luo, Xiaodan Wang, Gengyao Zhou, Yixuan Lyu, Dongqi Cui, Ying Zhang, Jing Wang, Ning Sun, Xiancang Ma, Rongrong Yang, Yan Li","doi":"10.1016/j.biopsych.2026.06.014","DOIUrl":"10.1016/j.biopsych.2026.06.014","url":null,"abstract":"<p><strong>Background: </strong>Sleep deprivation (SD) is a potent trigger of anxiety and poses a substantial threat to mental health. Although accumulating evidence suggests that disrupted intestinal function contributes to abnormal behaviors associated with SD, the specific mechanisms by which gut-derived signals modulate SD-related anxiety remain poorly understood.</p><p><strong>Methods: </strong>Combining behavioral analysis, chemogenetic manipulation, and neuropharmacological approaches in a male mouse model of SD, we investigated the circuit mechanism from colonic enterochromaffin (EC) cells to hippocampal neurogenesis. The involvement of vagal afferent signaling was further probed by pharmacological blockade of 5-HT₃ receptors.</p><p><strong>Results: </strong>We identified colonic EC cells as critical early responders to SD, whose dysfunction temporally precedes the emergence of anxiety phenotypes. Chemogenetic inhibition of EC cells mimicked the behavioral and neurogenic deficits observed after SD. Conversely, chemogenetic activation of EC cells during SD normalized 5-HT levels, rescued hippocampal neurogenesis, and alleviated anxiety-like behaviors. Mechanistically, 5-HT derived from EC cells activated vagal afferents via 5-HT₃ receptors, thereby promoting hippocampal neurogenesis and reducing anxiety-like behaviors.</p><p><strong>Conclusions: </strong>Our findings reveal a key role for colonic EC cells in regulating emotional homeostasis during SD. These results provide novel insights into the mechanisms underlying SD-induced anxiety and highlight potential therapeutic targets for preventing anxiety related to sleep loss.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315369","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":"Antipsychotic Drug Action, Novel Treatment Targets, and the Failure of Current Clinical Trial Designs in Evaluating New Target Molecules.","authors":"Anthony A Grace, Daniela L Uliana","doi":"10.1016/j.biopsych.2026.06.010","DOIUrl":"10.1016/j.biopsych.2026.06.010","url":null,"abstract":"<p><p>The discovery of antipsychotic drugs more than 65 years ago revolutionized the treatment of schizophrenia that was initially based on serendipitous findings with chlorpromazine. This later led to the dopamine (DA) hypothesis, linking hyperdopaminergic states to psychosis. While D₂-based antipsychotics effectively reduce positive symptoms, they fail to address cognitive and negative deficits. Preclinical studies have provided critical insights into schizophrenia pathophysiology and treatment. These studies show that hippocampal hyperactivity and loss of parvalbumin GABAergic (gamma-aminobutyric acidergic) neuron inhibition drive DA system dysregulation, which leads to pathological hyper-responsivity to stimuli. Antipsychotic drugs induce depolarization block in DA neurons that normalizes DA hyperactivity but does not correct upstream hippocampal dysfunction. Preclinical models have also identified potential novel treatments targeting the hippocampal hyperexcitability, including GABA α₅-positive allosteric modulators and evenamide. These compounds may have the ability to restore hippocampal inhibition, normalize positive symptom-related DA activity, and improve cognitive and negative symptoms without D₂-associated side effects. Clinical trial failures of novel agents, such as pomaglumetad, may be a product of prior D₂ antagonist exposure leading to postsynaptic supersensitivity rather than lack of efficacy. This evidence underscores the importance of patient treatment history and the design of trials that account for prior antipsychotic exposure when evaluating new compounds. Targeting upstream pathology in the hippocampus offers a promising approach for developing more effective, side effect-sparing treatments for schizophrenia.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283065","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":"Oral Clonidine and Brimonidine Eye Drops Attenuated Sertraline Discontinuation Symptoms.","authors":"Pierre Blier, Asma Almatrafi, Mostafa El Mansari","doi":"10.1016/j.biopsych.2026.05.009","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.05.009","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275836","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":"Distinctive Molecular Mechanisms in Higher Cortical Circuits Confer Vulnerability to Mental Disorders.","authors":"Min Wang, Veronica C Galvin, Mary Kate P Joyce, Dibyadeep Datta, Shengtao Yang, Anita A Disney, Amy F T Arnsten","doi":"10.1016/j.biopsych.2026.06.008","DOIUrl":"10.1016/j.biopsych.2026.06.008","url":null,"abstract":"<p><p>In this article, we review the molecular differences across the cortical hierarchy in primates that expand in the dorsolateral prefrontal cortex (dlPFC) to generate working memory and top-down control but also confer vulnerability in mental disorders. Research on molecular mechanisms early in the primate cortical hierarchy, e.g., in the primary visual cortex (V1), are often in concert with rodent, e.g., neurotransmission relies greatly on AMPA receptors (AMPARs), while modulation with attention involves NMDA receptors (NMDARs) and cholinergic mechanisms. However, there are also significant differences in cortical specializations and cholinergic receptor localization between the rodent and the primate V1. In contrast to V1, the recurrent excitatory microcircuits in layer III of the primate dlPFC that generate working memory express many distinct mechanisms; neurotransmission depends on NMDARs and acetylcholine (and thus arousal state), not AMPARs; extended neuronal firing underlying working memory depends on magnified calcium signaling in spines; however, excessive cytosolic calcium reduces firing, with powerful mechanisms to take the dlPFC offline during uncontrollable stress and/or inflammation, e.g., opening potassium channels on spines to rapidly weaken connections. Regulation of these powerful mechanisms is lost due to inflammation and/or genetic insults (e.g., gain-of-function mutations in CACNA1C, loss of function in GRM3), which may interact to induce loss of dendritic spines and/or tau pathology, cognitive impairments, and reduced top-down control. Many of the genetic risks for schizophrenia weaken layer III dlPFC spine connections, suggesting that multiple genotypes would produce a shared phenotype. The review also suggests new therapeutic targets that can act to reduce inflammation, regulate calcium, and strengthen synaptic efficacy in the primate dlPFC.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13312603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283107","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":"Sirtuin 2 Regulates Dorsal Hippocampal Actin Polymerization and Microtubule Acetylation-Dependent EB3 Activation to Modulate Opioid Withdrawal-Induced Aversive Memory and Associative Learning.","authors":"Jian-Dong Long, Song-Yu Yao, Wei-Wei Wu, Gui-Ying Zan, Zhi-Wen Wang, Xiang-Yan Wei, Xue-Lian Shu, Ye-Xiang Chen, Yun-Yue Ju, Jing Chen, Jing-Rui Chai, Ru-Feng Ye, Jia-Shuo Lu, Chi Xu, Zhong Chen, Jing-Gen Liu, Yu-Jun Wang","doi":"10.1016/j.biopsych.2026.06.001","DOIUrl":"10.1016/j.biopsych.2026.06.001","url":null,"abstract":"<p><strong>Background: </strong>Aversive memories formed during drug withdrawal can potentiate compulsive drug-seeking behavior. Dynamic rearrangement of the actin cytoskeleton in dendritic spines is crucial for aversive memory formation. We previously discovered that actin polymerization in the dorsal hippocampus plays a key role in this process, but the molecular mechanisms governing this reorganization remain unclear.</p><p><strong>Methods: </strong>Conditioned morphine withdrawal-induced conditioned place aversion behavior in male Sprague Dawley rats was developed to evaluate aversive memory associated with opioid withdrawal. Contextual fear conditioning and appetitive conditioning paradigms were used to assess the behavioral specificity of the identified mechanisms. Western blots and dendritic spine imaging detected actin rearrangement and spine density. Co-immunoprecipitation, genetic manipulation, and pharmacological approaches were used to investigate sirtuin 2 (Sirt 2) and its downstream signaling.</p><p><strong>Results: </strong>We demonstrate that Sirt 2, an NAD⁺-dependent deacetylase, critically regulates dorsal hippocampal actin polymerization and opioid withdrawal-associated aversive memory through modification of microtubules (MTs). Sirt 2-induced tubulin deacetylation triggers EB3 dephosphorylation by promoting translocation of Ca²⁺-dependent phosphatase calcineurin to MTs. This enhances EB3-drebrin interaction, driving actin remodeling through the p140Cap/Src/cortactin/cofilin pathway. Furthermore, pharmacological inhibition of Sirt 2 also attenuated contextual fear conditioning and showed a trend toward reducing appetitive conditioning, indicating a shared role across multiple memory processes.</p><p><strong>Conclusions: </strong>The current study elucidates the molecular mechanisms by which Sirt 2 regulates dorsal hippocampal actin dynamics and drives opioid withdrawal memory and associative learning. Our findings reveal a broader role for Sirt 2 in multiple forms of associative memory, offering potential therapeutic insights for withdrawal-induced compulsive behaviors and other memory-related disorders.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238735","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}