Neuropsychopharmacology最新文献

{"title":"Early-life adversity alters adult nucleus incertus neurons: implications for neuronal mechanisms of increased stress and compulsive behavior vulnerability.","authors":"Anna Gugula, Patryk Sambak, Aleksandra Trenk, Sylwia Drabik, Aleksandra Nogaj, Zbigniew Soltys, Andrew L Gundlach, Anna Blasiak","doi":"10.1038/s41386-025-02089-0","DOIUrl":"https://doi.org/10.1038/s41386-025-02089-0","url":null,"abstract":"<p><p>Early-life stress (ELS) arising from physical and emotional abuse disrupts normal brain development and impairs hypothalamic-pituitary-adrenal axis function, increasing the risk of psychopathological disorders and compulsive behaviors in adulthood. However, the underlying neural mechanisms remain unclear. The brainstem nucleus incertus (NI) is a highly stress-sensitive locus, involved in behavioral activation and stress-induced reward (food/alcohol) seeking, but its sensitivity to ELS remains unexplored. We used neonatal maternal separation stress in rats as a model for ELS and examined its impact on stress-related mRNA and neuropeptide expression in the NI, using fluorescent in situ hybridization and immunohistochemistry, respectively. Using whole-cell, patch-clamp recordings we determined the influence of ELS on the synaptic activity, excitability, and electrophysiological properties of NI neurons. Using c-Fos protein expression we also assessed the impact of ELS on the sensitivity of NI neurons to acute restraint stress in adulthood. ELS weakened the acute stress responsiveness of NI neurons, and caused dendritic shrinkage, impaired synaptic transmission and altered electrophysiological properties of NI neurons in a cell-type-specific manner. Additionally, ELS increased the expression of mRNA encoding corticotropin-releasing hormone receptor type 1 and the nerve-growth factor receptor, TrkA in adult NI. The multiple, cell-type specific changes in the expression of neuropeptides and molecules associated with stress and substance abuse in the NI, as well as impairments in NI neuron morphology and electrophysiology caused by ELS and observed in the adult brain, may contribute to the increased susceptibility to stress and compulsive behaviors observed in individuals with a history of ELS.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670199","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":"Central Med23 deficiency leads to malformation of dentate gyrus and ADHD-like behaviors in mice.","authors":"Bing-Yao Zhou, Ze-Xuan Li, Yi-Wei Li, Jin-Nan Li, Wei-Tang Liu, Xi-Yue Liu, Zhi-Bin Hu, Li Zhao, Jia-Yin Chen, Ling Hu, Ning-Ning Song, Xue Feng, Gang Wang, Lin Xu, Yu-Qiang Ding","doi":"10.1038/s41386-025-02088-1","DOIUrl":"https://doi.org/10.1038/s41386-025-02088-1","url":null,"abstract":"<p><p>Attention-deficit hyperactivity disorder (ADHD) is a prevalent psychiatric disorder with high heritability, while its etiology and pathophysiology remain unclear. Med23 is a subunit of the Mediator complex, a key regulator of gene expression by linking transcription factors to RNA polymerase II. The mutations of Med23 are associated with several brain diseases including microcephaly, epilepsy and intellectual disability, but its biological roles in brain development and possible behavioral consequence have not been explored in the animal model. In this study, Emx1-Cre mice were used to generate Med23 conditional knockout (Med23 CKO) mice that showed severe hypoplasia of the dentate gyrus (DG) with malformation of the dendritic tree and spines along with impaired short-term synaptic plasticity. Interestingly, Med23 CKO mice exhibited ADHD-like behaviors as shown by hyperactivity, inattention and impulsivity, as well as impaired sensory gating and working memory. Importantly, methylphenidate (MPH), a common drug for ADHD ameliorated these deficits in the CKO mice. Furthermore, we also revealed that the impaired synaptic plasticity was partially restored by MPH in an N-methyl-d-aspartate (NMDA) receptor-dependent way. Collectively, our data demonstrate Med23 deficiency causes DG malformation and ADHD-like behaviors, suggesting a novel mechanism underlying relevant brain diseases.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670198","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":"Preregistered multi-site preclinical randomized controlled trials: the beginning of a new day in reverse translational science?","authors":"Lorenzo Leggio, Giancarlo Colombo","doi":"10.1038/s41386-025-02090-7","DOIUrl":"https://doi.org/10.1038/s41386-025-02090-7","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670200","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":"Correction: Neuropsychopharmacology Volume 50 Issue 1.","authors":"","doi":"10.1038/s41386-025-02087-2","DOIUrl":"https://doi.org/10.1038/s41386-025-02087-2","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663948","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":"Grey matter morphometry in young adult e-cigarette users, tobacco cigarette users & non-using controls.","authors":"Kanwar Boparai, Hsiang-Yuan Lin, Peter Selby, Laurie Zawertailo","doi":"10.1038/s41386-025-02086-3","DOIUrl":"https://doi.org/10.1038/s41386-025-02086-3","url":null,"abstract":"<p><p>Despite the rise in electronic cigarette use in recent years, the neurobiological effects of daily e-cigarette use versus smoking cigarettes in young adults remains unknown. This study aimed to investigate the impact of regular, exclusive e-cigarette use on grey matter morphometry in young adults, age 18-25. Structural MRI data were collected from 3 distinct groups of participants (n = 78): daily, exclusive e-cigarette users; tobacco cigarette users; and non-using controls, to assess grey matter volume (GMV) differences. Voxel-based morphometry revealed significant GMV reductions in tobacco cigarette users in the left fusiform gyrus (FG), left and right inferior temporal gyrus (IFG), right middle temporal gyri, and right middle cingulate gyrus (MCG), compared to controls, as well as the anterior cingulate cortex (ACC), compared to both e-cigarette users and controls, even after adjusting for nicotine exposure history. Partial correlation analyses revealed that in tobacco cigarette users, GMV in the FG, ITG, MTG, and MCG displayed a strong, negative association with exposure history but not with nicotine dependence. GMV of the ACC was not associated with duration of use or nicotine dependence score, suggesting distinct relationships between ACC volume and smoking status and FG/ITG/MTG/MCG volume and smoking status. This indicates a distinct difference between regular tobacco cigarette and e-cigarette use, perhaps a relatively safer profile of e-cigarette use on GMV. These findings suggest that factors beyond nicotine, such as other toxicants in tobacco cigarette smoke, may contribute to the observed brain atrophy, or imply potential pre-existing vulnerabilities that might predispose individuals to take up smoking.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657878","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 sex in the association between cannabis use disorder and resting-state functional connectivity.","authors":"Janna Cousijn, Yara J Toenders, Anne Marije Kaag, Francesca Filbey, Emese Kroon","doi":"10.1038/s41386-025-02078-3","DOIUrl":"https://doi.org/10.1038/s41386-025-02078-3","url":null,"abstract":"<p><p>While Cannabis use disorder (CUD) is twice as prevalent in males, females transition more quickly from heavy use to CUD and experience more severe withdrawal. These clinically relevant sex differences contrast the lack of knowledge about the underlying brain mechanisms. This study investigated the relationship between CUD and resting-state functional brain connectivity (RSFC), assessing potential sex differences herein. RSFC of the Salience Network (SN), Basal Ganglia Network (BGN), Executive Control Network (ECN), and Default Mode Network (DMN) was compared between 152 individuals (76 males) with CUD and 114 matched controls (47 males). Within the CUD group, relationships between RSFC and heaviness of cannabis use, age of onset, and CUD symptom severity, along with their associations with sex, were investigated. CUD and control groups showed similar RSFC across all networks, regardless of sex. In the CUD group, heavier cannabis use correlated with higher RSFC across all networks and earlier age of onset was related to higher RSFC in the anterior SN, BGN, left ECN, and dorsal DMN. These associations were similar for males and females. CUD severity was related to higher RSFC in the anterior SN, which was moderated by sex, with a positive association seen only in males. In conclusion, CUD may not necessarily be associated with altered RSFC. Individual use characteristics such age of onset and severity of use may determine the potential impact of cannabis use on RSFC in a largely similar way in males and females.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657879","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":"DRN-SNc serotonergic circuit drives stress-induced motor deficits and Parkinson's disease vulnerability.","authors":"Yibo Yao, Chi Cui, Yulong Shi, Jie Lei, Tongxia Li, Ming Li, Xiang Peng, Xueke Yang, Kun Ren, Jian Yang, Gangan Luo, Junsong Du, Sitong Chen, Pei Zhang, Bo Tian","doi":"10.1038/s41386-025-02080-9","DOIUrl":"https://doi.org/10.1038/s41386-025-02080-9","url":null,"abstract":"<p><p>Stress is a recognized risk factor for Parkinson's disease (PD), but the mechanisms by which stress exacerbates PD symptoms through the serotonergic system are not fully understood. This study investigates the role of serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) in mediating stress-induced motor deficits and PD progression. Acute and chronic stress were induced in mice using an elevated platform (EP) and combined with MPTP administration to model early-stage PD. Acute EP stress caused transient motor deficits and significant activation of DRN^5-HT neurons projecting to substantia nigra compacta (SNc) dopaminergic (DA) neurons. Manipulating the DRN-SNc pathway with optogenetics and chemogenetics confirmed its critical role in stress-induced motor deficits. Activation of the SNc 5-HT2C receptor with an agonist replicated these deficits, while receptor inhibition prevented them, underscoring its importance. Chronic EP stress worsened MPTP-induced deficits and caused significant SNc^DA neurons loss, suggesting it accelerates PD progression. Prolonged chemogenetic inhibition of the DRN-SNc circuit mitigated chronic stress effects in MPTP-treated mice. These findings highlight the crucial role of the DRN-SNc serotonergic circuit and 5-HT2C receptors in stress-related motor deficits, suggesting potential targets for therapies aimed at treating both stress-related motor disorders and Parkinson's disease.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648196","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":"Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity.","authors":"Kyle A Brown, Musa I Ajibola, Todd D Gould","doi":"10.1038/s41386-025-02085-4","DOIUrl":"https://doi.org/10.1038/s41386-025-02085-4","url":null,"abstract":"<p><p>The pharmacologically active (R,S)-ketamine (ketamine) metabolite (2 R,6 R)-hydroxynorketamine (HNK) maintains ketamine's preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination. To distinguish the physiological mechanisms involved in the rapid from sustained actions of HNK, we utilized extracellular electrophysiology combined with pharmacology to develop an in vitro hippocampal slice incubation model that exhibited pharmacological fidelity to the 1) rapid synaptic potentiation induced by HNK at the Schaffer collateral-CA1 (SC-CA1) synapse during bath-application to slices collected from mice, and 2) maintenance of metaplastic (priming) activity that enhanced N-methyl-D-aspartate receptor (NMDAR) activation-dependent long-term potentiation (LTP) hours after in vivo dosing. We used this model to reveal novel mechanisms engaged in HNK's temporally-sensitive antidepressant-relevant synaptic actions, finding that the induction of synaptic potentiation by HNK did not require NMDAR activity, but NMDAR activity was necessary to maintain synaptic priming. HNK required protein kinase A (PKA) activity to rapidly potentiate SC-CA1 neurotransmission to facilitate synaptic priming that persistently promoted LTP formation. HNK's rapid actions were blocked by inhibitors of adenylyl cyclase 1 (AC1), but not an AC5 inhibitor. We conclude that HNK rapidly potentiates SC-CA1 synaptic efficacy, which then stimulates priming mechanisms that persistently favor plasticity. Targeting such priming mechanisms may be an effective antidepressant strategy, and our incubation model may aid in revealing novel pharmacological targets.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648197","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":"Lateral habenula induces cognitive and affective dysfunctions in mice with neuropathic pain via an indirect pathway to the ventral tegmental area.","authors":"Yue-Ying Liu, Ke Wu, Yu-Ting Dong, Ru Jia, Xing-Han Chen, An-Yu Ge, Jun-Li Cao, Yong-Mei Zhang","doi":"10.1038/s41386-025-02084-5","DOIUrl":"10.1038/s41386-025-02084-5","url":null,"abstract":"<p><p>Neuropathic pain, which has become a major public health concern, is frequently accompanied by the deterioration of affective behavior and cognitive function. However, the brain circuitry underlying these changes is poorly understood. Therefore, we aimed to identify in a mouse model the converging circuit that influences the sensory, affective, and cognitive consequences of neuropathic pain. The lateral habenula (LHb) and ventral tegmental area (VTA) have been confirmed to play critical roles in the regulation of pain, cognition, and depression. Given the essential role of the LHb in depression and cognition, we attempted to clarify how neural circuitry involving the LHb integrates pain-related information. Our data confirmed that the VTA receives projections from the LHb, but our results suggest that inhibition of this direct pathway has no effect on the behavior of mice with chronic neuropathic pain. The rostromedial tegmental nucleus (RMTg), a GABAergic structure believed to underlie the transient inhibition of DAergic neurons in the VTA, received glutamatergic inputs from the LHb and projected strongly to the VTA. Furthermore, our data suggest that a projection from LHb glutamatergic neurons to RMTg GABAergic neurons in the VTA, constituting an indirect LHb^Glu → RMTg^GABA → VTA^DA pathway, participates in peripheral nerve injury-induced nociceptive hypersensitivity, depressive-like behavior, and cognitive dysfunction. Ex vivo extracellular recordings of LHb neurons showed that the proportion of burst-firing cells in the LHb was significantly increased in indirect projections rather than in direct projections. This may explain the functional discrepancies between direct and indirect projections of the LHb to the VTA. Collectively, our study identifies a pivotal role of the LHb^Glu → RMTg^GABA → VTA^DA pathway in processing pain. This pathway may offer new therapeutic targets to treat neuropathic pain and its associated depressive-like and cognitive impairments.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634361","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":"Brain reactivity to nicotine cues mediates the link between resting-state connectivity and cue-induced craving in individuals who smoke or vape nicotine.","authors":"Laura Murray, Maria K Scavnicky, Cole Korponay, Scott E Lukas, Blaise B Frederick, Amy C Janes","doi":"10.1038/s41386-025-02083-6","DOIUrl":"https://doi.org/10.1038/s41386-025-02083-6","url":null,"abstract":"<p><p>Individual differences in brain intrinsic functional connectivity (FC) and reactivity to nicotine cues are linked to variability in clinical outcomes in nicotine dependence. However, the relative contributions and potential interdependencies of these brain imaging-derived phenotypes in the context of craving and nicotine dependence are unclear. Moreover, it is unknown whether these relationships differ in individuals who smoke versus vape nicotine. To investigate these questions, eighty-six individuals who use nicotine daily (n = 67 smoking, n = 19 vaping) completed either a smoking or vaping cue-reactivity task and a resting-state scan during functional magnetic resonance imaging (fMRI). Validating the efficacy of the smoking and vaping tasks, both cohorts displayed robust reactivity to nicotine versus neutral cues in the default mode network (DMN) and the anterior insula (AI), a primary node of the salience network (SN), which did not habituate over time. In the smoking and vaping groups, lower prefrontal reactivity to nicotine versus neutral cues and greater resting-state FC between nodes of the SN and DMN were associated with higher cue-induced craving. Moreover, we found that the former partially mediated the latter, suggesting a mechanism in which high resting SN-DMN connectivity increases craving susceptibility partly via a constraining effect on regulatory prefrontal reactivity to cues. These relationships were not impacted by group, suggesting that links between brain function and craving are similar regardless of smoking or vaping nicotine.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625474","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}