Molecular Psychiatry最新文献

{"title":"Crosstalk between alcohol use disorder and obesity: two sides of the same coin?","authors":"Lorenzo Leggio, Mehdi Farokhnia, Paul J Kenny, Marta Yanina Pepino, W Kyle Simmons","doi":"10.1038/s41380-025-03259-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03259-8","url":null,"abstract":"<p><p>Investigating similarities and differences between alcohol use disorder (AUD) and obesity is important because both AUD and obesity are public health concerns and share neurobiological and periphery-brain mechanisms. Furthermore, AUD and obesity often present with similar medical consequences related to organ damage, including liver and cardiovascular diseases. There is also growing evidence of changes in alcohol drinking in people who undergo bariatric surgery for obesity. In this non-systematic critical review, we identified relevant articles through PubMed searches, previous knowledge, and recursive reference searching. A librarian also used PubMed and Google Scholar for additional relevant articles, using terms such as alcohol, metabolic disorders, obesity, glucagon-like peptide-1 (GLP-1), bariatric surgery, and gut-brain axis. We provide an overview of the neurobiological, pathophysiological, neuroimaging, and clinical features related to the overlap and crosstalk between AUD and obesity. We also provide a summary of the currently approved medications for obesity and those for AUD and note the potential for some of these medications to work for both disorders. Specific to the latter point, we place emphasis on GLP-1 therapies, given their recent approval for weight loss and the growing evidence suggesting their potential efficacy for AUD and other addictions. We further review studies of the relationship between bariatric surgery and AUD and discuss potential mechanisms and future directions. In summary, studying the overlap between obesity and AUD may shed light on the mechanisms underlying the development and maintenance of both diseases. This knowledge, in turn, may help identify new therapeutic targets for AUD, and possibly comorbid obesity and/or other metabolic disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182239","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":"Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage.","authors":"Nadine Huber, Tomi Hietanen, Sami Heikkinen, Anastasia Shakirzyanova, Dorit Hoffmann, Hannah Rostalski, Ashutosh Dhingra, Salvador Rodriguez-Nieto, Sari Kärkkäinen, Marja Koskuvi, Eila Korhonen, Päivi Hartikainen, Katri Pylkäs, Johanna Krüger, Tarja Malm, Mari Takalo, Mikko Hiltunen, Jari Koistinaho, Anne M Portaankorva, Eino Solje, Annakaisa Haapasalo","doi":"10.1038/s41380-025-03272-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03272-x","url":null,"abstract":"<p><p>Frontotemporal dementia (FTD) is the second most common cause of dementia in patients under 65 years, characterized by diverse clinical symptoms, neuropathologies, and genetic background. Synaptic dysfunction is suggested to play a major role in FTD pathogenesis. Disturbances in the synaptic function can also be associated with the C9orf72 repeat expansion (C9-HRE), the most common genetic mutation causing FTD. C9-HRE leads to distinct pathological hallmarks, such as C9orf72 haploinsufficiency and development of toxic RNA foci and dipeptide repeat proteins (DPRs). FTD patient brains, including those carrying the C9-HRE, are also characterized by neuropathologies involving accumulation of TDP-43 and p62/SQSTM1 proteins. This study utilized induced pluripotent stem cell (iPSC)-derived cortical neurons from C9-HRE-carrying or sporadic FTD patients and healthy control individuals. We report that the iPSC neurons derived from C9-HRE carriers developed typical C9-HRE-associated hallmarks, including RNA foci and DPR accumulation. All FTD neurons demonstrated increased cytosolic accumulation of TDP-43 and p62/SQSTM1 and changes in nuclear size and morphology. In addition, the FTD neurons displayed reduced number and altered morphologies of dendritic spines and significantly altered synaptic function indicated by a decreased response to stimulation with GABA. These structural and functional synaptic disturbances were accompanied by upregulated gene expression in the FTD neurons related to synaptic function, including synaptic signaling, glutamatergic transmission, and pre- and postsynaptic membrane, as compared to control neurons. Pathways involved in DNA repair were significantly downregulated in FTD neurons. Only one gene, NUPR2, potentially involved in DNA damage response, was differentially expressed between the sporadic and C9-HRE-carrying FTD neurons. Our results show that the iPSC neurons from FTD patients recapitulate pathological changes of the FTD brain and strongly support the hypothesis of synaptic dysfunction as a crucial contributor to disease pathogenesis in FTD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176762","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":"Maternal psychiatric disorders before, during, and after pregnancy: a national cohort study in Sweden.","authors":"Emma Bränn, Jerry Guintivano, Yihui Yang, Louise Lundborg, Marion Opatowski, Fang Fang, Unnur A Valdimarsdóttir, Emma Fransson, Alkistis Skalkidou, Yi Lu, Donghao Lu","doi":"10.1038/s41380-025-03212-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03212-9","url":null,"abstract":"<p><p>Maternal mental health is a critical public health issue, yet the evidence on rates of incident psychiatric disorders before, during, and after pregnancy is limited. This study aimed to describe the calendar time trends and characterize and compare the risk of maternal psychiatric disorders before, during, and after pregnancy. Leveraging the national and regional registers in Sweden, we conducted a cohort study of all women who gave birth 2003-2019 in Sweden (1,799,010 pregnancies from 1,052,977 women). We identified any incident diagnosis of psychiatric disorders recorded during three periods: the preconceptional year, pregnancy, and the postpartum year. We calculated age and calendar year standardized incidence rate (SIR) of psychiatric disorders annually, and by week across three periods. We further estimated the incidence rate ratio (IRR) using the rate during corresponding preconceptional weeks as the reference. The SIR of maternal psychiatric disorder overall increased from 2003-2019, especially for preconceptional disorders. During the preconceptional year the weekly SIR of any psychiatric disorder was stable at around 25 per 1000 person-years. The SIR gradually decreased during pregnancy to a minimum of 4 per 1000 person-years and bounced back to the preconceptional levels during the postpartum year. This trend was similar in all subtypes of psychiatric disorders, except for depression and psychosis for which an increase was noted at 5-15 and 0-20 postpartum weeks, respectively. An increased incidence rate of maternal psychiatric disorder diagnosed before, during, and after pregnancy was found over time. Our findings suggest an increased risk of depression and psychosis shortly after delivery, although a lowered risk of other psychiatric disorders during and after pregnancy, compared to before pregnancy.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138087","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":"Defining suicidality phenotypes for genetic studies: perspectives of the Psychiatric Genomics Consortium Suicide Working Group.","authors":"Sarah M C Colbert, Eric T Monson, Ole A Andreassen, Olatunde O Ayinde, Peter B Barr, Cosmin A Bejan, Zuriel Ceja, Hilary Coon, Emily DiBlasi, Howard J Edenberg, Joel Gelernter, Alexander Hatoum, Anastasia Izotova, Emma C Johnson, Erin A Kaufman, Henry R Kranzler, Maria Koromina, Kelli Lehto, Woojae Myung, John I Nurnberger, Alessandro Serretti, Jordan W Smoller, Murray B Stein, Clement C Zai, Annette Erlangsen, Marie Gaine, Lourdes Martorell, Reeteka Sud, Claudio Toma, Tim B Bigdeli, Nathan A Kimbrel, Douglas Ruderfer, Anna R Docherty, J John Mann, Niamh Mullins","doi":"10.1038/s41380-025-03271-y","DOIUrl":"10.1038/s41380-025-03271-y","url":null,"abstract":"<p><p>Suicidality phenotypes, consisting of suicidal ideation (SI), suicide attempt (SA), and suicide death (SD), are all heritable but present unique challenges in genome-wide association studies (GWAS) due to their individual complexity, overlap with each other and with related self-harm phenotypes, and varying associations with psychiatric disorders. GWAS have uncovered several loci associated with suicidality phenotypes by meta-analyzing data from multiple cohorts. However, combining datasets from many research groups, where each group may use different study designs, phenotyping instruments, and definitions of suicidality phenotypes, presents challenges. Heterogeneity resulting from these differences can limit genetic discovery; harmonizing phenotype definitions to ensure consistency will greatly improve results. Here, we describe a standardized phenotyping protocol that draws on the expertise of a subgroup of clinicians, researchers, and experts from the Psychiatric Genomics Consortium Suicide Working Group to propose consensus definitions for SI, SA, and SD for genetic studies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150187","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":"Increased expression of ATase1/NAT8B or ATase2/NAT8 in the mouse results in an autistic-like phenotype with altered dendritic branching and spine formation.","authors":"Balagangadharan Kalimuthu, Haiyan Lu, Angelique Steenhagen, Qiping Dong, Mitchell Gray, Michael J Rigby, Andreas Endresen, Qiang Chang, Lingjun Li, Luigi Puglielli","doi":"10.1038/s41380-025-03228-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03228-1","url":null,"abstract":"<p><p>Neurons heavily depend on the ability of the secretory pathway to deliver correctly folded polypeptides to the periphery of the cell for the assembly, maintenance, and normal functioning of synapses. The endoplasmic reticulum (ER) acetylation machinery has emerged as a novel branch of the more general ER quality control machinery. It regulates the positive selection of correctly folded nascent glycoproteins, thus ensuring the efficiency of the conventional secretory pathway. ER acetylation requires the activity of two ER-luminal acetylCoA:lysine acetyltransferases, ATase1/NAT8B and ATase2/NAT8. Both acetyltransferases depend on the influx of acetyl-CoA into the ER from the cytosol, which is ensured by the coordinated action of the citrate transporters, SLC25A1 and SLC13A5, and the ER acetyl-CoA transporter, AT-1. Gene duplication events affecting ATase1 and ATase2 are associated with rare disease phenotypes that include autism and intellectual disability with dysmorphism. Here, we generated mice with neuron-specific overexpression of human ATase1 or ATase2. The animals display autistic-like behaviors with altered synaptic plasticity, altered neuronal morphology, and altered synaptic structure and function. Mechanistic assessment demonstrates that widespread proteomic changes and altered dynamics of the secretory pathway underly the synaptic defects. The phenotype of ATase1 and ATase2 overexpressing mice is reminiscent of SLC25A1, SLC13A5 and AT-1 overexpressing models. Therefore, when taken together, our results support the argument that the intracellular citrate/acetyl-CoA pathway, with the ATases acting as the last output, is immediately connected to the pathogenesis of certain rare forms of autism spectrum disorder.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138052","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 alpha7 nicotinic acetylcholine receptor mediates network dysfunction in a mouse model of local amyloid pathology.","authors":"Fani Koukouli, Chun-Lei Zhang, Ivan Lazarevich, Marie Rooy, Boris Lamotte d'Incamps, Daniela Gaspar Santos, Stéphanie Pons, Jérémy Peixoto, Camille Thiberge, Ifigeneia Nikolakopoulou, Jean-Pierre Changeux, Alberto Bacci, Boris S Gutkin, Christoph Schmidt-Hieber, Uwe Maskos","doi":"10.1038/s41380-025-03241-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03241-4","url":null,"abstract":"<p><p>Patient and animal model data suggest a link between the cholinergic neuromodulatory system and the amyloid beta (Aβ) peptide in causing Alzheimer's disease (AD). But how cholinergic dysfunctions contribute to AD pathology remains controversial. In a mouse model of local amyloid pathology, we show that in the early disease stages, the α7 nicotinic acetylcholine receptor (nAChR) is an important target of Aβ in the prefrontal cortex (PFC). Using in vivo two-photon calcium imaging and in vivo patch-clamp electrophysiology in the PFC of awake mice, we demonstrate that Aβ-mediated disruption of specifically the α7 nAChR subunit, expressed by distinct interneuron subtypes, results in substantial deficits in network activity. This is corroborated by electrophysiology experiments in slices. Combined with computational modeling, we propose that α7 nAChRs are occluded by Aβ early in the disease, whereas the heteropentameric α5 and β2 nAChRs are only partially inactivated and potentially provide novel therapeutic targets for intervention. Accordingly, we show that galantamine, an approved acetylcholine-esterase inhibitor (AChE-I), which acts as a positive allosteric modulator (PAM) of α5-containing nAChRs at low concentrations, reduces neuronal hyperactivity.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131558","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":"Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa.","authors":"Zheng-An Lu, Alexander Ploner, Andreas Birgegård, Mikael Landén, Cynthia M Bulik, Sarah E Bergen","doi":"10.1038/s41380-025-03264-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03264-x","url":null,"abstract":"<p><p>Anorexia nervosa (AN) has extensive genetic correlations with other psychiatric disorders, and genetic risk for different psychiatric disorders was associated with distinct clinical courses in AN. Uncovering associations between transdiagnostic psychiatric genetic liability and AN outcomes can facilitate its personalized treatment. In this study, we investigated the associations between transdiagnostic psychiatric genetic liability and outcomes of AN. Genomic structural equation models were fitted to genome-wide association data for AN and psychiatric disorders with high genetic correlations with AN (obsessive-compulsive symptoms [OCS], major depressive disorder [MDD], schizophrenia, and anxiety disorders) to extract one shared and five trait-specific genetic components. Next, we calculated the polygenic risk scores (PRS) for these components, including PRS_shared, PRS_AN-specific, PRS_OCS-specific, PRS_MDD-specific, PRS_SCZ-specific and PRS_ANX-specific, which index the shared genetic liability to all five psychiatric traits, and genetic liability specific to AN, OCS, MDD, SCZ and ANX, respectively. We then tested associations between these PRSs and clinical outcomes reported between 1997 and 2018 among AN cases from the Anorexia Nervosa Genetics Initiative (ANGI), linked to Swedish National Registers. The clinical outcomes included cumulative disease burden (i.e., number of diagnoses, medication prescriptions, and inpatient days), risks of psychiatric comorbidities, and AN symptomatology. Among 4028 included AN cases, the mean (SD) birth year was 1985 (9), and 3947 (98.0%) were female. Within AN, +1 SD increase of PRS_shared was associated with 9-39% excess risk of disease burden and psychiatric comorbidity, whereas the associations between PRS_AN-specific and most clinical outcomes were statistically non-significant. +1 SD increase of PRS_MDD-specific was associated with 3-29% increased risk of AN disease burden. Our findings show that shared psychiatric liability is associated with more adverse AN outcomes, whereas AN-specific liability is not a good indicator for its clinical course. This study provides a novel perspective on factors influencing heterogeneity in AN clinical course.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125187","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":"Mapping symptom-general and symptom-specific targets for transcranial magnetic stimulation in schizophrenia: an electric-field modeling meta-analysis.","authors":"Lorina Sinanaj, Konstantinos Pallis, Anahita Fazel Dehkordi, Philippe Huguelet, Stefan Kaiser, Indrit Bègue","doi":"10.1038/s41380-025-03238-z","DOIUrl":"https://doi.org/10.1038/s41380-025-03238-z","url":null,"abstract":"<p><p>Negative, positive, and cognitive symptoms of schizophrenia relate to disruptions in partially distinct brain circuits. Although promising, transcranial magnetic stimulation (TMS) strategies across and within symptom domains remain to be established due to TMS protocol heterogeneity. For this, we combined standard meta-analysis with electric field (E-field) modeling to identify stimulation sites where E-field strength was associated most significantly with clinical improvement. Standard meta-analysis of randomized, sham-controlled studies in 4283 patients demonstrated the benefit of TMS across symptom domains, regardless of target or protocol. TMS significantly improved negative and cognitive symptoms with high-frequency stimulation applied to the left prefrontal cortex, whereas positive symptoms improved with low-frequency TMS applied to the left temporoparietal cortex. In-depth examination of these results with E-field modeling identified stimulation of the left dorsomedial prefrontal cortex (L-DMPFC), left orbitofrontal cortex (L-OFC), and left cerebellar crus II and right lobule IX to be significantly associated with improvement across all symptom domains. Greater overlap of studies' stimulation targets with L-DMPFC and L-OFC related to improved outcomes. For negative symptoms, E-field distribution in L-DMPFC and L-OFC related most significantly to clinical improvement. Greater proximity to L-DMPFC stimulation site indicated better outcomes, with trend-level significance for L-OFC. In the cognitive domain, E-field distribution in the left dorsolateral prefrontal cortex was related to clinical improvement. Finally, the strongest E-field association with clinical improvement was found in the right cerebellar lobules VIIIA, VIIIB, and IX for positive symptoms. These results support symptom-general and symptom-specific TMS approaches for distinct therapeutic goals towards personalized neuromodulation in schizophrenia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125279","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":"Lineage specification into GABAergic, glutamatergic, dopaminergic, and astrocytic phenotypes using MUSE stem cells: a novel approach for modeling neurodegenerative and psychiatric disorders.","authors":"Domenico Aprile, Deanira Patrone, Sura Hilal Ahmed Al Sammarraie, Nicola Alessio, Gianfranco Peluso, Giovanni Di Bernardo, Umberto Galderisi","doi":"10.1038/s41380-025-03251-2","DOIUrl":"https://doi.org/10.1038/s41380-025-03251-2","url":null,"abstract":"<p><p>The study of neurodegenerative and psychiatric disorders is often hampered by the limited accessibility of relevant neural tissues and the limitations of existing in vitro models. MUSE cells (Multilineage differentiating stress enduring), which are non-tumorigenic and stress-resistant stem cells, offer a robust alternative to traditional models such as induced pluripotent stem cells (iPSCs), which suffer from genetic variability and residual epigenetic memory. Possessing key pluripotency markers such as NANOG, OCT3/4, and SOX2, and capable of differentiating into all three germ layers, MUSE cells are ideally suited for both research and therapeutic applications. In this study, we have developed protocols for differentiating MUSE cells into neural progenitors, providing a critical foundation for modeling early neural development and dysfunction. These neural progenitors were then directed to specify into GABAergic, glutamatergic, dopaminergic neurons, and astrocytes, enabling detailed studies of specific lineage dysfunctions associated with neurodegenerative and psychiatric conditions such as schizophrenia, bipolar disorder, and Alzheimer's disease. This approach not only enhances the physiological relevance of our models but also allows us to investigate the cellular mechanisms underlying these complex diseases more effectively. By improving our understanding of neural lineage specification and early developmental alterations, MUSE cells facilitate the development of targeted therapies and reduce reliance on animal models, thus advancing the path from research to clinical applications.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125332","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":"CB₁ receptors on a subset of vagal afferent neurons modulate voluntary ethanol intake in mice.","authors":"Alexa Herrerias, Anna Oliverio, Szabolcs Dvorácskó, Arthi Thyagarajan, Lee Chedester, Jie Liu, Resat Cinar, Malliga R Iyer, George Kunos, Grzegorz Godlewski","doi":"10.1038/s41380-025-03266-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03266-9","url":null,"abstract":"<p><p>Gut-brain signaling influences alcohol consumption and addiction behaviors. We found that selectively deleting cannabinoid receptor 1 (CB₁R) from advillin⁺ peripheral sensory neurons eliminates the inhibitory effect of the peripheral CB₁R antagonist JD5037 on voluntary ethanol intake (VEI). Similar results were seen in mice with CB₁R deletion in Phox2b⁺ nodose ganglia (NGA), but not in Wnt⁺ dorsal root ganglia. These findings were corroborated with MRI-1891, another non-brain penetrant CB₁R antagonist. The inhibition of VEI by JD5037 was lost in Gpr65^Cre;Cnr1^lox/lox mice but remained intact in Glp1r^Cre;Cnr1^lox/lox mice. Additionally, deleting the ghrelin receptor (Ghsr) from Phox2b⁺ NGA neurons blocked the inhibition of alcohol intake either by a Ghsr or by CB₁R antagonists. Thus, CB₁R on Gpr65⁺ NGA projections to the mucosa of the gastrointestinal tract is essential for VEI. These findings also suggest a mutual interdependence of endocannabinoid and ghrelin signaling in controlling VEI via a gut-brain axis.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102940","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}