Molecular Psychiatry最新文献

{"title":"Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay","authors":"Senwei Tan, Qiumeng Zhang, Rui Zhan, Si Luo, Yaoling Han, Bin Yu, Candace Muss, Veronique Pingault, Sandrine Marlin, Andrée Delahaye, Sophia Peters, Claudia Perne, Martina Kreiß, Nino Spataro, Juan Pablo Trujillo-Quintero, Caroline Racine, Frederic Tran-Mau-Them, Chanika Phornphutkul, Aaron D. Besterman, Julian Martinez, Xiuxia Wang, Xiaoyu Tian, Siddharth Srivastava, David K. Urion, Jill A. Madden, Hind Al Saif, Michelle M. Morrow, Amber Begtrup, Xing Li, Sarah Jurgensmeyer, Peter Leahy, Shimin Zhou, Faxiang Li, Zhengmao Hu, Jieqiong Tan, Kun Xia, Hui Guo","doi":"10.1038/s41380-024-02806-z","DOIUrl":"https://doi.org/10.1038/s41380-024-02806-z","url":null,"abstract":"<p>De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including <i>GSK3B</i>. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with <i>GSK3B</i> variants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that <i>GSK3B</i> is enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that <i>Gsk3b</i> knockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in <i>GSK3B</i> loss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"18 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541632","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":"Long-term clinical outcome of a novel bilateral capsulotomy with focused ultrasound in refractory obsessive-compulsive disorder treatment.","authors":"Kyung Won Chang, Jhin Goo Chang, Hyun Ho Jung, Chan-Hyung Kim, Jin Woo Chang, Se Joo Kim","doi":"10.1038/s41380-024-02799-9","DOIUrl":"https://doi.org/10.1038/s41380-024-02799-9","url":null,"abstract":"<p><p>Magnetic resonance-guided focused ultrasound (MRgFUS) capsulotomy is a promising treatment for refractory obsessive-compulsive disorder (OCD); however, long-term clinical outcome studies are lacking. We aimed to investigate the long-term efficacy and safety of MRgFUS capsulotomy in patients with refractory OCD. Ten of the eleven patients who underwent MRgFUS capsulotomy for treatment-resistant OCD between 2013 and 2014 were included in this study. Clinical outcomes were assessed after 10 years of follow-up post-MRgFUS capsulotomy using tools such as neuropsychological test, the Frontal Systems Behavior Scale (FrSBe), and a locally developed MRgFUS-patient-centered outcomes questionnaire. After 10 years of follow-up, there was a mean improvement of 52.3% in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score. Seven out of the ten participants responded fully (Y-BOCS reduction ≥35% + CGI-I 1 or 2) to the procedure, two of whom achieved remission (Y-BOCS score ≤12 and CGI-S 1 or 2). Obsessive-compulsive symptoms and overall functioning significantly reduced and improved, respectively (Y-BOCS = 20.7 after 2 years vs. 16.4 after 10 years, p = 0.012; Global Assessment of Functioning = 57.4 after 2 years vs. 69.0 after 10 years, p = 0.011). The patients experienced significantly improved frontal lobe-related functions (FrSBe Sum before 91.0 ± 17.6 vs. after 78.6 ± 17.7, p < 0.05). No adverse effects, including cases of suicide and neurological deficits, were reported. The majority of the respondents were generally satisfied with MRgFUS capsulotomy. MRgFUS capsulotomy is an effective and safe treatment option for the treatment of severe refractory OCD with sustained efficacy even after 10 years.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522495","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 burden of rare copy number variants in obsessive-compulsive disorder","authors":"Matthew W. Halvorsen, Elles de Schipper, Julia Bäckman, Nora I. Strom, Kristen Hagen, Kerstin Lindblad-Toh, Elinor K. Karlsson, Nancy L. Pedersen, John Wallert, Cynthia M. Bulik, Bengt Fundín, Mikael Landén, Gerd Kvale, Bjarne Hansen, Jan Haavik, Manuel Mattheisen, Christian Rück, David Mataix-Cols, James J. Crowley","doi":"10.1038/s41380-024-02763-7","DOIUrl":"https://doi.org/10.1038/s41380-024-02763-7","url":null,"abstract":"<p>Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2248 deeply phenotyped OCD cases and 3608 unaffected controls from Sweden and Norway. Cases carry an elevated burden of CNVs ≥30 kb in size (OR = 1.12, <i>P</i> = 1.77 × 10⁻³). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02–0.11, <i>P</i> = 2.58 × 10⁻³). This signal was largely driven by CNVs overlapping protein-coding regions (OR = 1.19, <i>P</i> = 3.08 × 10⁻⁴), particularly deletions impacting loss-of-function intolerant genes (pLI &gt;0.995, OR = 4.12, <i>P</i> = 2.54 × 10⁻⁵). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation <i>P</i> = 2.60 × 10⁻³). In cases where sufficient clinical data were available (<i>n</i> = 1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (<i>P</i> &lt; 0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (<i>P</i> = 0.02). The results demonstrate a contribution of rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"47 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490756","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":"Highly demarcated structural alterations in the brain and impaired social incentive learning in Tbx1 heterozygous mice.","authors":"Takeshi Hiramoto, Akira Sumiyoshi, Risa Kato, Takahira Yamauchi, Takeshi Takano, Gina Kang, Marisa Esparza, Bailey Matsumura, Lucas J Stevens, Yukiko J Hiroi, Takaki Tanifuji, Rie Ryoke, Hiroi Nonaka, Akihiro Machida, Kensaku Nomoto, Kazutaka Mogi, Takefumi Kikusui, Ryuta Kawashima, Noboru Hiroi","doi":"10.1038/s41380-024-02797-x","DOIUrl":"https://doi.org/10.1038/s41380-024-02797-x","url":null,"abstract":"<p><p>Copy number variants (CNVs) are robustly associated with psychiatric disorders and changes in brain structures. However, because CNVs contain many genes, the precise gene-phenotype relationship remains unclear. Although various volumetric alterations in the brains of 22q11.2 CNV carriers have been identified in humans and mouse models, it is unknown how each gene encoded in the 22q11.2 region contributes to structural alterations, associated mental illnesses, and their dimensions. Our previous studies identified Tbx1, a T-box family transcription factor encoded in the 22q11.2 CNV, as a driver gene for social interaction and communication, spatial and working memory, and cognitive flexibility. However, it remains unclear how TBX1 impacts the volumes of various brain regions and their functionally linked behavioral dimensions. In this study, we used volumetric magnetic resonance imaging analysis to comprehensively evaluate brain region volumes and behavioral alterations relevant to affected structures in congenic Tbx1 heterozygous mice. Our data showed that the volumes of the anterior and posterior portions of the amygdaloid complex and its surrounding cortical regions were most robustly reduced in Tbx1 heterozygous mice. In an amygdala-dependent task, Tbx1 heterozygous mice were impaired in their ability to learn the incentive value of a social partner. The volumes of the primary and secondary auditory cortexes were increased, and acoustic, but not non-acoustic, sensorimotor gating was impaired in Tbx1 heterozygous mice. Our findings identify the brain's regional volume alterations and their relevant behavioral dimensions associated with Tbx1 heterozygosity.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504549","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":"Role of glia in delirium: proposed mechanisms and translational implications.","authors":"Áine Bríd Heffernan, Moritz Steinruecke, Georgia Dempsey, Siddharthan Chandran, Bhuvaneish T Selvaraj, Zoeb Jiwaji, Maria Stavrou","doi":"10.1038/s41380-024-02801-4","DOIUrl":"https://doi.org/10.1038/s41380-024-02801-4","url":null,"abstract":"<p><p>Delirium is a common acute onset neurological syndrome characterised by transient fluctuations in cognition. It affects over 20% of medical inpatients and 50% of those critically ill. Delirium is associated with morbidity and mortality, causes distress to patients and carers, and has significant socioeconomic costs in ageing populations. Despite its clinical significance, the pathophysiology of delirium is understudied, and many underlying cellular mechanisms remain unknown. There are currently no effective pharmacological treatments which directly target underlying disease processes. Although many studies focus on neuronal dysfunction in delirium, glial cells, primarily astrocytes, microglia, and oligodendrocytes, and their associated systems, are increasingly implicated in delirium pathophysiology. In this review, we discuss current evidence which implicates glial cells in delirium, including biomarker studies, post-mortem tissue analyses and pre-clinical models. In particular, we focus on how astrocyte pathology, including aberrant brain energy metabolism and glymphatic dysfunction, reactive microglia, blood-brain barrier impairment, and white matter changes may contribute to the pathogenesis of delirium. We also outline limitations in this body of work and the unique challenges faced in identifying causative mechanisms in delirium. Finally, we discuss how established neuroimaging and single-cell techniques may provide further mechanistic insight at pre-clinical and clinical levels.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504550","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":"Association of the GRIK4 rs1954787 polymorphism with clinical response in antidepressant-treated depressed patients: results from a prospective cohort and meta-analysis","authors":"Kenneth Chappell, Romain Colle, Khalil El Asmar, Florence Gressier, Jérôme Bouligand, Séverine Trabado, Bruno Fève, Laurent Becquemont, Emmanuelle Corruble, Céline Verstuyft","doi":"10.1038/s41380-024-02765-5","DOIUrl":"https://doi.org/10.1038/s41380-024-02765-5","url":null,"abstract":"<p>Major Depressive Disorder (MDD) is the leading cause of disability worldwide. Genetic factors influence the effect of its main treatment option, antidepressant drugs (ATD). The <i>GRIK4</i> rs1954787(T&gt;C) genetic polymorphism was associated with response following 1–3 months of ATD treatment in some studies, but not others. We aimed to analyze its association with clinical outcomes in a cohort of 6-month ATD-treated patients and meta-analysis. Clinical data were obtained at baseline and after 1 (M1), 3 (M3), and 6 (M6) months of ATD treatment in 390 patients of the METADAP cohort. Mixed-effects models were used to assess the association of the <i>GRIK4</i> rs1954787 polymorphism with the Hamilton Depression Rating Scale (HDRS) score and response and remission rates across time. Meta-analyses of ATD treatment response were performed with previously meta-analyzed data and METADAP. Compared to C allele carriers at M3 (n = 200), TT homozygotes at M3 (n = 66) had higher HDRS scores (coef = 3.37, 95% CI [1.30–5.54], <i>P</i>_<i>adj</i> = 0.0046) and lower remission rates (OR = 0.36, 95% CI [0.16–0.76], <i>P</i>_<i>adj</i> = 0.029). At M6, greater differences between TT homozygotes (n = 53) and C allele carriers (n = 152) were observed for HDRS scores (coef = 4.68, 95% CI [2.17–7.18], <i>P</i>_<i>adj</i> = 0.00091) and remission rates (OR = 0.26, 95% CI [0.12–0.54], <i>P</i>_<i>adj</i> = 0.0016). Meta-analyses of response were significant when comparing C vs T alleles (OR = 1.31, 95% CI [1.06–1.62], <i>P</i> = 0.014) and CC vs TT genotypes (OR = 1.63, 95% CI [1.10–2.38], <i>P</i> = 0.019). Altogether, our results support an association of the <i>GRIK4</i> rs1954787(T&gt;C) polymorphism with clinical improvement following ATD treatment. This association should be further assessed in other longitudinal studies. Its position within the glutamatergic system may help in understanding the mechanism of ATD action.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"60 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490433","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":"Systematic review on resting-state fMRI in people with AUD and people who binge drink","authors":"Gabriel C. Rodríguez, Michael A. Russell, Eric D. Claus","doi":"10.1038/s41380-024-02796-y","DOIUrl":"https://doi.org/10.1038/s41380-024-02796-y","url":null,"abstract":"<p>Resting-state functional magnetic resonance imaging (rsfMRI) has become ubiquitous in neuroimaging to study disorders, including alcohol use disorder (AUD), given its potential to serve as a biomarker of psychiatric symptoms. The number of techniques, sample heterogeneity, and findings demand the assessment of results to identify potential biomarkers for the development of treatment. This systematic review aimed to synthesize the alcohol rsfMRI literature by summarizing the results by analysis approach and groups to examine these findings in the context of the neurobiology of addiction model. Three databases were systematically searched, resulting in the inclusion of 17 studies with a total of 784 participants (387 were people with AUD, 38 engaged in binge drinking, and 359 were controls). Seed-based functional connectivity studies were the most prominent. Compared to controls, people who binge drink and people with AUD showed greater connectivity of the Middle Frontal Gyrus—a region associated with the preoccupation/anticipation stage of the theory. Regions of the prefrontal and limbic cortex were most consistently reported in studies. The different types of analyses, sample size, and variability in the sample may have contributed to differences reported across studies. This review synthesizes and examines the results of different studies using the neurobiology of addiction theory, which may inform future studies on potential regions of interest, recruitment approaches, and analysis methods. Standardizing the methods for such a heterogeneous population could lead to more rapid development of neurobiologically-informed treatments for AUD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"98 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489603","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 prediction model for electroconvulsive therapy effectiveness in patients with major depressive disorder from the Dutch ECT Consortium (DEC)","authors":"Dore Loef, Adriaan W. Hoogendoorn, Metten Somers, Roel J. T. Mocking, Dominique S. Scheepens, Karel W. F. Scheepstra, Maaike Blijleven, Johanna M. Hegeman, Karen S. van den Berg, Bart Schut, Tom K. Birkenhager, Willemijn Heijnen, Didi Rhebergen, Mardien L. Oudega, Sigfried N. T. M. Schouws, Eric van Exel, Bart P. F. Rutten, Birit F. P. Broekman, Anton C. M. Vergouwen, Thomas J. C. Zoon, Rob M. Kok, Karina Somers, Esmée Verwijk, Jordy J. E. Rovers, Gijsbert Schuur, Jeroen A. van Waarde, Joey P. A. J. Verdijk, Dieneke Bloemkolk, Frank L. Gerritse, Hanneke van Welie, Bartholomeus C. M. Haarman, Sjoerd M. van Belkum, Maurice Vischjager, Karin Hagoort, Edwin van Dellen, Indira Tendolkar, Philip F. P. van Eijndhoven, Annemiek Dols","doi":"10.1038/s41380-024-02803-2","DOIUrl":"https://doi.org/10.1038/s41380-024-02803-2","url":null,"abstract":"<p>Reliable predictors for electroconvulsive therapy (ECT) effectiveness would allow a more precise and personalized approach for the treatment of major depressive disorder (MDD). Prediction models were created using a priori selected clinical variables based on previous meta-analyses. Multivariable linear regression analysis was used, applying backwards selection to determine predictor variables while allowing non-linear relations, to develop a prediction model for depression outcome post-ECT (and logistic regression for remission and response as secondary outcome measures). Internal validation and internal-external cross-validation were used to examine overfitting and generalizability of the model’s predictive performance. In total, 1892 adult patients with MDD were included from 22 clinical and research cohorts of the twelve sites within the Dutch ECT Consortium. The final primary prediction model showed several factors that significantly predicted a lower depression score post-ECT: higher age, shorter duration of the current depressive episode, severe MDD with psychotic features, lower level of previous antidepressant resistance in the current episode, higher pre-ECT global cognitive functioning, absence of a comorbid personality disorder, and a lower level of failed psychotherapy in the current episode. The optimism-adjusted R² of the final model was 19%. This prediction model based on readily available clinical information can reduce uncertainty of ECT outcomes and hereby inform clinical decision-making, as prompt referral for ECT may be particularly beneficial for individuals with the above-mentioned characteristics. However, despite including a large number of pretreatment factors, a large proportion of the variance in depression outcome post-ECT remained unpredictable.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"94 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488377","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 dysbiosis produces long-lasting behavioral changes in offspring","authors":"Jacob Hudobenko, Claudia M. Di Gesù, Patrick R. Mooz, Joseph Petrosino, Nagireddy Putluri, Bhanu P. Ganesh, Kristen Rebeles, Frank W. Blixt, Venugopal R. Venna, Louise D. McCullough","doi":"10.1038/s41380-024-02794-0","DOIUrl":"https://doi.org/10.1038/s41380-024-02794-0","url":null,"abstract":"<p>Advanced maternal age (AMA) is defined as a pregnancy in a woman older than 35 years of age. AMA increases the risk for both maternal and neonatal complications, including miscarriage and stillbirth. AMA has also been linked to neurodevelopmental and neuropsychiatric disorders in the offspring. Recent studies have found that age-associated compositional shifts in the gut microbiota contribute to altered microbial metabolism and enhanced inflammation in the host. We investigated the specific contribution of the maternal microbiome on pregnancy outcomes and offspring behavior by recolonizing young female mice with aged female microbiome prior to pregnancy. We discovered that pre-pregnancy colonization of young dams with microbiome from aged female donors significantly increased fetal loss. There were significant differences in the composition of the gut microbiome in pups born from dams recolonized with aged female biome that persisted through middle age. Offspring born from dams colonized with aged microbiome also had significant changes in levels of neurotransmitters and metabolites in the blood and the brain. Adult offspring from dams colonized with an aged microbiome displayed persistent depressive- and anxiety-like phenotypes. Collectively, these results demonstrate that age-related changes in the composition of the maternal gut microbiome contribute to chronic alterations in the behavior and physiology of offspring. This work highlights the potential of microbiome-targeted approaches, even prior to birth, may reduce the risk of neuropsychiatric disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"8 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487574","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":"Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats","authors":"Gabriele Floris, Konrad R. Dabrowski, Mary Tresa Zanda, Stephanie E. Daws","doi":"10.1038/s41380-024-02788-y","DOIUrl":"https://doi.org/10.1038/s41380-024-02788-y","url":null,"abstract":"<p>Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in &gt;50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT_2AR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT_2AR agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT_2AR antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4–24 h prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT_2AR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 h later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ~2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked &gt;90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, <i>Il17ra</i>. Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including <i>Il17a</i>, and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"233 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452186","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}