Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

{"title":"Executive dysfunction in Parkinson's disease: From neurochemistry to circuits, genetics and neuroimaging","authors":"Shuyan Tong ,&nbsp;Ruiwen Wang ,&nbsp;Huihua Li ,&nbsp;Zhu Tong ,&nbsp;Deqin Geng ,&nbsp;Xiangrong Zhang ,&nbsp;Chao Ren","doi":"10.1016/j.pnpbp.2025.111272","DOIUrl":"10.1016/j.pnpbp.2025.111272","url":null,"abstract":"<div><div>Cognitive decline is one of the most significant non-motor symptoms of Parkinson's disease (PD), with executive dysfunction (EDF) being the most prominent characteristic of PD-associated cognitive deficits. Currently, lack of uniformity in the conceptualization and assessment scales for executive functions impedes the early and accurate diagnosis of EDF in PD. The neurobiological mechanisms of EDF in PD remain poorly understood. Moreover, the treatment of cognitive impairment in PD has progressed slowly and with limited efficacy. Thus, this review explores the characteristics and potential mechanisms of EDF in PD from multiple perspectives, including the concept of executive function, commonly used neuropsychological tests, neurobiochemistry, genetics, electroencephalographic activity and neuroimaging. The available evidence indicates that degeneration of the frontal-striatal circuit, along with mutations in the Catechol-<em>O</em>-methyltransferase (COMT) gene and Leucine-rich repeat kinase 2 (LRRK2) gene, may contribute to EDF in patients with PD. The increase in theta and delta waves, along with the decrease in alpha waves, offers potential biomarkers for the early identification and monitoring of EDF, as well as the development of dementia in patients with PD. The PD cognition-related pattern (PDCP) pattern may serve as a tool for monitoring and assessing cognitive function progression in these patients and is anticipated to become a biomarker for cognitive disorders associated with PD. The aim is to provide new insights for the early and precise diagnosis and treatment of EDF in PD.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111272"},"PeriodicalIF":5.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysbiosis is associated with the behavioral phenotype observed in the triple-hit Wisket rat model of schizophrenia","authors":"Szonja B. Plesz ,&nbsp;Leatitia G. Adlan ,&nbsp;Alexandra Büki ,&nbsp;Nóra Makra ,&nbsp;Balázs Ligeti ,&nbsp;Bence Ágg ,&nbsp;Dóra Szabó ,&nbsp;Zoltán S. Zádori ,&nbsp;Péter Ferdinandy ,&nbsp;Gyongyi Horvath ,&nbsp;Gabriella Kekesi","doi":"10.1016/j.pnpbp.2025.111276","DOIUrl":"10.1016/j.pnpbp.2025.111276","url":null,"abstract":"<div><div>Comorbidities between gastrointestinal diseases and psychiatric disorders have been widely reported, with the gut–brain axis implicated as a potential biological basis. Thus, dysbiosis may play an important role in the etiology of schizophrenia, which is barely detected. Triple-hit Wisket model rats exhibit various schizophrenia-like behavioral phenotypes. The present study aimed to compare the diversity and abundance of gut microbiota in Wisket model and control rats; furthermore, to correlate the microbial taxonomic profiles to indices of behavioral change.</div><div>Tail-flick and Ambitus tests were used to assess acute heat pain sensitivity, and record exploration and locomotor activity along with motivation in young adult, control and Wisket model rats. Fecal microbiota composition was profiled by deep sequencing of bacterial 16S rRNA, and it was correlated to behavioral phenotype.</div><div>Wisket rats exhibited significantly decreased pain sensitivity, lower locomotor activity and exploration, and impaired motivation compared with controls. No significant differences were observed in bacterial alpha diversity between the groups; however, clear differences in community structure were observed. Wisket rats showed decreases in several genera of <em>Firmicutes</em> and <em>Saccharimonas</em>, and increases in <em>Bacteriodetes</em> and <em>Helicobacter</em> phyla compared with controls. Correlation analysis revealed significant associations between the microbiota profile and the behavioral phenotype.</div><div>This is the first demonstration that fecal microbiota composition is markedly altered in a triple-hit schizophrenia rat model, suggesting the contribution of the microbiota–gut–brain axis in the development of the schizophrenia-like behavioral phenotype. Thus targeting the gut microbiota may be a novel approach to treat such impairments.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111276"},"PeriodicalIF":5.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What are the levels and interactions of neuroligin-1, neuroligin-3, and inflammatory cytokines (IL-6, IL-8) in children diagnosed with autism spectrum disorder?","authors":"Kübra Kılınç ,&nbsp;Serhat Türkoğlu ,&nbsp;Ramazan Kocabaş ,&nbsp;Hasan Ali Güler ,&nbsp;Çiğdem Yılmaz ,&nbsp;Ayşe Büyükateş","doi":"10.1016/j.pnpbp.2025.111275","DOIUrl":"10.1016/j.pnpbp.2025.111275","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is characterized by deficits in social interaction, restricted interests, and repetitive behaviors. Several genes, including synaptic proteins and environmental risk factors, play a role in the etiology of autism. We aimed to evaluate the relationship between neuroligin-1 (NLGN-1) and neuroligin-3 (NLGN-3) levels, which are neuronal cell adhesion molecules (CAMs), and inflammatory cytokine (IL-6, IL-8) levels with disease severity and symptom clusters and with each other in children with ASD. Eighty children diagnosed with autism who met the inclusion criteria and sixty-five typically developing children matched for age and sex were included in the study. The children were evaluated psychiatrically through a semi-structured interview, DSM-5 criteria, the Childhood Autism Rating Scale (CARS), and the Social Communication Questionnaire (SCQ). IL-6, IL-8, NLGN-1, and NLGN-3 levels were analyzed in peripheral serum samples using human ELISA kits. IL-8 and NLGN-3 levels were higher in the autism group (<em>p</em> &lt; 0.001, p &lt; 0.001). IL-6 was positively related to CARS and SCQ total scores (<em>p</em> = 0.021, <em>p</em> = 0.040, respectively). IL-8, and NLGN-3 were positively associated with the all subtests of the SCQ and the SCQ total score (all <em>p</em> values &lt;0.001). NLGN-1, NLGN-3, and inflammatory cytokine (IL-6, IL-8) levels were positively correlated (all p values &lt;0.001). Neuroligins play a central role in the brain's ability to process information and maybe a key target in the pathogenesis of ASD. Further research is needed to determine whether, to what extent and how neuronal CAMs and immunity modulate each other and whether this contributes to ASD pathogenesis. Future studies should also be expanded to investigate the influence of variables such as oxidative stress, metalloproteases responsible for ectodomain shedding, or epigenetic regulation.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111275"},"PeriodicalIF":5.3,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attention-deficit/hyperactivity disorder-related psychomotor activity and altered neuronal activity in the medial prefrontal cortex and striatum in the A53T mouse model of Parkinson's disease and other synucleinopathies: Findings from an “endophenotype” approach","authors":"Olga Dubljević ,&nbsp;Željko Pavković ,&nbsp;Maja Srbovan ,&nbsp;Milica Potrebić ,&nbsp;Miloš Stanojlović ,&nbsp;Vesna Pešić","doi":"10.1016/j.pnpbp.2025.111273","DOIUrl":"10.1016/j.pnpbp.2025.111273","url":null,"abstract":"<div><div>Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with an increased risk of Parkinson's disease (PD) and other synucleinopathies later in life. The severity of the ADHD phenotype may play a significant role in this association. There is no indication that any of the existing animal models can unify these disorders. Using the Open Field Test, amphetamine-challenge test, Western blot and immunohistochemical analysis of neuronal activity markers (c-Fos, FosB and ΔFosB) we performed a deliberate neurobehavioral characterization of 6-month-old hemizygous A53T carriers (A53T+) of the JAX006823 strain, evaluating the utility of this transgenic mouse model of PD and other synucleinopathies in ADHD/PD continuum research. Adhering to the “endophenotype” approach, non-transgenic littermates (A53T-) and C57BL/6J mice (used to maintain the colony) were examined with A53T+ mice, to differentiate between biomarkers of transgenicity and endophenotypic traits related to the genetic background of the strain. Obtained results revealed that increased behavioral and acute striatal response to novelty, increased basal neuronal activity of the ventromedial prefrontal cortex and rate-dependent calming effect of amphetamine were endophenotypic characteristics of the strain. Increased acute response of the medial prefrontal cortex to novelty and chronic increase in neuronal activity of the striatum appeared as the mark of transgenicity. To the best of our knowledge, this is the first study to indicate external validity of a transgenic mouse model of PD and other synucleinopathies with the neurobehavioral pathology associated with ADHD, hinting at its potential in preclinical research of ADHD/PD continuum. The full capacity of the model remains to be explored.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111273"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time-dependent fear memory generalization triggered by phosphodiesterase 5 inhibition during reconsolidation","authors":"Nathalie Carla Cardoso ,&nbsp;Jeferson Machado Batista Sohn ,&nbsp;Ana Maria Raymundi ,&nbsp;Mateus Reis Santos ,&nbsp;Jos Prickaerts ,&nbsp;Lucas Gazarini ,&nbsp;Cristina Aparecida Jark Stern","doi":"10.1016/j.pnpbp.2025.111274","DOIUrl":"10.1016/j.pnpbp.2025.111274","url":null,"abstract":"<div><div>Fear generalization, a lack of discrimination between safe and unsafe cues, is a hallmark of posttraumatic stress disorder. The phosphodiesterase 5 (PDE5) regulates the cyclic guanosine monophosphate (cGMP) pathway, which has been proposed to be involved in fear memory generalization. However, whether PDE5 activity underlies fear memory generalization remains unexplored. Considering the importance of retrieval-induced reconsolidation in memory maintenance, we aimed to investigate whether PDE5 inhibition during reconsolidation of recent fear memory affects generalization over time in adult male Wistar rats submitted to contextual fear conditioning. The PDE5 inhibition with vardenafil (VAR) 1 mg/kg i.p. during reconsolidation triggered a time-dependent fear generalization without affecting fear memory in the paired context. Fear generalization and impaired pattern separation appear to be interlinked. Likewise, an impairment of object pattern separation was observed in the VAR-treated group at the remote time point. These effects depended on memory retrieval and were restricted to the reconsolidation time window. A chemogenetic inhibition of the anterior cingulate cortex (ACC), a region involved in allocating remote memories and generalization, prevented the effects of VAR. Moreover, VAR infusion into the ACC (6 μg/0.2 μL) after retrieval also promoted fear generalization and impaired OPS in remote time point, suggesting that ACC underlies the behavioral outcomes of the treatment with VAR. In conclusion, our results suggest that inhibiting PDE5 during the reconsolidation of a recent fear memory recruits the activity of the ACC, triggering fear memory generalization and impairing object pattern separation over time.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111274"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local cortical structure pattern and genetic links in schizophrenia: An MRI and CRISPR/Cas9 study","authors":"Pei-Shan Hou ,&nbsp;Shu-Fei Lin ,&nbsp;Jun-Ding Zhu ,&nbsp;Chih-Yun Chung ,&nbsp;Shih-Jen Tsai ,&nbsp;Albert C. Yang","doi":"10.1016/j.pnpbp.2025.111270","DOIUrl":"10.1016/j.pnpbp.2025.111270","url":null,"abstract":"<div><div>While the etiology of schizophrenia (SZ) remains elusive, its diverse phenotypes suggest the involvement of distinct functional cortical areas, and the heritability of SZ implies the underlying genetic factors. This study aimed to integrate imaging and molecular analyses to elucidate the genetic underpinnings of SZ. We investigated the local cortical structural pattern changes in Brodmann areas (BAs) by calculating the cortical structural pattern index (SPI) using magnetic resonance imaging analysis from 194 individuals with SZ and 330 controls. Significant local structural changes were detected in certain Brodmann areas in symmetric or asymmetric patterns, such as symmetric changes in the BA4 primary motor area and BA23 part of posterior cingulate cortex, and asymmetric changes in the BA13 insula, BA11 inferior orbitofrontal area, and BA 24, and BA 31 cingulate cortex. Following genome-wide association tests, we found genetic variants and SNP-mapped genes and verified the areal preferential expression profiles in the developing human and mouse neocortex. Finally, we performed a loss-of-function analysis using the CRISPR/Cas9 system to investigate the effects of disrupting the SZ-related SNP-mapped Morf4l1, Reep3, or Tmed3 gene on cortical cell fate to understand their roles in generating appropriate composition of cortical neurons. This study outlines a pipeline for identifying local structural changes, associated genetic causes, and potential molecular mechanisms underlying mental disorders. Additionally, these data shed light on establishing a structurally integral cerebral cortex for higher cognitive functions.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111270"},"PeriodicalIF":5.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subdiaphragmatic vagotomy reduces hypothalamic oxytocin expression and blood levels after oral MDMA administration in male rats","authors":"Yong Yue ,&nbsp;Xiayun Wan ,&nbsp;Guilin Liu ,&nbsp;Tingting Zhu ,&nbsp;Dan Xu ,&nbsp;Mingming Zhao ,&nbsp;Yi Cai ,&nbsp;Rumi Murayama ,&nbsp;Hirofumi Hashimoto ,&nbsp;Naohiko Anzai ,&nbsp;Kenji Hashimoto","doi":"10.1016/j.pnpbp.2025.111260","DOIUrl":"10.1016/j.pnpbp.2025.111260","url":null,"abstract":"<div><div>3,4-Methylenedioxymethamphetamine (MDMA) is a widely recognized entactogen frequently used recreationally. It is known for its interaction with the serotonin and oxytocin systems, which underlie its entactogenic effects in humans. Recently, we demonstrated that the gut-brain axis, mediated by the subdiaphragmatic vagus nerve, contributes to MDMA-induced resilience enhancement in rodents. This study investigates whether subdiaphragmatic vagotomy (SDV) affects plasma oxytocin levels and the expression of oxytocin and c-Fos in the hypothalamus following a single oral dose of MDMA in rats. SDV significantly reduced baseline plasma oxytocin levels and oxytocin expression in the paraventricular and supraoptic nuclei of the hypothalamus. Furthermore, SDV markedly attenuated MDMA-induced increases in plasma oxytocin and the expression of oxytocin and c-Fos in these hypothalamic regions. These findings suggest that the subdiaphragmatic vagus nerve plays a critical role in brain-body communication, mediating MDMA's pharmacological effects on the oxytocin system.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111260"},"PeriodicalIF":5.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lycopene mitigates paclitaxel-induced cognitive impairment in mice; Insights into Nrf2/HO-1, NF-κB/NLRP3, and GRP-78/ATF-6 axes","authors":"Nora Zakaria ,&nbsp;Esther T. Menze ,&nbsp;Doaa A. Elsherbiny ,&nbsp;Mariane G. Tadros ,&nbsp;Mina Y. George","doi":"10.1016/j.pnpbp.2025.111262","DOIUrl":"10.1016/j.pnpbp.2025.111262","url":null,"abstract":"<div><div>Chemotherapy-induced cognitive impairment, referred to as “chemobrain”, is widely acknowledged as a significant adverse effect of cancer therapy. Paclitaxel, a chemotherapeutic drug, has been reported to cause cognitive impairment clinically and in animal models. However, the precise mechanisms are not fully understood. The current study explored the potential neuroprotective effect of lycopene in paclitaxel-induced cognitive impairment in mice and its potential underlying mechanisms. Mice were randomly allocated into six groups: control, paclitaxel-treated (10 mg/kg), lycopene-treated (5, 10, and 20 mg/kg) + paclitaxel, and lycopene alone-treated (20 mg/kg) groups. The effect of lycopene treatment on behavioral function and histological examination was assessed. Lycopene (20 mg/kg) was selected for additional investigation into the underlying mechanisms. Lycopene treatment counteracted paclitaxel-induced oxidative stress by reducing lipid peroxidation and enhancing catalase levels. Additionally, lycopene-treated mice demonstrated a significant elevation in nuclear factor erythroid 2-related factor 2 with no significant effect on hemeoxygenase-1. Moreover, paclitaxel administration elevated endoplasmic reticulum stress markers; glucose-regulated protein78, activating Transcription Factor 6, C/EBP <em>homologous protein,</em> and apoptosis marker annexin V which were significantly reduced by lycopene treatment. Furthermore, lycopene mitigated paclitaxel-induced neuroinflammation through the reduction of the levels of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome axis markers; nuclear factor-κB, NLRP3, caspase-1, interleukin-1β, and interleukin-18. Our study findings may provide new evidence that lycopene mitigates paclitaxel-induced cognitive impairment in mice by reversing oxidative stress, endoplasmic reticulum stress, and inflammatory mechanisms.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111262"},"PeriodicalIF":5.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of cerebrospinal fluid metabolites in mediating the relationship between cathepsins and narcolepsy type 1: A comprehensive Mendelian randomization analysis","authors":"Yanjuan Wu ,&nbsp;Qiming Gan ,&nbsp;Xiaofen Su ,&nbsp;Yutong Ding ,&nbsp;Quanzhen Liu ,&nbsp;Jingcun Wang ,&nbsp;Yuting Zhang ,&nbsp;Nuofu Zhang ,&nbsp;Kang Wu","doi":"10.1016/j.pnpbp.2025.111263","DOIUrl":"10.1016/j.pnpbp.2025.111263","url":null,"abstract":"<div><h3>Introduction</h3><div>To investigate the potential causal relationship between cathepsins and Narcolepsy Type 1 (NT1), along with the mediating influence of cerebrospinal fluid metabolites.</div></div><div><h3>Method</h3><div>We performed a comprehensive Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) data. Data on nine plasma cathepsins and 338 cerebrospinal fluid metabolites were sourced from the IEU OpenGWAS database, and NT1 were obtained from the FinnGen consortium's R10 release. Univariate MR (UVMR), multivariate MR (MVMR) and gene co-localization analyses were used to explore the potential causal relationship between cathepsins and NT1. In addition, mediation analyses were performed to explore the role of cerebrospinal fluid metabolites in mediating the relationship.</div></div><div><h3>Result</h3><div>In UVMR study, we identified a significant positive association between genetically elevated levels of plasma cathepsin B (OR = 2.022, 95 % CI: 1.456–2.809, <em>p</em> &lt; 0.01) and cathepsin F (OR = 0.676, 95 % CI: 0.473–0.966, <em>p</em> = 0.031) with NT1. However, in the MVMR analysis, only cathepsin B maintained a consistent effect (OR = 1.920, 95 % CI: 1.378–2.675, <em>p</em> &lt; 0.001). Subsequent co-localization analysis indicated shared causal variants between cathepsin B and NT1, further highlighting the robustness of our findings. Additionally, mediation MR revealed that the association between cathepsin B and NT1 was mediated by sphingomyelin and 1-(1-alkenyl-palmitoyl1)-2-propenoyl-gpc, accounting for 2.6 % and 4.7 % of the effect, respectively.</div></div><div><h3>Conclusion</h3><div>Our findings suggest a probable causal relationship between increased cathepsin B levels and NT1, with the potential of cerebrospinal fluid fatty acid metabolism disorder playing a mediating role in the development of this association. This indicates the potential of cathepsin B as a promising biomarker for NT1, highlighting significant implications for the diagnosis and treatment of this condition.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111263"},"PeriodicalIF":5.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the genetic links between depression and type 2 diabetes","authors":"Ancha Baranova ,&nbsp;Dongming Liu ,&nbsp;Vikas Chandhoke ,&nbsp;Hongbao Cao ,&nbsp;Fuquan Zhang","doi":"10.1016/j.pnpbp.2025.111258","DOIUrl":"10.1016/j.pnpbp.2025.111258","url":null,"abstract":"<div><h3>Background</h3><div>Type 2 diabetes (T2D) is a chronic metabolic disorder that has high comorbidity with mental disorders. The genetic relationships between T2D and depression are far from being well understood.</div></div><div><h3>Methods</h3><div>We performed genetic correlation, polygenic overlap, Mendelian randomization (MR) analyses, cross-trait meta-analysis, and Bayesian colocalization analysis to assess genetic relationships between T2D and depression, in the forms of major depressive disorder (MDD) and depressed affect (DAF). Then, the summary data-based MR (SMR) analysis was performed to prioritize genes contributing to MDD and to T2D from functional perspective. MDD-driven signaling pathways were constructed to understand the influence of MDD on T2D at the molecular level.</div></div><div><h3>Results</h3><div>T2D has positive genetic correlations both with MDD (r_g = 0.14) and with DAF (r_g = 0.19). The polygenic overlap analysis showed that about 60 % of causal variants for T2D are shared with MDD and DAF. The MR analysis indicated that genetic liabilities to both MDD (OR: 1.24, 95 % CI: 1.11–1.38) and DAF (OR: 1.48, 95 % CI: 1.23–1.78) are associated with an increased risk for T2D, while genetic liability to T2D is not associated with the risk for MDD (OR: 1.00, 95 % CI: 0.99–1.01) or DAF (OR: 1.01, 95 % CI: 1.00–1.02). The cross-trait meta-analysis identified 271 genomic loci, of which 29 were novel. Genetic predisposition to MDD and T2D shares six overlapping loci, involving some well-characterized genes, such as <em>TCF4</em> and <em>NEGR1</em>. Colocalization analysis revealed three shared chromosome regions between MDD and T2D, which covers mediator genes including SCYL1, DENND1A, and MAD1L1. Molecular pathway analysis suggests mechanisms that promote the development of T2D through inflammatory pathways overactive in patients with MDD. The SMR analysis and the meta-analysis highlighted seven genes with functional implications for both MDD and T2D, including <em>TNKS2</em>, <em>CCDC92</em>, <em>FADS1</em>, <em>ERI1</em>, <em>THUMPD3</em>, <em>NUCKS1</em>, and <em>PM20D1</em>.</div></div><div><h3>Conclusions</h3><div>Our study points out that depression, in the forms of MDD and DAF, may increase the risk of T2D. Analysis of underlying genetic variation and the molecular pathways, connecting depression and T2D, indicate that the pathophysiological foundations of these two conditions have a notable overlap.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"137 ","pages":"Article 111258"},"PeriodicalIF":5.3,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}