Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

{"title":"Uncovering novel endocannabinoidome-gut microbiome-brain axis-based therapeutic targets in a Fragile X Syndrome mouse model","authors":"Antonella Campanale ,&nbsp;Hayatte-Dounia Mir ,&nbsp;Elizabeth Dumais ,&nbsp;Antonio Inserra ,&nbsp;Nicolas Flamand ,&nbsp;Mallar Chakravarty ,&nbsp;Ilse Gantois ,&nbsp;Nadeem Siddiqui ,&nbsp;Nahum Sonenberg ,&nbsp;Gabriella Gobbi ,&nbsp;Cristoforo Silvestri ,&nbsp;Vincenzo Di Marzo","doi":"10.1016/j.pnpbp.2025.111575","DOIUrl":"10.1016/j.pnpbp.2025.111575","url":null,"abstract":"<div><h3>Background</h3><div>Autism Spectrum Disorder (ASD) is a neurodevelopmental condition associated with increased risk of psychiatric, gastrointestinal, and metabolic comorbidities. Recent studies highlight the bidirectional role of the gut microbiome (GM) and endocannabinoidome (eCBome)-axis in the gut-brain axis, suggesting its therapeutic potential for ASD and comorbidities.</div></div><div><h3>Methods</h3><div>We investigated the eCBome-GM-brain axis in the Fragile X Messenger Ribonucleoprotein 1 (<em>Fmr1</em>^{<em>−/y</em>}) mouse model, known as a genetic model of ASD, to identify therapeutic targets. Fecal GM composition was analysed by 16S rDNA sequencing, brain eCBome profile by HPLC-MS/MS and qRT-PCR, and fecal short chain fatty acids by GC-FID.</div></div><div><h3>Results</h3><div>Significant eCBome-GM-brain axis dysregulation was observed in <em>Fmr1</em>^{<em>−/y</em>} compared to wild-type mice. GM analyses revealed potential gut dysbiosis, increased permeability, and inflammation. Specifically, elevated <em>Akkermansia</em> and <em>Eubacterium siraeum</em>—linked to gut barrier dysfunction—and <em>Ruminococcus</em> and <em>Clostridium</em>, associated with ASD severity, were identified. Concurrently, decreased levels of the gut health biomarker <em>Roseburia</em> and the taxa <em>Helicobacte</em>r and <em>Anaeroplasma</em> were observed.</div><div>Brain region-specific eCBome alterations underscored neuroinflammation. In the HPC, reduced anti-inflammatory dihomogamma-linolenic acid (DGLA) was accompanied by elevated pro-inflammatory 12-hydroxy-heptadecatrienoic acid, a mediator of microglial activation. In the PFC, decreased DGLA, 1/2-linoleoylglycerol, and N-linoleoyl-ethanolamine suggested neuroinflammation; elevated prostaglandin D2, a marker of autophagy impairment, underscores further mechanisms of dysfunction. Upregulation of cannabinoid type 2 and PPAR-γ receptor genes in the PFC suggested a compensatory response to neuroinflammation. Correlations between eCBome and GM alterations highlighted potential links between gut dysbiosis, systemic inflammation, and neurodevelopmental atypicalities.</div></div><div><h3>Conclusions</h3><div>The <em>Fmr1</em>^{<em>−/y</em>} ASD mouse model harbors significant eCBome-GM-brain axis alterations. This study highlights specific GM taxa and eCBome components as potential therapeutic targets for clinical validation in Fragile X Syndrome and ASD.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111575"},"PeriodicalIF":3.9,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745513","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":"Enriched and deficient omega-3 PUFA exposure from gestation to adulthood modulates anxiety-related behavior and stress- and neuroplasticity-related brain gene expression in mice","authors":"Santiago Bianconi ,&nbsp;Verónica I. Cantarelli ,&nbsp;Juan E. Robledo Almonacid ,&nbsp;Emilio Zingerling ,&nbsp;Diego M. Weigandt ,&nbsp;María del Carmen Baez ,&nbsp;Marina F. Ponzio ,&nbsp;Michael J. Williams ,&nbsp;Helgi B. Schiöth ,&nbsp;María E. Santillán ,&nbsp;Graciela Stutz ,&nbsp;Valeria P. Carlini","doi":"10.1016/j.pnpbp.2025.111581","DOIUrl":"10.1016/j.pnpbp.2025.111581","url":null,"abstract":"<div><div>Omega-3 polyunsaturated fatty acids (PUFAs) are essential for brain development and function, affecting inflammation, neurotransmission, and neuroplasticity. These nutrients are associated with benefits in managing stress, sleep disorders, anxiety, and mild cognitive impairment. This study investigated the effects of chronic exposure to varying omega-3 PUFA levels, from gestation to adulthood, on behavioral and molecular aspects related to memory, anxiety, and depression in male mice. Dams received one of three diets: Control (soybean oil, 7 %), omega-3 Deficient (sunflower oil, 7 %), or omega-3 Enriched (4.2 % cod liver oil +2.8 % soybean oil). After weaning, the offspring continued on their respective diets until adulthood. The omega-3 Deficient diet led to increased locomotor activity, anxiety-like behavior, and a trend toward greater immobility time in the tail suspension test. It also upregulated the expression of <em>Avp</em> and its receptor <em>Avpr1b</em> within the hypothalamic-pituitary axis, suggesting a potential mechanistic link between omega-3 deficiency and mood disorders. In contrast, the Enriched group exhibited reduced locomotor activity and anxiolytic-like behavior in the elevated plus maze. At the molecular level, the Deficient diet downregulated <em>Grin1</em>, while the Enriched diet upregulated <em>Creb1</em> in the hippocampus, providing insight into how omega-3 PUFAs influence cognitive processes. Chronic insufficient omega-3 consumption throughout development and adulthood may negatively affect anxiety- and depression-related responses, while high omega-3 intake may play a protective role in anxiety regulation. These findings deepen our understanding of the role of omega-3 PUFAs in affective and cognitive regulation, highlighting the significance of balanced intake to support mental health.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111581"},"PeriodicalIF":3.9,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738865","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":"Population pharmacokinetic analysis for simultaneous fit of clozapine and norclozapine concentrations in adult psychiatric patients","authors":"Bojana Panić ,&nbsp;Vera Lukić ,&nbsp;Katarina Vučićević ,&nbsp;Branislava Miljković ,&nbsp;Srđan Milovanović ,&nbsp;Marija Jovanović","doi":"10.1016/j.pnpbp.2025.111583","DOIUrl":"10.1016/j.pnpbp.2025.111583","url":null,"abstract":"<div><h3>Background</h3><div>Clozapine (CLZ) exhibits a high potential for pharmacokinetic interactions due to its extensive and complex metabolism. Additionally, several patient-related factors contribute to the pharmacokinetic variability, making treatment optimization even more challenging. The goal of this study was to develop a parent-metabolite population pharmacokinetic model for CLZ and its primary metabolite norclozapine (NCLZ) and to evaluate sources of variability in a real-world clinical setting.</div></div><div><h3>Methods</h3><div>Data from routine therapeutic drug monitoring (TDM) of 126 adult in- and out-patients with psychiatric disorders were used for the analysis. A nonlinear mixed-effects modeling approach was applied for data analysis to simultaneously fit CLZ and NCLZ concentrations.</div></div><div><h3>Results</h3><div>A one-compartment model for the drug with an additional compartment for NCLZ was used to fit the concentration-time data. The population pharmacokinetic value of oral clearance for CLZ (CL/F) for a typical patient (female, non-smoker) was 26.4 L/h. Male sex and positive smoking status were associated with an increase in CL/F of 25.9 % and 29.2 %, respectively. The estimated value of metabolite clearance (CL_m/F) for a typical patient was 29.6 L/h, while male sex and valproic acid (VPA) use were associated with its increases for 45.1 % and 95.5 %, respectively.</div></div><div><h3>Conclusion</h3><div>The developed population pharmacokinetic model describes the simultaneous disposition of CLZ and NCLZ in adult psychiatric patients, accounting for impact of patient and co-therapy factors. In addition to the well-established effects of sex and smoking status on CLZ pharmacokinetics, the model characterizes the significant impact of VPA co-therapy, primarily on NCLZ disposition.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111583"},"PeriodicalIF":3.9,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738864","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":"Corticosterone regulates the balance between freezing and rearing in defensive responses to predator threat","authors":"J.L. Baumbach ,&nbsp;C.Y.Y. Mui ,&nbsp;A.M. Leonetti ,&nbsp;L.J. Martin","doi":"10.1016/j.pnpbp.2025.111579","DOIUrl":"10.1016/j.pnpbp.2025.111579","url":null,"abstract":"<div><div>The hormonal stress response critically shapes how animals respond to threats. We examined how corticosterone (CORT) synthesis modulates defensive behaviors in mice exposed to the synthetic predator odor 2,4,5-trimethylthiazoline (TMT). Pharmacological inhibition of CORT synthesis using metyrapone reduced freezing and increased rearing during TMT exposure, without impairing threat recognition—evidenced by robust conditioned place aversion and context-specific freezing. We also found that freezing increased upon repeated TMT exposure, but this effect was blunted when CORT synthesis was blocked during the initial encounter. Furthermore, stress priming via restraint or footshock replicated the effects of prior TMT exposure, enhancing freezing and suppressing rearing. These findings suggest that while recognition of TMT's aversiveness remains intact without CORT, this hormone is essential for determining the qualitative and temporal dynamics of defensive responses. Our results reveal a key role for CORT in shaping behavioral flexibility during threat perception.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111579"},"PeriodicalIF":3.9,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726764","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":"Broad transcriptomic effects of Egr1 knockdown in the mouse nucleus accumbens core and its role in cocaine locomotor sensitization","authors":"Yuki Nakamura ,&nbsp;Mélody Labarchède ,&nbsp;Tiago Mendes ,&nbsp;Yukari Nakamura ,&nbsp;Sophie Longueville ,&nbsp;Giulia Albertini ,&nbsp;Lucile Marion-Poll ,&nbsp;Louise-Laure Mariani ,&nbsp;Denis Hervé ,&nbsp;Anne Roumier ,&nbsp;Jean-Antoine Girault","doi":"10.1016/j.pnpbp.2025.111574","DOIUrl":"10.1016/j.pnpbp.2025.111574","url":null,"abstract":"<div><div>Immediate early genes are widely used markers of neuronal activation, but their function in neurons is not well understood. We focused on the role of <em>Egr1</em> in the nucleus accumbens core (NAc-c) in the long-lasting behavioral effects of cocaine, using an AAV expressing short hairpin RNA (<em>Egr1</em>-shRNA). <em>Egr1</em> knockdown did not alter acute cocaine locomotor effects or conditioned place preference. In contrast, shEgr1 markedly decreased the locomotor sensitization induced by repeated cocaine administration. Because EGR1 is a transcription factor, we explored the transcriptomic alterations using RNAseq completed by RT-qPCR and protein studies. <em>Egr1</em> knockdown modified the expression of numerous genes. Analysis of the upregulated genes revealed indirect activation of astrocytes and microglia evidenced by immunohistofluorescence, but shEgr1-induced dampening of cocaine sensitization was unaffected by minocycline, a microglia inhibitor. Proteasome genes were upregulated by shEgr1, possibly contributing to its functional consequences. Downregulated genes included potential EGR1 targets and comprised many genes characteristic of striatal neurons, including those coding signaling proteins (DARPP-32, CDK5 activator p35), glutamate ionotropic (NMDA NR1/2B, AMPA GluA1–3) and metabotropic (mGluR1/5) receptors, and postsynaptic proteins (PSD-95). We confirmed these alterations at the protein level and found decreased cocaine-induced phospho-Ser845-GluA1. Thus our study shows the broad transcriptional consequences of silencing <em>Egr1</em> in neurons. It provides a mechanism by which <em>Egr1</em> knockdown in the NAc-c can alter cocaine-induced locomotor sensitization, through downregulation of many genes including key components of glutamate neurotransmission. This broad role of EGR1 in regulating transcription provides clues about its function and role in learning, memory, and synaptic plasticity.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111574"},"PeriodicalIF":3.9,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710506","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":"NMDA glutamate receptor polymorphisms modulate antipsychotic-induced hyperprolactinemia in schizophrenia","authors":"Olga Yu. Fedorenko ,&nbsp;Evgeniya G. Poltavskaya ,&nbsp;Elena G. Kornetova ,&nbsp;Maxim B. Freidin ,&nbsp;Anna V. Bocharova ,&nbsp;Anastasiya S. Boiko ,&nbsp;Vadim A. Stepanov ,&nbsp;Nikolay A. Bokhan ,&nbsp;Svetlana A. Ivanova ,&nbsp;Kuzma Strelnikov","doi":"10.1016/j.pnpbp.2025.111569","DOIUrl":"10.1016/j.pnpbp.2025.111569","url":null,"abstract":"<div><div>Dopamine receptor inhibition underlies both the therapeutic and adverse effects of antipsychotics, but the mechanisms modulating these effects in patients with schizophrenia remain incompletely understood. Hyperprolactinemia (HPRL), a direct consequence of D2 dopamine receptor blockade, provides a unique clinical model to investigate how genetic variation in glutamatergic signaling influences the downstream effects of dopaminergic disruption. We hypothesized that polymorphisms in <em>GRIN2A</em> and <em>GRIN2B</em>, encoding NMDA glutamate receptor subunits, modify the neuroendocrine consequences of dopamine receptor inhibition. By studying antipsychotic-induced HPRL, we aimed to demonstrate that NMDA receptor genetic variants shape the functional outcomes of dopaminergic perturbation.</div><div>In a cross-sectional analysis of 536 schizophrenia patients, we measured prolactin levels—a sensitive biomarker of D2 receptor inhibition—and genotyped 23 <em>GRIN2A</em>/<em>GRIN2B</em> variants. Logistic regression assessed gene-drug relationships while controlling for clinical covariates.</div><div>NMDA receptor genetic variation significantly influenced susceptibility to HPRL, with distinct effects observed between antipsychotic classes with the highest effect for the typical antipsychotics, which are D2 dopamine receptor antagonists. This demonstrates that glutamatergic genotypes predict interindividual variability in the neuroendocrine response to dopamine receptor blockade.</div><div>These results provide the first clinical evidence in support of the hypothesis that NMDA receptor polymorphisms modulate the effects of dopaminergic inhibition in schizophrenia. Beyond HPRL, this dopamine-glutamate relationships paradigm may extend to other clinical outcomes of antipsychotic treatment, including therapeutic response and neurological side effects. Our findings underscore the importance of glutamatergic pathways in determining the functional consequences of dopamine receptor targeting.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"143 ","pages":"Article 111569"},"PeriodicalIF":3.9,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684522","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 altered trajectories of cerebellar gray matter volume in attention-deficit/hyperactivity disorder","authors":"Shuting Li ,&nbsp;Leilei Ma ,&nbsp;Yanpei Wang","doi":"10.1016/j.pnpbp.2025.111577","DOIUrl":"10.1016/j.pnpbp.2025.111577","url":null,"abstract":"<div><div>Increasing evidence implicates atypical cerebellar development in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, the trajectories of cerebellar subregions from childhood into adulthood—and the impact of ADHD on those trajectories—remain unclear.</div><div>We analyzed the publicly available ADHD-200 dataset, comprising 871 participants aged 7.09–20.90 years (325 with ADHD, 546 typically developing [TD] controls). High-resolution T1-weighted images were processed with the automated CERES segmentation pipeline to obtain absolute gray matter volumes for the whole cerebellum and 12 lobular subdivisions (lobules I–VI, VIIB, VIIIA, VIIIB, IX–X, and crus I–II). Relative volume is also employed in this study, which refers to the relative proportion of absolute volume to intracranial volume. Age-related change was modeled with linear regression models that included diagnosis-by-age interactions. For absolute volume, a significant age-by-diagnosis interaction was observed in the right lobule I–II and bilateral lobule X. Follow-up analyses revealed that, compared with TD individuals, those with ADHD exhibited a steeper age-related increase in gray matter volume in these regions, indicating smaller volumes at younger ages and a more pronounced age-associated rise across the observed age range. For relative volume, significant age-by-diagnosis interaction effects were found in the bilateral lobule IV and bilateral crus II. Follow-up analyses indicated that both ADHD and TD individuals showed age-related decreases in gray matter volume; however, this decline was more pronounced in the ADHD group. Taken together, the divergent age-related patterns of absolute and relative gray matter volume suggest that overall intracranial volume expansion may lag behind cerebellar growth in ADHD, such that the relative cerebellar differences are proportionally less marked than the global brain differences.</div><div>These findings unravel normative and ADHD developmental trajectories of cerebellar gray matter volume from childhood through adulthood and provide a neuroanatomical framework for optimizing the cerebellum-focused prevention and intervention strategies in ADHD.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"143 ","pages":"Article 111577"},"PeriodicalIF":3.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684600","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":"Circulating levels of gut hormones in anorexia nervosa before and after short-term weight restoration","authors":"Theresa Kolb ,&nbsp;Louisa Licht ,&nbsp;Friederike I. Tam ,&nbsp;Evelina M. Stender ,&nbsp;Michaela Ohme ,&nbsp;Alessandra Borsini ,&nbsp;Stefan Ehrlich ,&nbsp;Nikolaos Perakakis","doi":"10.1016/j.pnpbp.2025.111576","DOIUrl":"10.1016/j.pnpbp.2025.111576","url":null,"abstract":"<div><div>Gastrointestinal hormones such as glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP), glucagon, and glicentin are important regulators of appetite and glucose homeostasis. While agonists of GLP-1 and GIP receptors are approved treatments for type 2 diabetes and obesity, their role in anorexia nervosa (AN) remains largely unknown.</div><div>In this study, we measured fasting serum levels of GLP-1, GIP, glucagon, and glicentin in 80 female patients with AN before (acAN-T1) and after short-term weight restoration (acAN-T2) compared to 80 age-matched female healthy controls (HC).</div><div>GIP levels were higher (42.9%) in acAN-T1 than in HC, while GLP-1, glicentin, and glucagon showed no group differences. Additionally, acAN-T1 patients exhibited lower fasting glucose (<em>-</em>8.4%) and insulin (<em>-</em>42.6%) levels than HC. In acAN-T2, GIP, GLP-1, and glicentin levels decreased (<em>-</em>30.4%, <em>-</em>9.7%, −15.7 %, respectively), with only GIP normalizing. Glucose and insulin levels increased (4.5% and 41.4%, respectively), although they remained lower than in HC.</div><div>Importantly, changes in GIP levels after short-term weight restoration negatively correlated (<em>r</em> = <em>-</em>0.279) with changes in glucose levels. Furthermore, GIP levels in acAN-T1 were positively associated with disordered eating and depressive symptoms, independent of BMI-SDS.</div><div>These results reveal that GIP shows a distinct pattern of dysregulation and normalization in AN and link GIP levels to both glucose metabolism and symptom severity in AN. Thus, our findings support the rationale for investigating GIP receptor-targeted therapies in AN.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111576"},"PeriodicalIF":3.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696344","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":"More insights into disruption and decoupling of individual metabolic connectomes in Parkinson's disease","authors":"Song'an Shang ,&nbsp;Daixin Li ,&nbsp;Jun Yao ,&nbsp;Weikai Li ,&nbsp;Zhendong Guo ,&nbsp;Xiang Lv ,&nbsp;Lanlan Chen ,&nbsp;Jie Shi ,&nbsp;Yu-Chen Chen ,&nbsp;Jing Ye","doi":"10.1016/j.pnpbp.2025.111578","DOIUrl":"10.1016/j.pnpbp.2025.111578","url":null,"abstract":"<div><h3>Purpose</h3><div>Metabolic disturbances are hallmark pathological features of Parkinson's disease (PD) and can be noninvasively captured by arterial spin labeling (ASL). However, the metabolic pattern of disconnections beyond regional alterations remains scarcely documented. We aimed to comprehensively investigate metabolic impairments in PD at the individual network scale by utilizing abundant hemodynamic metrics.</div></div><div><h3>Methods</h3><div>The multi-delay (m-ASL) was employed to obtain corrected cerebral blood flow (CBF), arterial cerebral blood volume and arterial transit time from groups of PD patients and healthy controls (HCs). For the comparison or cross-modality analysis, the uncorrected CBF and grey matter volume were also acquired via the ASL approach with single post-labeling delay (s-ASL) and T1 sequences, respectively. Metabolic similarity network (MSN) based on perfusion data and structural similarity network (SSN) were constructed for each individual, followed by analyses of connectivity, topology, classification and coupling.</div></div><div><h3>Results</h3><div>Metabolic similarity networks in patients with PD belong to small-world connectomes but exhibit decreased global integration and local segregation at the global level. The impairments in nodal centralities, modular architectures and connectivity strengths were diverse among MSNs. m-ASL improved the diagnostic efficiency of CBF-MSN by the CBF correction and further optimized the classification performance via the integration of all MSNs. Decoupling of SSN-MSN presented pathologically increased coefficients within subnetworks, deriving from altered metabolic and structural connectivity.</div></div><div><h3>Conclusion</h3><div>Our study revealed the complex metabolic disconnections and SSN–MSN decoupling that underlie the complicated neurodegenerative process in PD, highlighting the clinical implications of m-ASL for comprehensive investigations of the metabolic pattern of disconnection syndromes.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"143 ","pages":"Article 111578"},"PeriodicalIF":3.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684599","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":"Agomelatine normalizes region-specific, diurnal mGluR5 dysregulation in a chronic mild stress rat model of depression","authors":"Celine Knudsen ,&nbsp;Majken B. Thomsen ,&nbsp;Kristoffer Højgaard ,&nbsp;Sofie L. Christiansen ,&nbsp;Ove Wiborg ,&nbsp;Heidi K. Müller ,&nbsp;Anne M. Landau ,&nbsp;Betina Elfving","doi":"10.1016/j.pnpbp.2025.111572","DOIUrl":"10.1016/j.pnpbp.2025.111572","url":null,"abstract":"<div><div>Desynchronization of circadian rhythms is a hallmark of major depressive disorder (MDD). Agomelatine is an atypical antidepressant that acts as a melatonin receptor agonist and serotonin receptor antagonist. It has shown efficacy in alleviating symptoms of MDD with a favorable side effect profile. In the brain, agomelatine also modulates the glutamatergic system and in the present study, we investigated the effects of chronic mild stress (CMS) and agomelatine treatment on metabotropic glutamate receptor 5 (mGluR5) and synaptic vesicle glycoprotein 2 A (SV2A) binding in the medial prefrontal cortex (mPFC) and hippocampus (HP) in postmortem brain tissue derived from male rats using autoradiography. To account for diurnal influences, assessments were conducted at two time points: light-on (ZT6) and light-off (ZT18). The sucrose consumption test classified animals into four groups: Control, anhedonic-like, agomelatine responders, and non-responders.</div><div>CMS increased mGluR5 binding in the prelimbic cortex of the mPFC during the light-on phase, an effect that was normalized by agomelatine treatment in responder rats. Agomelatine also reduced mGluR5 binding in the infralimbic cortex of the mPFC. No changes in mGluR5 binding were detected during the light-off phase or in the HP at either time point. Presynaptic density, assessed by SV2A levels, remained unchanged across all groups and time points.</div><div>These findings reveal significant region-specific and diurnal alterations in mGluR5, emphasizing the role of time-of-day dependent timing in regulating mGluR5 and its association with depressive-like behaviors. Furthermore, the selective normalization of mGluR5 by agomelatine in responders reinforces its potential as a targeted therapeutic approach for MDD.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"143 ","pages":"Article 111572"},"PeriodicalIF":3.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684598","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}