Pub Date : 2025-12-08DOI: 10.1016/j.pnpbp.2025.111579
J.L. Baumbach , C.Y.Y. Mui , A.M. Leonetti , L.J. Martin
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.
{"title":"Corticosterone regulates the balance between freezing and rearing in defensive responses to predator threat","authors":"J.L. Baumbach , C.Y.Y. Mui , A.M. Leonetti , 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}
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 Egr1 in the nucleus accumbens core (NAc-c) in the long-lasting behavioral effects of cocaine, using an AAV expressing short hairpin RNA (Egr1-shRNA). Egr1 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. Egr1 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 Egr1 in neurons. It provides a mechanism by which Egr1 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.
{"title":"Broad transcriptomic effects of Egr1 knockdown in the mouse nucleus accumbens core and its role in cocaine locomotor sensitization","authors":"Yuki Nakamura , Mélody Labarchède , Tiago Mendes , Yukari Nakamura , Sophie Longueville , Giulia Albertini , Lucile Marion-Poll , Louise-Laure Mariani , Denis Hervé , Anne Roumier , 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}
Pub Date : 2025-12-05DOI: 10.1016/j.pnpbp.2025.111569
Olga Yu. Fedorenko , Evgeniya G. Poltavskaya , Elena G. Kornetova , Maxim B. Freidin , Anna V. Bocharova , Anastasiya S. Boiko , Vadim A. Stepanov , Nikolay A. Bokhan , Svetlana A. Ivanova , Kuzma Strelnikov
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 GRIN2A and GRIN2B, 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.
In a cross-sectional analysis of 536 schizophrenia patients, we measured prolactin levels—a sensitive biomarker of D2 receptor inhibition—and genotyped 23 GRIN2A/GRIN2B variants. Logistic regression assessed gene-drug relationships while controlling for clinical covariates.
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.
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.
{"title":"NMDA glutamate receptor polymorphisms modulate antipsychotic-induced hyperprolactinemia in schizophrenia","authors":"Olga Yu. Fedorenko , Evgeniya G. Poltavskaya , Elena G. Kornetova , Maxim B. Freidin , Anna V. Bocharova , Anastasiya S. Boiko , Vadim A. Stepanov , Nikolay A. Bokhan , Svetlana A. Ivanova , 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}
Pub Date : 2025-12-04DOI: 10.1016/j.pnpbp.2025.111577
Shuting Li , Leilei Ma , Yanpei Wang
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.
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.
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.
{"title":"Unraveling the altered trajectories of cerebellar gray matter volume in attention-deficit/hyperactivity disorder","authors":"Shuting Li , Leilei Ma , 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}
Pub Date : 2025-12-04DOI: 10.1016/j.pnpbp.2025.111576
Theresa Kolb , Louisa Licht , Friederike I. Tam , Evelina M. Stender , Michaela Ohme , Alessandra Borsini , Stefan Ehrlich , Nikolaos Perakakis
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.
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).
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 (-8.4%) and insulin (-42.6%) levels than HC. In acAN-T2, GIP, GLP-1, and glicentin levels decreased (-30.4%, -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.
Importantly, changes in GIP levels after short-term weight restoration negatively correlated (r = -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.
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.
{"title":"Circulating levels of gut hormones in anorexia nervosa before and after short-term weight restoration","authors":"Theresa Kolb , Louisa Licht , Friederike I. Tam , Evelina M. Stender , Michaela Ohme , Alessandra Borsini , Stefan Ehrlich , 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}
Pub Date : 2025-12-04DOI: 10.1016/j.pnpbp.2025.111578
Song'an Shang , Daixin Li , Jun Yao , Weikai Li , Zhendong Guo , Xiang Lv , Lanlan Chen , Jie Shi , Yu-Chen Chen , Jing Ye
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
{"title":"More insights into disruption and decoupling of individual metabolic connectomes in Parkinson's disease","authors":"Song'an Shang , Daixin Li , Jun Yao , Weikai Li , Zhendong Guo , Xiang Lv , Lanlan Chen , Jie Shi , Yu-Chen Chen , 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}
Pub Date : 2025-12-03DOI: 10.1016/j.pnpbp.2025.111572
Celine Knudsen , Majken B. Thomsen , Kristoffer Højgaard , Sofie L. Christiansen , Ove Wiborg , Heidi K. Müller , Anne M. Landau , Betina Elfving
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.
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.
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.
{"title":"Agomelatine normalizes region-specific, diurnal mGluR5 dysregulation in a chronic mild stress rat model of depression","authors":"Celine Knudsen , Majken B. Thomsen , Kristoffer Højgaard , Sofie L. Christiansen , Ove Wiborg , Heidi K. Müller , Anne M. Landau , 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}
Pub Date : 2025-12-03DOI: 10.1016/j.pnpbp.2025.111571
Paweł Krukow , Natalia Kopiś-Posiej , Víctor Gutiérrez-de Pablo , Víctor Rodríguez-González , Carlos Gómez , Jesús Poza
Childhood adversity is considered a risk factor for neurocognitive development impairments in adulthood, although research evidence for this notion is rather inconclusive. This study aimed to examine the effects of childhood trauma on rudimentary cognitive processes and their neurophysiological underpinnings in non-clinical samples of young adults. Two groups were formed based on scores from the Childhood Trauma Questionnaire: a high early trauma group (high-ACE) and a low early trauma group (low-ACE). All participants performed two versions of the choice reaction time (RT) task, while their brain activity was recorded via electroencephalography (EEG) to reconstruct global network dynamics in response to displayed stimuli. Results indicated that the high-ACE group exhibited greater RTs intra-individual variability and altered functional connectivity (FC) dynamics compared to the low-ACE group, particularly in the short foreperiod block. Performance inconsistency indexes and FC strength values were significantly correlated in the high-ACE group (p < 0.05, Spearman's correlation, FDR-corrected). Our findings showed that adults with higher early trauma exposure demonstrate reduced network flexibility and difficulties in connectivity resource allocation, which is quantified by means of delayed and less dynamic FC responses following stimulus presentation. This study contributes to the understanding of how childhood adversities alter brain functional repertoire and basic cognitive mechanisms, including those that process non-affective stimuli.
{"title":"Altered task-related brain network dynamics and performance consistency in a non-clinical group burdened with childhood trauma","authors":"Paweł Krukow , Natalia Kopiś-Posiej , Víctor Gutiérrez-de Pablo , Víctor Rodríguez-González , Carlos Gómez , Jesús Poza","doi":"10.1016/j.pnpbp.2025.111571","DOIUrl":"10.1016/j.pnpbp.2025.111571","url":null,"abstract":"<div><div>Childhood adversity is considered a risk factor for neurocognitive development impairments in adulthood, although research evidence for this notion is rather inconclusive. This study aimed to examine the effects of childhood trauma on rudimentary cognitive processes and their neurophysiological underpinnings in non-clinical samples of young adults. Two groups were formed based on scores from the Childhood Trauma Questionnaire: a high early trauma group (high-ACE) and a low early trauma group (low-ACE). All participants performed two versions of the choice reaction time (RT) task, while their brain activity was recorded via electroencephalography (EEG) to reconstruct global network dynamics in response to displayed stimuli. Results indicated that the high-ACE group exhibited greater RTs intra-individual variability and altered functional connectivity (FC) dynamics compared to the low-ACE group, particularly in the short foreperiod block. Performance inconsistency indexes and FC strength values were significantly correlated in the high-ACE group (<em>p</em> < 0.05, Spearman's correlation, FDR-corrected). Our findings showed that adults with higher early trauma exposure demonstrate reduced network flexibility and difficulties in connectivity resource allocation, which is quantified by means of delayed and less dynamic FC responses following stimulus presentation. This study contributes to the understanding of how childhood adversities alter brain functional repertoire and basic cognitive mechanisms, including those that process non-affective stimuli.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"143 ","pages":"Article 111571"},"PeriodicalIF":3.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684596","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}
Pub Date : 2025-12-02DOI: 10.1016/j.pnpbp.2025.111570
Yitian Wang , Qian Li , Beisheng Yang , Yufei Chen , Xinyi Chen , Ting Li , Fenghua Long , Haoran Li , Graham J. Kemp , Fei Li , Qiyong Gong
Objectives
This study aimed to compare the local gyrification index (LGI) between first-episode drug-naive major depressive disorder (MDD) patients and healthy controls (HC), to investigate associated alterations in functional connectivity (FC) and effective connectivity (EC), and to examine the relationships of neuroimaging alterations to cognitive performances and to neurotransmitter profiles.
Methods
Structural and resting-state functional magnetic resonance imaging were acquired from 159 MDD patients and 141 HC. LGI was calculated using FreeSurfer software. Seed-based FC and EC analyses were performed in regions showing significant group differences in LGI to explore the associated functional alterations. Neuropsychological tests for cognitive function included attention, working memory, processing speed, and executive function. Spatial correlation analysis was performed between LGI alterations and neurotransmitter receptor/transporter density maps.
Results
Compared to HC, MDD patients showed significantly lower LGI in bilateral anterior cingulate cortex (ACC), left medial orbitofrontal cortex (mOFC), left inferior parietal cortex, and right lateral occipital cortex; lower FC between left mOFC and left superior frontal gyrus, and lower EC from left caudal ACC to right middle frontal gyrus. Lower LGI correlated with impaired cognitive performance in attention, working memory, and processing speed in MDD. Spatial patterns of altered LGI were positively correlated with distributions of serotonin transporter, dopamine transporter, acetylcholine transporter, and histamine receptor.
Conclusion
In MDD, impaired LGI in critical regions of the default mode network and occipital cortex is linked to prefrontal network functional dysconnectivity and to cognitive deficits. The spatial relationship of impaired LGI to specific neurotransmitter systems throws light on neurodevelopmental aspects of MDD pathophysiology.
{"title":"Lower cortical gyrification and connectivity in major depressive disorder associated with cognition deficits and neurotransmitter profiles","authors":"Yitian Wang , Qian Li , Beisheng Yang , Yufei Chen , Xinyi Chen , Ting Li , Fenghua Long , Haoran Li , Graham J. Kemp , Fei Li , Qiyong Gong","doi":"10.1016/j.pnpbp.2025.111570","DOIUrl":"10.1016/j.pnpbp.2025.111570","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to compare the local gyrification index (LGI) between first-episode drug-naive major depressive disorder (MDD) patients and healthy controls (HC), to investigate associated alterations in functional connectivity (FC) and effective connectivity (EC), and to examine the relationships of neuroimaging alterations to cognitive performances and to neurotransmitter profiles.</div></div><div><h3>Methods</h3><div>Structural and resting-state functional magnetic resonance imaging were acquired from 159 MDD patients and 141 HC. LGI was calculated using FreeSurfer software. Seed-based FC and EC analyses were performed in regions showing significant group differences in LGI to explore the associated functional alterations. Neuropsychological tests for cognitive function included attention, working memory, processing speed, and executive function. Spatial correlation analysis was performed between LGI alterations and neurotransmitter receptor/transporter density maps.</div></div><div><h3>Results</h3><div>Compared to HC, MDD patients showed significantly lower LGI in bilateral anterior cingulate cortex (ACC), left medial orbitofrontal cortex (mOFC), left inferior parietal cortex, and right lateral occipital cortex; lower FC between left mOFC and left superior frontal gyrus, and lower EC from left caudal ACC to right middle frontal gyrus. Lower LGI correlated with impaired cognitive performance in attention, working memory, and processing speed in MDD. Spatial patterns of altered LGI were positively correlated with distributions of serotonin transporter, dopamine transporter, acetylcholine transporter, and histamine receptor.</div></div><div><h3>Conclusion</h3><div>In MDD, impaired LGI in critical regions of the default mode network and occipital cortex is linked to prefrontal network functional dysconnectivity and to cognitive deficits. The spatial relationship of impaired LGI to specific neurotransmitter systems throws light on neurodevelopmental aspects of MDD pathophysiology.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"143 ","pages":"Article 111570"},"PeriodicalIF":3.9,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679573","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}
Pub Date : 2025-12-02DOI: 10.1016/j.pnpbp.2025.111573
Peiyi Wu , Ziyi Wang , Caijiu Deng , Yifang Zhou , Xiaowei Jiang , Lingtao Kong , Yuning Zhou , Qikun Sun , Ting Sun , Zhengjiao Tuo , Lei Wang , Yuang Liu , Yuxin Shen , Yanqing Tang
Background
Adolescent major depressive disorder (AMDD) emerges during a period of significant neurobiological reorganization, yet its specific pathophysiological mechanisms remain poorly understood. This study investigated structural-functional brain coupling (SC-FC coupling) in AMDD and its relationship with neurotransmitter systems and molecular profiles.
Methods
We examined 107 adolescents with AMDD and 78 healthy controls. Participants underwent multimodal neuroimaging (DTI, resting-state fMRI), clinical assessment, and cognitive testing. We analyzed regional SC-FC coupling abnormalities and their associations with neurotransmitter distributions. Gene expression profiles underlying coupling alterations were examined through partial least squares regression with Allen Human Brain Atlas data. Cell-type enrichment analysis was performed using established transcriptomic references, and developmental expression trajectories were mapped using BrainSpan developmental transcriptome atlas through CSEA tool.
Results
AMDD was characterized by decoupling in the default mode network and hypercoupling in somatomotor networks. These alterations demonstrated significant potential for diagnostic classification (AUC = 0.83–0.85) and correlated with clinical symptom severity. The spatial distribution of coupling alterations was significantly associated with multiple neurotransmitter systems, most robustly with dopaminergic and serotonergic markers. At the transcriptomic level, these alterations were correlated with distinct gene expression profiles, which were further linked to cell-type-specific signatures: genes associated with decoupled regions were enriched in neuronal lineages, while those associated with hypercoupled regions showed enrichment in glial cells.
Conclusions
These findings suggest that SC-FC alterations in AMDD are linked to neurotransmitter systems and cell-type-specific gene expression. These associations may reflect developmentally sensitive mechanisms that could inform age-appropriate intervention strategies for adolescent depression.
{"title":"Structure-function coupling alterations in adolescent depression correlate with neurotransmitter systems and cell-type-specific transcriptomics","authors":"Peiyi Wu , Ziyi Wang , Caijiu Deng , Yifang Zhou , Xiaowei Jiang , Lingtao Kong , Yuning Zhou , Qikun Sun , Ting Sun , Zhengjiao Tuo , Lei Wang , Yuang Liu , Yuxin Shen , Yanqing Tang","doi":"10.1016/j.pnpbp.2025.111573","DOIUrl":"10.1016/j.pnpbp.2025.111573","url":null,"abstract":"<div><h3>Background</h3><div>Adolescent major depressive disorder (AMDD) emerges during a period of significant neurobiological reorganization, yet its specific pathophysiological mechanisms remain poorly understood. This study investigated structural-functional brain coupling (SC-FC coupling) in AMDD and its relationship with neurotransmitter systems and molecular profiles.</div></div><div><h3>Methods</h3><div>We examined 107 adolescents with AMDD and 78 healthy controls. Participants underwent multimodal neuroimaging (DTI, resting-state fMRI), clinical assessment, and cognitive testing. We analyzed regional SC-FC coupling abnormalities and their associations with neurotransmitter distributions. Gene expression profiles underlying coupling alterations were examined through partial least squares regression with Allen Human Brain Atlas data. Cell-type enrichment analysis was performed using established transcriptomic references, and developmental expression trajectories were mapped using BrainSpan developmental transcriptome atlas through CSEA tool.</div></div><div><h3>Results</h3><div>AMDD was characterized by decoupling in the default mode network and hypercoupling in somatomotor networks. These alterations demonstrated significant potential for diagnostic classification (AUC = 0.83–0.85) and correlated with clinical symptom severity. The spatial distribution of coupling alterations was significantly associated with multiple neurotransmitter systems, most robustly with dopaminergic and serotonergic markers. At the transcriptomic level, these alterations were correlated with distinct gene expression profiles, which were further linked to cell-type-specific signatures: genes associated with decoupled regions were enriched in neuronal lineages, while those associated with hypercoupled regions showed enrichment in glial cells.</div></div><div><h3>Conclusions</h3><div>These findings suggest that SC-FC alterations in AMDD are linked to neurotransmitter systems and cell-type-specific gene expression. These associations may reflect developmentally sensitive mechanisms that could inform age-appropriate intervention strategies for adolescent depression.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"143 ","pages":"Article 111573"},"PeriodicalIF":3.9,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679545","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}
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