Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

{"title":"Uncovering the female phenotype in the VPA autism model: Brain-region specific synaptic pattern, microglial priming and behavioral singularity","authors":"Marianela E. Traetta ,&nbsp;Martin G. Codagnone ,&nbsp;Einav Litvak ,&nbsp;María José Maleville Corpa ,&nbsp;Nonthué A. Uccelli ,&nbsp;Sandra C. Zárate ,&nbsp;Analía G. Reinés","doi":"10.1016/j.pnpbp.2025.111591","DOIUrl":"10.1016/j.pnpbp.2025.111591","url":null,"abstract":"<div><div>Neurodevelopmental disorders, such as autism spectrum disorders (ASD), exhibit a poorly understood male bias. While sex differences may provide key insights into ASD etiology and treatment, the female side of animal models, such as prenatal valproic acid (VPA) exposure, remains incompletely characterized. Here, we evaluated the behavioral, synaptic, and microglial profiles of female VPA rats. Female VPA animals exhibited social deficits, including a decreased sociability index in the three-chamber test and reduced play and social-recognition behaviors in a peer-interaction test, while exploratory and repetitive activities were preserved. At the synaptic level, the medial prefrontal cortex (mPFC) showed increased synaptophysin (SYN) immunostaining, whereas the hippocampal subfield CA3, displayed reduced SYN. Additionally, CA3 neurons exhibited increased neuronal cell adhesion molecule (NCAM) immunostaining, while the mPFC showed increased levels of its polysialylated form (PSA-NCAM), resulting in distinct NCAM/PSA-NCAM ratio shifts in each region. <em>In vitro</em>, hippocampal and cortical neurons from female VPA animals exhibited preserved synaptic puncta number and dendritic tree length and responded to glutamate-induced remodeling similarly to controls, suggesting no intrinsic neuronal alterations. Microglia from the mPFC and the hippocampus exhibited a less ramified morphology, with increased cell numbers in the mPFC. Isolated and cultured microglia retained this reactive phenotype, yet they responded to the exposure to synaptic terminals similarly to controls. Our findings indicate that female VPA rats display a distinctive social deficit linked to brain-area-specific synaptic remodeling impairment and microglial reactivity. Sex-differences in the VPA model could provide valuable insights into neuron-glia interactions underlying autism.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111591"},"PeriodicalIF":3.9,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145812104","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":"Expression of concern: \"Adolescent nicotine abstinence increases anxiety and depressive-like behaviors, alcohol consumption, oxidative stress and inflammatory response accompanied by attenuated serotonergic/dopaminergic and cholinergic function in rats\" [Progress in Neuro-Psychopharmacology & Biological Psychiatry, volume 141 (2025), 111464].","authors":"","doi":"10.1016/j.pnpbp.2025.111542","DOIUrl":"https://doi.org/10.1016/j.pnpbp.2025.111542","url":null,"abstract":"","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"143 ","pages":"111542"},"PeriodicalIF":3.9,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764314","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":"Presence of an unfamiliar peer reverses escalated cocaine intake in male rats: Involvement of the subthalamic nucleus","authors":"Cassandre Vielle,&nbsp;Lucie Vignal,&nbsp;Alix Tiran-Cappello,&nbsp;Julie Meffre,&nbsp;Nicolas Maurice,&nbsp;Mickael Degoulet,&nbsp;Cécile Brocard,&nbsp;Florence Pelletier,&nbsp;Yann Pelloux ,&nbsp;Christelle Baunez","doi":"10.1016/j.pnpbp.2025.111588","DOIUrl":"10.1016/j.pnpbp.2025.111588","url":null,"abstract":"<div><div>The immediate social context critically modulates drug consumption. The presence of an unfamiliar conspecific, naive to the drug, at the time of consumption reduces cocaine self-administration in male rats during short-access sessions, as well as drug intake in human cocaine users. The subthalamic nucleus (STN), a brain structure involved in cocaine addiction and limbic processes, has been proposed to mediate such social influence on this limited level of drug intake. Whether this influence extends to escalated drug consumption remains an open question. In this study, we compared the effect of the presence of an unfamiliar peer, naive to cocaine, on cocaine self-administration in rats having been exposed to either short (2 h) or long-access sessions (6 h). We showed that the presence of the peer markedly reduced both limited and escalated cocaine intake in male rats. Preliminary tests in females revealed no effect of the peer's presence during short-access sessions; therefore, subsequent experiments were conducted in males only. Assessing the effect of STN photo-inhibition or high frequency (HF) stimulation in male rats, we demonstrated that it had no effect in the absence of the conspecific in short-access sessions, but STN photo-manipulation suppressed the influence of the peer's presence. Moreover, STN photo-inhibition and HF stimulation decreased drug consumption in long-access sessions, but no additive effect was observed when associated with the peer's presence, confirming an overriding effect of STN manipulation. Taken together, these results highlight the potential influence of socially oriented manipulations on cocaine intake and further position the STN as a critical mediator of the effect of social presence on addictive-like behaviors.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111588"},"PeriodicalIF":3.9,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792050","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":"Differential effects of chronic restraint stress on two active avoidance tasks in rats","authors":"Alba López-Moraga ,&nbsp;Mirte De Ceuninck ,&nbsp;Yana Van der Heyden ,&nbsp;Laura Vercammen ,&nbsp;Rupert Palme ,&nbsp;Bram Vervliet ,&nbsp;Tom Beckers ,&nbsp;Laura Luyten","doi":"10.1016/j.pnpbp.2025.111586","DOIUrl":"10.1016/j.pnpbp.2025.111586","url":null,"abstract":"<div><div>Although avoidance can serve an adaptive function in daily life, excessive or persistent avoidance can form a debilitating symptom of anxiety-related disorders. The transition from adaptive to maladaptive avoidance remains poorly understood, but stress is a potential contributing factor. We investigated the effects of chronic restraint stress on two active avoidance procedures: two-way active avoidance (2WAA) and platform-mediated avoidance (PMA). Whereas 2WAA entails a low-cost response, avoidance in the PMA task comes with a cost, i.e., no access to food. We hypothesized that chronic restraint stress would hinder avoidance acquisition in the 2WAA task, but increase avoidance acquisition in the PMA task. In two experiments, male and female rats underwent either chronic restraint stress or a control procedure. In Experiment 1, all rats (<em>N</em> = 31) were then trained in a 2WAA acquisition and extinction procedure, in two contexts. Stressed rats showed significantly reduced avoidance acquisition, while extinction was unaffected. In Experiment 2 (<em>N</em> = 32), stressed rats and controls were trained in a PMA acquisition and extinction procedure. Contrary to our hypothesis, we did not find effects on avoidance acquisition, although we found group and sex differences in lever press suppression. All rats gradually extinguished defensive behaviors during extinction. Overall, chronic restraint stress had limited effects on PMA, but significantly impaired avoidance acquisition in the 2WAA task without affecting its extinction. These divergent effects may relate to differences in response cost or differences in safety of the context (i.e., a permanent safe area in PMA, but not in 2WAA).</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111586"},"PeriodicalIF":3.9,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776713","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":"Exogenous estradiol and progesterone administration in healthy women does not affect decision making in Iowa gambling task","authors":"Christian Eric Deuter ,&nbsp;Michael Kaczmarczyk ,&nbsp;Hanna Deus ,&nbsp;Anna Kallidou ,&nbsp;Christian Otte ,&nbsp;Katja Wingenfeld","doi":"10.1016/j.pnpbp.2025.111589","DOIUrl":"10.1016/j.pnpbp.2025.111589","url":null,"abstract":"<div><div>Decision-making is based on the integration of various emotional and cognitive processes and is the precondition for planned, structured action. Earlier studies show an increased risk tolerance during fertile phases of the cycle, i.e. the days before ovulation with high estradiol and low progesterone levels. Various studies indicate an influence of the menstrual cycle on decision-making behavior, potentially due to cyclical fluctuations in hormone levels. Estradiol and progesterone in particular can be regarded as the key hormones in cycle regulation. Previous research in humans has primarily been based on self-reported cycle information and correlative relationships. In the described study, we have investigated the influence of an experimental administration of estradiol, progesterone and both hormones in combination in a placebo-controlled, randomized study with young, healthy women (<em>N</em> = 116, mean age 25.7 years). The established and widely used Iowa Gambling Task (IGT) served as the outcome measure. To assess decisions under ambiguity and risk, we separately analyzed task performance in early and late trials of the task. The treatment groups did not differ significantly in either outcome. We discuss the findings against the background of the existing research literature on menstrual cycle and hormone effects as well as specific characteristics of the task and conclude that the previously reported effects are either task or context specific or the hormonal fluctuations of the cycle were not reflected by our manipulation.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111589"},"PeriodicalIF":3.9,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776739","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":"Distinguishing resilience from susceptibility: Brain network alterations during fear learning in response to childhood unpredictability","authors":"Xinyu Cao ,&nbsp;Shanshan Wang ,&nbsp;Junhui Zhang ,&nbsp;Yanqing Zhang ,&nbsp;Jingjing Luo ,&nbsp;Yuanyuan Chen ,&nbsp;Jiaxin Xiang ,&nbsp;Jianjun Zhu","doi":"10.1016/j.pnpbp.2025.111587","DOIUrl":"10.1016/j.pnpbp.2025.111587","url":null,"abstract":"<div><div>Not all individuals exposed to childhood unpredictability develop psychopathology. This study breaks new ground by identifying the neural network signatures that distinguish resilience from susceptibility following such adversity. Using fear learning paradigms, we acquired fMRI data from 213 participants and constructed whole-brain functional connectivity networks. Innovatively, we employed dual resilience metrics—psychological (depressive symptoms) and biological (inflammatory TNF-alpha levels)—to classify participants into resilient and susceptible groups. Graph theory analysis found that the resilient group exhibited a sparser global network structure compared to the susceptible group. At the nodal level, the susceptible group showed increased nodal degree centrality in eight brain regions across multiple functional networks, compared to both the resilient and control groups. Furthermore, network-based statistic revealed that the resilient group demonstrated stronger connectivity between the default mode network (DMN) and both the frontoparietal and attention networks during fear learning. In contrast, susceptibility was associated with stronger connectivity between the visual network (VN), dorsal attention network (DAN), DMN, and frontoparietal network (FPN), alongside weaker connectivity within and between the DMN, DAN, and FPN. Importantly, network connectivity-based models predicted an individual's classification into the resilient or susceptible group with 89 % accuracy. Our findings uncover abnormal connectome organization within the DMN, DAN, FPN, and VN, shedding light on the neural mechanisms underlying vulnerability and resilience in the context of childhood unpredictability. By identifying these neurobiological markers of resilience, our work opens new avenues for early identification of vulnerability and development of targeted interventions to promote adaptive brain functioning in at-risk populations.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111587"},"PeriodicalIF":3.9,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776722","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":"Lactobacillus-rich microbiota promotes adaptive behavioral responses to multifactorial stress and preserves gut function, while antibiotic-induced dysbiosis suppresses these effects in mice","authors":"Luiza S. Marques,&nbsp;Juliano T.K. Jung,&nbsp;Maiza Carlin,&nbsp;Maria C.B.F. de Albuquerque,&nbsp;Cristina W. Nogueira","doi":"10.1016/j.pnpbp.2025.111590","DOIUrl":"10.1016/j.pnpbp.2025.111590","url":null,"abstract":"<div><div>The microbiota–gut–brain axis regulates gastrointestinal and neurobehavioral processes, including stress responses. Although stress and dysbiosis independently impact host physiology, their combined effects remain poorly understood. This study evaluated antibiotic-induced dysbiosis and multifactorial stress (MFS) effects on stress-coping and intestinal functionality by exploring the microbiota-gut-brain interaction. Male Swiss mice were divided into Control, Dysbiosis, MFS, and Dysbiosis+MFS groups. Dysbiosis was induced by administration of 10 mL/kg/day of an antibiotic cocktail containing Vancomycin 0.5 g/L, Metronidazole 1 g/L, Neomycin Sulfate 1 g/L, and Ampicillin 1 g/L. In MFS groups, mice underwent a 7-day multifactorial model (tail pressure, predator odor, water deprivation, 45° tilted cage, food deprivation, immobilization, and predator sound). Mice performed elevated plus maze, forced swimming, and tail suspension tests. Intestinal transit rate (%), fecal moisture content, and relative weights of the cecum and adrenal glands were assessed. Protein contents of occludin, claudin-1, and 5-HT4R in the colon, and glucocorticoid receptor in the hippocampus were determined. The microbiota profile of colorectal feces was analyzed by 16S rRNA sequencing. Dysbiosis and MFS interaction impacted the total sequences and alpha diversity of gut microbiota. Dysbiosis modified the composition of gut microbiota at the phylum, genus, and species levels, while MFS maintained Lactobacillus abundance. Dysbiosis induced intestinal dysfunction, while MFS attenuated intestinal barrier disruption without affecting other dysbiosis-induced effects. Dysbiosis and MFS individually decreased the weight gain of mice. Dysbiosis mitigated adaptive stress-coping behavior induced by MFS. Lactobacillus-rich microbiota promoted adaptive stress-coping behaviors and preserved gut function, while antibiotic-induced dysbiosis impaired both.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111590"},"PeriodicalIF":3.9,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776703","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":"On the possibility to modulate psychopathic traits via non-invasive brain stimulation: A systematic review and meta-analysis","authors":"Célia F. Camara ,&nbsp;Carmen S. Sergiou ,&nbsp;Andrés Molero Chamizo ,&nbsp;Alejandra Sel ,&nbsp;Nathzidy G. Rivera Urbina ,&nbsp;Michael A. Nitsche ,&nbsp;Paul H.P. Hanel","doi":"10.1016/j.pnpbp.2025.111582","DOIUrl":"10.1016/j.pnpbp.2025.111582","url":null,"abstract":"<div><div>The affective and interpersonal features of psychopathy describe impairments in socio-affective processes such as affective empathy, prosocial motivation and guilt. Research in neuroscience shows that these processes are associated with distinct neural circuits and cortical excitability patterns that appear to be dysregulated in individuals with psychopathy, with emerging research suggesting the potential of non-invasive brain stimulation (NIBS) to address such disruptions. To investigate this possibility, we conducted a meta-analysis of 64 sham- or active-controlled studies (122 effects) across three modalities: repeated transcranial magnetic stimulation (rTMS), theta-burst stimulation (TBS), and transcranial direct current stimulation (tDCS). Protocols were classified as excitatory (high-frequency rTMS, anodal tDCS) or inhibitory (low-frequency rTMS, continuous TBS, cathodal tDCS) depending on the expected polarity and directionality of their effects. Excitatory protocols yielded small-to-moderate improvements in socio-affective outcomes (Hedges' g ≈ 0.33–0.33), whereas only cathodal tDCS produced modest reductions among inhibitory protocols (g = −0.43). However, over 90 % of the included studies were conducted in healthy adult samples, limiting direct generalizability to psychopathy. In fact, the only available study in psychopathic individuals reported null effects. Together, these findings provide preliminary proof-of-concept for the potential of NIBS to modulate socio-affective processes relevant to psychopathy but also point to substantial methodological variability and the absence of direct evidence for psychopathy treatment in current research. Addressing these gaps is essential to evaluate the feasibility of implementing NIBS methods as a viable intervention for psychopathy.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111582"},"PeriodicalIF":3.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745414","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":"Neuropharmacological targets for schizophrenia treatment: An update","authors":"Caroline Araujo Costa Lima ,&nbsp;Marta Eduarda Oliveira Barbosa ,&nbsp;Fábio José Coelho Souza-Junior ,&nbsp;Sarah Viana Farias ,&nbsp;Eneas Andrade Fontes-Junior ,&nbsp;Cristiane Socorro Ferraz Maia","doi":"10.1016/j.pnpbp.2025.111580","DOIUrl":"10.1016/j.pnpbp.2025.111580","url":null,"abstract":"<div><div>Schizophrenia is a severe chronic psychiatric disorder that affects around 24 million people worldwide. It is characterized by a combination of positive (such as hallucinations and delusions), negative (including asociality, alogia, and avolition), and cognitive symptoms (implicating attention, memory, and executive functions). These symptoms contribute to significant personal, social and occupational impairments, substantially affecting the patients' quality of life. The etiology of schizophrenia is multifactorial, involving both genetics and environmental factors, with strong evidence supporting a neurodevelopmental origin. Additionally, schizophrenia pathophysiology has been associated with dysregulations in several systems, including the dopaminergic, glutamatergic and purinergic systems, and a chronic neuroinflammatory process. These findings reinforce that this condition is most likely the result of a complex relationship between biological, environmental, and neurochemical factors. Current pharmacological treatment remains focused on dopaminergic activity, particularly through the use of antipsychotics. However, both the glutamatergic and purinergic systems have been explored as possible therapeutic targets and have presented themselves as promising alternatives. In addition, the interaction between all these neurochemical systems in the context of schizophrenia has been poorly reported. Here, we provide a perspective of the dopaminergic, glutamatergic, and purinergic pathways integration, contributing to schizophrenia pathophysiology, suggesting potential targets for pharmacological approaches.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"144 ","pages":"Article 111580"},"PeriodicalIF":3.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752342","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":"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}