Maternal preeclampsia (PE) contributes to neurodevelopmental disorders. However, the underlying molecular mechanism remains unclear. We investigated the potential biological regulatory mechanisms by establishing an anima...Maternal preeclampsia (PE) contributes to neurodevelopmental disorders. However, the underlying molecular mechanism remains unclear. We investigated the potential biological regulatory mechanisms by establishing an animal model and primary cell culture. Data from the Adolescent Brain Cognitive Development human study revealed that the striatum mediates maternal PE and offspring behavioral disorders. In a rat PE model, offspring exhibited abnormal behaviors and reduced striatal vascular density, with disrupted blood-brain barrier (BBB) and swollen astrocytes. Primary astrocytes and brain microvascular endothelial cells (BMECs) were cultured. Astrocytes from PE-exposed offspring weakened tube-formation ability and BBB-related protein expression in BMECs. Transcript sequencing identified B-cell lymphoma 2 (BCL2) as a key neurodevelopmental gene affected by PE. Astrocytes with BCL2 knockdown weakened tube-formation and BBB-related protein expression in BMECs, matching PE offspring astrocytes. BCL2 knockdown in newborn rats resulted in disrupted BBB, and abnormal behaviors, similar to PE-exposed offspring. In summary, reduced astrocyte BCL2 levels contributed to BBB disruption in the striata of PE-exposed offspring, providing new insights into the mechanisms underlying neurodevelopmental disorders.
Schizophrenia is characterized by striking symptom heterogeneity, yet the mapping between specific clinical phenotypes and their underlying biological substrates remains elusive. To bridge this gap, we applied an integra...Schizophrenia is characterized by striking symptom heterogeneity, yet the mapping between specific clinical phenotypes and their underlying biological substrates remains elusive. To bridge this gap, we applied an integrative, multi-scale framework combining symptom network analysis, connectome-based predictive modeling (CPM), and transcriptomic mapping in a multi-center cohort of schizophrenia patients. This approach revealed a hierarchical dissociation between phenotypic topology and underlying biological mechanisms among the identified high-centrality core symptoms: Conceptual Disorganization, Unusual Thought Content, and Blunted Affect. While Conceptual Disorganization and Unusual Thought Content exhibited clinical coherence as psychosis-related features, CPM uncovered a divergence in their neural substrates. Conceptual Disorganization shared greater neurofunctional isomorphism with Blunted Affect-characterized by converging dysconnectivity within the Somatomotor Network (SMN) and subcortical circuits-whereas Unusual Thought Content displayed a distinct architecture driven by prominent Default Mode Network regulation beyond the shared sensorimotor substrate. Transcriptomic annotation further stratified these dimensions: psychosis-related networks were underpinned by synaptic regulatory genes, whereas Blunted Affect was enriched for intracellular MAPK signaling and metabolic processes. These findings delineate a hierarchical model in which distinct molecular etiologies-synaptic versus metabolic-cascade into shared systems-level failures at the "somato-cognitive interface". We conclude that while symptoms may group clinically, their treatment requires targeting separable molecular pathways that converge on common circuit bottlenecks. This framework reconciles symptom heterogeneity with overlapping biological substrates, advocating for a mechanism-based stratification of schizophrenia.
Methamphetamine (METH) addiction causes serious psychiatric and neurological disorders, while the overall efficacy of current interventions remains unsatisfactory. Endurance exercise is one effective approach to facilita...Methamphetamine (METH) addiction causes serious psychiatric and neurological disorders, while the overall efficacy of current interventions remains unsatisfactory. Endurance exercise is one effective approach to facilitate drug abstinence and functional rehabilitation, although its exact mechanism has not been fully elucidated. In the current work, we successfully suppressed drug craving behaviors in METH addicts by 48 weeks of aerobic exercise, and a metabolomics study indicated the elevation of serum N-Acetylneuraminic acid (Neu5Ac) specifically in exercised individuals. Further studies in rodent models of METH exposure replicated both behavioral improvement and the increase of Neu5Ac levels in circulation and the striatum. More importantly, we demonstrated that exercise stimulated the hepatic tissues to synthesize Neu5Ac, which modulates synaptic protein in the striatum to alleviate METH-seeking behaviors. In sum, our results propose a liver-brain axis in which exercise reshapes liver metabolism to facilitate drug abstinence.
Zarea A, Cassinari K, Lecoquierre F
… +45 more, Quenez O, Charbonnier C, Schramm C, Lacour M, Rousseau S, Richard AC, Rovelet-Lecrux A, Lecourtois M, Olaso R, Boland A, Deleuze JF, Gilissen C, Veltman JA, Vissers LE, Bellenguez C, Dols-Icardo O, Hardy J, Holstege H, Hulsman M, Lambert JC, Mead S, Ramirez A, Sims R, van Swieten J, Wagner M, Williams J, Bombois S, Boutoleau-Bretonniere C, Charmard-Witkowski L, de la Sayette V, Deramecourt V, Etcharry-Bouyx F, Gabelle A, Gueriot C, Le Guyader G, Le Ber I, Lebouvier T, Martinaud O, Michon A, Quelin C, Sarazin M, Sévin M, Thauvin-Robinet C, Wallon D, Nicolas G
The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset ≤65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOA...The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset ≤65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOAD patients-unaffected parents trios. After assessing known monogenic genes, we performed trio-based exome sequencing and jointly analyzed novel trios with 12 previously reported ones. Of these, we selected 16 trios for genome sequencing. We identified three patients with a pathogenic DNM in APP or PSEN1. Then, from the 46 remaining trios, we identified 38 non-synonymous coding DNM and 4 de novo copy number variants (CNVs) in exome data. Four DNM (2 novel, in SPHK2 and DDR1) and bi-allelic inherited variants in two genes affected Alzheimer disease-related genes. No significant burden of rare coding variants in exome/genome data from 5643 EOAD cases and 16097 controls was identified using nested windows centered on each DNM position, at the transcript level. From genome data, one non-coding DNM was predicted to affect splicing in an AD-associated gene, PINX1. Overall, 48% probands carried ≥1 inherited risk factor with odds ratio (OR) > 1.5 and GWAS-defined Genetic Risk Scores (GRS) distribution was more consistent with random distribution than enrichment in higher scores in probands. We confirm that DNMs in known monogenic genes explain sEOAD in a minority of cases, while candidate DNMs in other genes might account for a small proportion of additional cases. The majority of sEOAD patients may have a complex etiology including multiple inherited variants, however, GRS might not explain most of its genetic component.
Eskinazi M, Nasserdine R, Cusin RM
… +19 more, Baniotoupoulos P, Saccaro LF, De Pieri M, Corino T, Seragnoli F, Briefer JF, Aboulafia Brakha T, Richard-Lepouriel H, Penzenstadler L, Böge K, Kirchner M, Zullino D, Højlund M, Sapienza J, Bosia M, Catalan A, Vieta E, Solmi M, Sabé M
Serotonergic psychedelics are increasingly investigated as treatments for affective disorders. Concerns persist regarding their potential to induce hypomania or mania, particularly in individuals with bipolar spectrum vu...Serotonergic psychedelics are increasingly investigated as treatments for affective disorders. Concerns persist regarding their potential to induce hypomania or mania, particularly in individuals with bipolar spectrum vulnerability. Whether these substances precipitate transient mood switches or contribute to persistent bipolar illness or diagnostic transition remains unclear. We conducted a systematic review of human studies examining manic or hypomanic symptoms following exposure to serotonergic psychedelics (psilocybin, LSD, mescaline, DMT/ayahuasca) or MDMA (CRD420251160656). Databases and trial registries were searched through January 26, 2026. Eligible designs included randomized and non-randomized clinical studies, registry-based cohorts, cross-sectional surveys, and longitudinal observational studies. Outcomes included dysphoria/euphoria, manic or hypomanic symptoms and transition to bipolar disorder. Risk of bias was assessed using ROBINS-I, ROB2 or NIH tools. Twenty-three studies met inclusion criteria, four contributing to meta-analysis. Rates of psychedelic-associated dysphoria/euphoria, hypomania or mania ranged from 5.8% in controlled trials of psilocybin-assisted psychotherapy for major depressive disorders to 30% in naturalistic studies of individuals with bipolar disorder. When present, manic symptoms were typically acute and self-limited. Observational studies identified higher risks among individuals with bipolar I disorder, familial vulnerability, polysubstance use, and unsupervised or illegal use. Registry-based cohorts examining diagnostic transitions showed a prevalence of subsequent transition to bipolar disorder of 4% (95% CI 2-8%; N = 7478; I² = 32.1%), with little evidence for a hallucinogen-specific signal. Overall, serotonergic psychedelics appear to pose a low but clinically meaningful relative risk of transient mood-related symptoms in susceptible individuals while remaining relatively safe in controlled clinical settings. Long-term outcomes and repeated exposure remain insufficiently studied, underscoring the need for rigorous longitudinal research.
Atypical peripheral blood cytokine concentrations have been shown in autism, but no clear pattern has been observed. This systematic review and meta-analysis summarised current state of findings, expanded the range of cy...Atypical peripheral blood cytokine concentrations have been shown in autism, but no clear pattern has been observed. This systematic review and meta-analysis summarised current state of findings, expanded the range of cytokines, accounted for study risk of bias, and examined relations between cytokines and autism traits. Literature comparing peripheral blood cytokine in autistic and non-autistic people was systematically searched in Ovid Embase, MEDLINE and APA PsycINFO, Web of Science and Scopus, resulting in 98 studies and 54 cytokines (4236 autistic, 3333 non-autistic controls; age 2 to 65 years) in the meta-analysis. Study risk of bias was assessed using adapted Newcastle-Ottawa Scale. Compared to controls, autistic people had elevated levels of IL1-beta (Hedges' g = 0.620, 95%CI[0.32, 0.92]), IL4 (g = 0.245, 95%CI [0.07, 0.42]), IL6 (g = 0.365, 95%CI [0.011, 0.62]), IL8 (g = 0.384, 95%CI [0.15, 0.62]), IFN-gamma (g = 0.404, 95%CI [0.09, 0.72]), TNF-alpha (g = 0.31, 95%CI [0.11, 0.51]), CXCL1/GRO-α (g = 0.364, 95%CI [0.058, 0.670]) and MIF (g = 0.560, 95%CI [0.14, 0.98]). Over a third of studies were classified as having a high risk of bias; their removal revealed higher IL7 and IL1RA in autism relative to controls. Narrative synthesis produced no strong evidence for an association between cytokine and autism traits among autistic individuals. Altogether, our findings support a predominance of pro-inflammatory cytokines, while also indicating potential modulatory contributions from inhibitory cytokines, which reflect group-level differences between autistic and non-autistic individuals, but not variations of autism traits within the autistic population. However, higher-quality studies with low risk of bias are needed before firm conclusions can be drawn.
Genome-wide association studies (GWAS) and multi-omics analyses have identified numerous risk loci and thousands of potential causal genes associated with Alzheimer's disease (AD). However, the synergistic pathogenic con...Genome-wide association studies (GWAS) and multi-omics analyses have identified numerous risk loci and thousands of potential causal genes associated with Alzheimer's disease (AD). However, the synergistic pathogenic contributions of multiple low-risk causal genes within a single locus remain poorly understood. Polygenic synergism at the 11p11.2 locus was systematically examined in AD pathogenesis. Three causal genes (MTCH2, NDUFS3, and PSMC3) exhibited coordinated down-regulation in both AD patients and AD mouse models. Individual knockdown in cultured cells altered mitochondrial function and disrupted AD-associated pathways, as revealed by transcriptomic profiling. Integrated RNA-seq analysis and experimental validation demonstrated that the concurrent down-regulation of all three genes synergistically enhanced mitochondrial reactive oxygen species (ROS) generation and activated the caspase-7-mediated apoptotic pathway. Notably, pharmacological caspase inhibition with Q-VD-OPh attenuated neuronal apoptosis, ameliorated memory deficits, and reduced Aβ plaque deposition in APP/PS1 mice. Simultaneous down-regulation of multiple genes at the 11p11.2 locus contributed to mitochondrial dysfunction and apoptosis in AD, highlighting polygenic synergism as a key pathogenic mechanism.
Panic disorder is a prevalent and disabling condition marked by recurrent panic attacks and high treatment resistance. While previous research has focused on dysfunction within canonical fear circuits, the neurobiologica...Panic disorder is a prevalent and disabling condition marked by recurrent panic attacks and high treatment resistance. While previous research has focused on dysfunction within canonical fear circuits, the neurobiological basis of panic disorder may involve broader alterations across multiple brain systems. Here, we conducted a meta-analysis of functional neuroimaging experiments to identify consistent patterns of altered brain activity in panic disorder. We found increased activity in a prefrontal-hippocampus-brainstem axis, which was not confined to traditional fear-related regions. This pattern showed robust spatial associations with serotonergic and dopaminergic receptor distributions and was significantly explained by gene expression profiles of candidate genes, accounting for over one-third of the variance and supporting a polygenic model of the disorder. Further enrichment analyses revealed that the brain pattern is characterized by low neurodevelopmental and evolutionary expansion and reduced oxygen metabolism, consistent with theories of brainstem-based hypersensitivity. Functional annotation linked the identified brain pattern to emotional arousal, memory, learning, and goal-directed behavior, suggesting that panic disorder reflects psychophysiological interactions of higher-order cognitive systems and evolutionary older biological processes. These findings suggest that panic disorder involves widespread neural alterations beyond fear circuitry and highlight potential molecular and functional targets for future mechanistic and therapeutic research.
Berg H, Emich A, Cooper SE
… +9 more, Hunt C, Webler RD, Manbeck AB, Hammell A, Burton PC, Sponheim SR, Kushner MG, Kay KN, Lissek S
Mol Psychiatry
· 2026 May · PMID 42203972
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Full text
Avoidance behavior is a prominent and impairing feature of anxiety disorders, trauma- and stressor-related disorders, and obsessive-compulsive disorder. A transdiagnostic approach to identifying the neural basis of avoid...Avoidance behavior is a prominent and impairing feature of anxiety disorders, trauma- and stressor-related disorders, and obsessive-compulsive disorder. A transdiagnostic approach to identifying the neural basis of avoidance is a promising avenue to shed light on the heterogeneity among individuals affected by these conditions, collectively termed anxiety-related disorders (ARDs). In this cross-sectional study, 58 adults with ARDs and 77 healthy comparisons (HC) completed self-report measures of anxiety sensitivity (i.e., "fear of fear") and intolerance of uncertainty (i.e., "fear of the unknown"), two transdiagnostic correlates of ARDs. Participants then completed an avoidance task during functional magnetic resonance imaging (fMRI), involving a threat cue paired with shock, safety cues, and safe generalization stimuli with varying resemblance to the threat cue. We examined neural activity preceding avoidance decisions in two phases: a) threat reactivity and b) mental simulation. Threat reactivity in anterior insula and dorsomedial prefrontal cortex tracked threat-relevance of stimuli, as expected. ARD status and anxiety sensitivity both strengthened the relationship of threat reactivity in right and left anterior insula with maladaptive avoidance. We then applied multi-voxel pattern analysis (MVPA) to decode avoidance behavior from neural activity during mental simulation. For those with higher intolerance of uncertainty, avoidance behavior was less concordant with neural activity in motor cortex and intraparietal sulcus. Our results suggest that anxiety sensitivity and intolerance of uncertainty differentially alter the neural mechanisms of avoidance behavior in anxiety-related psychopathology, potentially warranting distinct intervention strategies.
Many studies have confirmed that a subset of children with autism spectrum disorder (ASD) have unusually high urinary concentrations of microbially-derived metabolites (MDMs) such as p-cresol sulfate and indoxyl sulfate....Many studies have confirmed that a subset of children with autism spectrum disorder (ASD) have unusually high urinary concentrations of microbially-derived metabolites (MDMs) such as p-cresol sulfate and indoxyl sulfate. We hypothesized that these MDMs may affect neurodevelopment through the gut-brain axis and that a sub-phenotype characterized by gut dysbiosis may be present in most ASD individuals. This multi-site study involved measuring the concentrations of many MDMs in the urine of 52 children with ASD and 47 healthy, typically developing (TD) children, aged 2 to 11 years. The measurements were conducted first with semiquantitative Liquid Chromatography and Mass Spectrometry (LC-MS), followed by targeted quantitative LC-MS. The ASD group had significantly higher concentrations of many MDMs compared to the TD group. The MDMs included phenylalanine-derived, tryptophan-derived, and yeast-derived MDMs. Almost all children with ASD had one or more MDMs at concentrations above any TD child, and sometimes 100-1000× higher. The children with ASD had an average of 3 MDMs at levels above any TD child, compared to zero (by definition) for the TD children. Classification using one or more elevated MDM yielded a sensitivity of 90% and a specificity of 100%. This MDM System is a promising non-invasive method for diagnostic screening for ASD in children ages 2 to 11 years. These data also suggest approximately 90% of children with ASD have a distinct phenotype of ASD, which we propose naming ASD associated with Microbially-Derived Metabolites (ASD-MDM), defined by objective, quantitative laboratory measurements of these metabolites in urine.
In observational studies, an unhealthy dietary pattern during pregnancy is associated with an increased likelihood of offspring ADHD. We investigated whether such associations may be partly attributable to genetic confou...In observational studies, an unhealthy dietary pattern during pregnancy is associated with an increased likelihood of offspring ADHD. We investigated whether such associations may be partly attributable to genetic confounding. Polygenic scores (PGSs) for a healthy dietary pattern were calculated for mother, father, and child trios in the COPSAC cohort. Diagnoses and trait scores of ADHD were assessed in the children at age 10. Using trio models, we tested whether the association between maternal genetic liability to a healthy dietary pattern and offspring ADHD could be accounted for by genetic confounding. In COPSAC trio models (N-trio=437), a maternal healthy dietary pattern PGS was associated with reduced ADHD trait score after adjustment for child and paternal dietary pattern PGS, suggesting indirect genetic effects consistent with causal effects from maternal diet. However, this was not replicated in MoBa (N-trio=41 580) or ALSPAC (N-trio=1 211), where direct genetic effect estimates implied an important role for genetic confounding. Collectively, these genetic results indicate a potential pathway by which genetic confounding can inflate observed associations between maternal dietary pattern in pregnancy and offspring ADHD, and do not provide any robust evidence consistent with a causal pathway between the two. These findings should be interpreted in the light of both the limited predictive power of the dietary pattern PGS, which accounted for only a small proportion of pregnancy diet variance, and the multi-faceted nature of diet as an exposure.
Schiele J, Tsai PL, Schimmele T
… +14 more, Beck S, Meyer M, Mannes M, Desmond LW, Noschka R, Huber-Lang M, Haffner-Luntzer M, Jarczok MN, Lowry CA, Reif A, Langgartner D, Stenger S, Slattery DA, Reber SO
According to the "Old Friends" hypothesis, the increased prevalence of stress-associated disorders in urban concrete landscapes of high-income countries is at least in part due to a reduced exposure to immunoregulatory m...According to the "Old Friends" hypothesis, the increased prevalence of stress-associated disorders in urban concrete landscapes of high-income countries is at least in part due to a reduced exposure to immunoregulatory microorganisms. The latter is particularly impactful when occurring during early prenatal and postnatal life. Accordingly, our own preclinical studies demonstrate that non-pathogenic rapid-growing mycobacteria, including Mycobacterium (M.) vaccae NCTC 11659 and M. vaccae ATCC 15483, have immunoregulatory and stress-protective effects when administered repeatedly prior to or during stressor exposure. Here, we advance these findings by showing that repeated intragastric (i.g.) administration of a heat-killed preparation of M. vaccae ATCC 15483 to female C57BL/6 N mice provides intergenerational stress protection. Their male offspring, despite never directly receiving administration of rapid-growing mycobacteria, were protected against multiple adverse consequences of chronic stress in adulthood. Moreover, correlational analyses implicate the fecal microbiome as a potential mediator of these effects, with M. vaccae ATCC 15483 intergenerationally facilitating α-diversity and increasing the relative abundance of bacterial taxa known to be potent short-chain fatty acid producers. Repeated intragastric (i.g.) administration of a heat-killed preparation of Mycobacterium (M.) vaccae ATCC 15483 (MvacATCC)vs. its vehicle borate-buffered saline (BBS) to adult nulliparous female C57BL/6N mice was intergenerationally protective against multiple negative physiological and immunological consequences of chronic subordinate colony housing (CSC; compared with respective single-housed control (SHC) mice), including adrenal hypertrophy, splenomegaly, thymus involution, and tibia growth reduction as well as increased splenic toll-like receptor (TLR) 2 and TLR4 protein concentrations and splenocyte ex vivo (re)activity, but also decreased splenic ex vivo glucocorticoid sensitivity, regulatory T cell (Treg) counts and Treg suppression capacity in their male offspring. In contrast, CSC-induced increase in splenic myeloid cell counts as well as of neutrophilic chemotactic activity was not affected intergenerationally by MvacATCC. Moreover, fecal microbiome analyses before and after CSC showed that MvacATCC intergenerationally facilitated α-diversity and relative abundance of bacterial taxa known to be potent short-chain fatty acid (SCFA) producers. Of note, we abstained from showing respective data of female offspring in the graphical abstract (*), as the intergenerational resilience effects of MvacATCC on female offspring were difficult to interpret. The latter was due to the fact that chronic adult stressor exposure (i.e., social instability paradigm, SIP) per se did not affect any of the physiological and immunological readouts reported in females. The graphical abstract was created with Biorender.com.
Barendse MEA, Poortman SR, Ching CRK
… +22 more, Cahn W, Cannon DM, Castro-Fornieles J, Delavari F, Fullerton JM, Hillegers M, McDonald C, Mitchell PB, Mueller BA, Pena M, Ozerdem A, Piguet C, Roberts G, Saccaro LF, Saricicek Aydogan A, de la Serna E, Sponheim SR, Sugranyes G, Xuan L, Zorlu N, Thompson PM, van Haren NEM
Bipolar and psychotic disorders are highly heritable and associated with widespread white matter microstructure abnormalities. In this project, we compare white matter microstructure of unaffected first-degree relatives...Bipolar and psychotic disorders are highly heritable and associated with widespread white matter microstructure abnormalities. In this project, we compare white matter microstructure of unaffected first-degree relatives of individuals with bipolar disorder (FDR-BD) or psychotic disorder (FDR-SZ) to that of control participants. As secondary, exploratory aims, we examined the associations of childhood traumatic experiences and working memory with white matter microstructure across relatives and controls. Finally, we compared participants with BD or SZ to controls. We combined 11 samples from 9 institutions with 408 FDR-BD, 542 FDR-SZ, 841 controls, 255 BD and 464 SZ. Analysis of the diffusion-weighted imaging data followed the ENIGMA pipeline protocols, resulting in mean fractional anisotropy (FA). Sample-level analyses were linear mixed-effects models with group as the main predictor, adjusting for age and sex and correcting for dependence between family members. Samples were combined using random-effects meta-analysis. FDR-BD showed higher FA in the posterior limb of the internal capsule (PLIC) than controls. FDR-SZ did not demonstrate any FA differences from controls. Participants with BD or SZ diagnoses from the same samples did show the expected lower FA than controls in several tracts. Working memory scores were more positively related to FA in the PLIC in FDR-SZ than in controls. The level of childhood traumatic experiences was not related to FA. White matter deficits observed in people with SZ and BD were not detected in FDR-BD and FDR-SZ, suggesting that these findings in patients are not due to familial risk but may pertain to illness itself.
Recent genomic research, considered in the wider context of knowledge from outside genomics, provides significant conceptual insights into the aetiology and pathogenesis of schizophrenia. The evidence indicates that gene...Recent genomic research, considered in the wider context of knowledge from outside genomics, provides significant conceptual insights into the aetiology and pathogenesis of schizophrenia. The evidence indicates that genetic risk is expressed across the lifespan, from foetal development through to adulthood, and involves multiple neuronal types and brain regions. Schizophrenia appears to be primarily a neuronal disorder, with synaptic dysfunction playing a central role in pathogenesis both during development and in mature adult brain function, alongside earlier non-synaptic neurodevelopmental mechanisms. Importantly, non-familial genetic and environmental factors substantially influence neurodevelopmental impairment, and this is often reflected in cognitive performance falling below familial expectations. Cognitive deficits and structural brain abnormalities are weakly correlated with familial genetic risk and are better understood as markers of neurodevelopmental vulnerability rather than causal mediators. Genomic findings also position schizophrenia within a neurodevelopmental continuum, spanning childhood-onset disorders to adult-onset psychiatric conditions, and suggest heterogeneity within schizophrenia, with some cases exhibiting stronger neurodevelopmental involvement. These findings challenge notions that schizophrenia can be ascribed to, or understood by studying, dysfunction in particular neuronal types, brain regions or circuits, or to defects at a particular stage of neurodevelopment. While schizophrenia appears to be predominantly a neuronal disorder, pathophysiology appears to be manifest widely across time and space, and in different neuronal types across the adult and foetal brain. Moreover, despite schizophrenia's high heritability, there is mounting evidence that non-familial genetic and environmental factors play important roles in the neurodevelopmental processes that impact on schizophrenia risk. Finally, variation in the impact of the neurodevelopmental factors appears to be key to understanding some of the heterogeneity within schizophrenia and the relationship between schizophrenia and other conditions. These observations have profound implications for future research, particularly in clarifying pathogenic mechanisms and refining diagnostic frameworks.
Cortical brain morphology in early-onset psychosis (EOP; age of onset <19 years) is poorly understood, partly due to recruitment constraints linked to its low incidence. We pooled T1-weighted magnetic resonance imaging (...Cortical brain morphology in early-onset psychosis (EOP; age of onset <19 years) is poorly understood, partly due to recruitment constraints linked to its low incidence. We pooled T1-weighted magnetic resonance imaging (MRI) data from 387 adolescents with EOP (mean age=16.1 ± 1.5; 49.6% female) and 338 healthy controls (CTR; mean age=15.8 ± 1.9, 54.4% female) from nine research sites worldwide. Using harmonized processing protocols, we extracted cortical brain metrics from 34 bilateral regions. Univariate regression analyses revealed widespread lower bilateral cortical thickness (left/right hemisphere: d = -0.36/-0.31), surface area (left/right: d = -0.42/-0.41), cortical volume (left/right: d = -0.58/-0.56), and Local Gyrification Index (LGI; left/right: d = -0.39/-0.52) in EOP relative to CTR. Diagnostic subgroup analyses showed broader and more pronounced case-control differences in early-onset schizophrenia for area, volume, and LGI. We found no associations with antipsychotic medication use, illness duration, age of onset, or positive symptoms. Negative symptoms were related to smaller left lingual volume (partial r = -0.21; p = 0.014) and antidepressant users had smaller area (d = -0.43; p = 0.034) and volume (d = -0.50; p = 0.003) of the right rostral anterior cingulate compared to non-users. Cortical thickness alterations in EOP showed a similar pattern to those observed in prior studies on adults with schizophrenia (SCZ; r = 0.62) and bipolar disorders (BD; r = 0.61). However, surface area alterations were overall 1.5 times greater for EOP than adult SCZ and 4.6 times greater than adult BD. In the largest study of its kind, we observed a widespread pattern of cortical alterations in adolescents with psychotic disorders, highlighting the potential impact of aberrant neurodevelopment on cortical morphology in this clinical group.
One of the major causative genes involved in Frontotemporal dementia (FTD) is Granulin (GRN), encoding for Progranulin (PGRN). GRN mutation carriers show a substantial heterogeneity with high variability in age at onset...One of the major causative genes involved in Frontotemporal dementia (FTD) is Granulin (GRN), encoding for Progranulin (PGRN). GRN mutation carriers show a substantial heterogeneity with high variability in age at onset and pathological presentation, even within the same family or identical mutations, suggesting the presence of additional genetic factors. Single nucleotide polymorphisms in the Transmembrane protein 106B (TMEM106B) locus were identified as a genetic risk-associated factor for FTD. The top variant identified was the non-coding rs1990622, with the major allele (T) associated with an increased risk to develop FTD, while subjects with the minor allele (C) were less likely to develop disease, suggesting a protective effect. In this study, we investigate in a large Italian cohort of GRN mutation carriers, how the coding variant TMEM106B-rs3173615, in linkage disequilibrium with rs1990622, modulates age at onset, survival, and PGRN levels, including, up to date, the highest sample size of homozygous protective allele carriers. Genetic screening for TMEM106B-rs3173615 was performed on a total of 187 GRN mutation carriers, comprising 131 FTD patients and 56 pre-symptomatic subjects. Individuals with the protective genotype (GG) had a risk of FTD onset reduced by 80%, with a median age at onset of 77 years compared to a median age at onset of 63 years for individuals without the protective genotype. TMEM106B-rs3173615 acts as a genetic modifier of age at onset in the presence of GRN mutations and could be considered in clinical practice to optimize risk stratification for FTD.
Varela-Andrés N, Hernández-Del Caño C, Cebrián-León A
… +11 more, Blanco A, Los Arcos-López de Pariza I, Fernández Del Campo IS, García-Losada S, Arévalo JC, Sánchez-Martín M, Bajo-Grañeras R, Martín R, Sánchez-Aguilera A, Merchán MA, Deogracias R
Brain-derived neurotrophic factor (BDNF) is a master regulator of neuronal differentiation and inhibitory circuit maturation in the mammalian brain. Yet, its downstream mediators in distinct neuronal populations remain i...Brain-derived neurotrophic factor (BDNF) is a master regulator of neuronal differentiation and inhibitory circuit maturation in the mammalian brain. Yet, its downstream mediators in distinct neuronal populations remain incompletely defined. Here, we identify mitogen- and stress-activated kinase 1 (MSK1) as a critical mediator of BDNF signalling during postnatal striatal development. MSK1 expression predominates in GABAergic neurons across the cortex and striatum, with region-specific dynamics: MSK1 expression in cortical GABAergic interneurons declines from postnatal day 5 (P5) to day 30 (P30), while expression in striatal GABAergic medium spiny neurons (MSNs) persists into adulthood. Using a novel Msk1 KO mouse model, generated by deleting exon IV of Msk1, we find that striatal volume and MSN dendritic complexity decrease by P60, without cortical neuron alterations, underscoring MSK1´s striatal-specific role. Mechanistically, MSK1 drives BDNF-induced MeCP2 phosphorylation at serine 421 in MSNs via MAPK/ERK, independently of CaMKII, forming a nuclear complex with MeCP2, thus amplifying MSK1´s role in transcriptional regulation. This MSK1-MeCP2 signalling is also involved in BDNF-dependent and independent morphological developmental processes of cultured striatal neurons. Accordingly, Msk1 KO striatum shows dysregulated GABAergic (Gad1, Gabrg3) and dopaminergic (Drd1, Drd2, Drd3) gene expression, mirroring profiles in MeCP2 deficient models. Behaviourally, Msk1 KO mice display hypersociability, impaired nest-building, and increased depressive-like behaviour in the forced swimming test, contributing to striatal circuit dysfunction. These findings link MSK1-mediated molecular disruptions to inhibitory circuit imbalances and behaviours reminiscent of psychiatric disorders, positioning MSK1 as a potential therapeutic target for neurodevelopmental and psychiatric disorders, including those associated with MeCP2 dysfunction.
Considerable individual variations in empathic abilities have been observed, but the contributing factors and underlying neural mechanisms remain poorly understood. Dominance hierarchy is a fundamental phenomenon in grou...Considerable individual variations in empathic abilities have been observed, but the contributing factors and underlying neural mechanisms remain poorly understood. Dominance hierarchy is a fundamental phenomenon in grouped animals and human beings, which has a profound impact on mental health and behaviors. Here, we show that social rank modulates empathic pain responses, with subordinate mice displaying significantly stronger empathic pain than dominant counterparts. Our findings reveal that the glutamatergic projection from the anterior cingulate cortex (ACC) to the nucleus accumbens core (NAcC) is critical for the development of empathic pain in subordinate mice. Selective activation of the ACC-NAcC pathway enhances empathic pain intensity in dominant mice, whereas inhibition of the pathway attenuates such responses in subordinate mice. Through synaptic molecular screening, we identified Galntl6 as a key regulator of enhanced synaptic glutamate transmission from ACC to D1-type medium spiny neurons (D1 MSNs) in the NAcC. Collectively, these findings provide a framework for understanding the neural basis of the impact of social status on empathic pain.
The serotonin system is the main therapeutic target for selective serotonin reuptake inhibitors (SSRIs) in treating depression, yet the mechanism of action of SSRIs remains incompletely understood. To investigate the mol...The serotonin system is the main therapeutic target for selective serotonin reuptake inhibitors (SSRIs) in treating depression, yet the mechanism of action of SSRIs remains incompletely understood. To investigate the molecular and transcriptional effects of SSRI administration on serotonin neurons, we performed spatial transcriptomics, a spatially resolved RNA-sequencing method in intact brain tissue. Mouse brain sections containing the dorsal raphe nucleus and adjacent midbrain structures were analyzed, revealing six distinct serotonergic subpopulations with unique molecular signatures and spatial distributions. Both acute and chronic fluoxetine treatment induced a large number of changes in gene expression in the dorsal raphe nucleus. Notably, Htr1a expression increased following acute treatment but decreased after chronic administration, supporting previous findings on serotonin transporter blockade effects on 5-HT1A autoreceptors. Gene enrichment and network analysis identified key pathways modulated by SSRI administration, including Ras, MAPK and cAMP signaling pathways as well as pathways involved in axonal guidance. Additionally, we observed treatment-dependent opposing transcriptional changes in neuropeptides, particularly Thyrotropin-releasing hormone (Trh) and Prodynorphin (Pdyn), with distinct spatial localization within the dorsal raphe nucleus. Collectively, our transcriptomic and in situ hybridization analyses reveal spatial and cell-type-specific heterogeneity in SSRI action within the dorsal raphe nucleus, providing new insights into the molecular basis of SSRI treatment effects.