Molecular Psychiatry[JOURNAL]
Sun
200 papers
Towards modelling mental disorders in zebrafish. Neurexins severely modulate anxiety, affiliative social behaviour and aggression.
Nguyen Q, Guo F, Das J … +4 more , Hatzimanolis O, Mowry B, Cristino AS, Giacomotto J
Mol Psychiatry · 2026 Jun · PMID 42362769 · Publisher ↗
Neurexin (nrxn) genes encode synaptic cell-adhesion molecules that have been repetitively associated with neurodevelopmental and mental disorders. While the zebrafish animal model offers tremendous advantages for dissect...
Neurexin (nrxn) genes encode synaptic cell-adhesion molecules that have been repetitively associated with neurodevelopmental and mental disorders. While the zebrafish animal model offers tremendous advantages for dissecting neural development/function, no complete loss-of-function (LOF) nrxn zebrafish models are currently available. In this study, we generated the first collection of zebrafish knockout lines for each nrxn gene, with mutations ranging from transmembrane domain- to full genomic locus-deletions. Surprisingly, all homozygous lines developed normally, presenting no gross neurodevelopmental or obvious early behavioural abnormalities. However, this absence of early phenotypes translated into profound, paralog-specific behavioural alterations emerging during later developmental stages. All neurexin knockouts affected mating behaviour, complicating the generation and maintenance of homozygous lines. Except for this shared behavioural alteration, nrxn1, but not nrxn2 or nrxn3, led to marked changes in affiliative social behaviour and aggression. In contrast, nrxn2 mutants exhibited severe anxiety-like behaviours, including bottom-dwelling and repetitive freezing/seizure events. Strikingly, nrxn1 full-locus deletion mutants showed opposing behaviour, spending most of their time near the surface. The two also displayed opposite responses to open/closed field transitions; confinement alleviated nrxn2 anxiety but enhanced nrxn1 surface-dwelling. Meanwhile, nrxn3 mutants behaved normally in all our initial tests. In summary, our study introduces a complete set of zebrafish mutants covering the whole nrxn gene family, presenting striking adult behavioural alterations despite the absence of noticeable early defects; echoing the delayed onset of human psychiatric disorders such as schizophrenia. This work confirms the value of zebrafish to study mental disorders and unlock a novel platform to unravel the pathogenic contribution of neurexins and associated subtle neurodevelopmental changes/timing that drive the emergence of mental illnesses.
Targeting cortico-striatal-amygdalar networks via theta-band frontoparietal synchronization in opioid use disorder: a randomized tACS-fMRI Trial.
Soleimani G, Kuplicki R, Paulus MP … +1 more , Ekhtiari H
Mol Psychiatry · 2026 Jun · PMID 42362768 · Publisher ↗
Theta-band oscillation is integral to fronto-parietal connectivity in the executive control network and its top-down regulation on subcortical areas. External frontoparietal synchronization using theta-frequency transcra...
Theta-band oscillation is integral to fronto-parietal connectivity in the executive control network and its top-down regulation on subcortical areas. External frontoparietal synchronization using theta-frequency transcranial alternating current (tACS) is a technology to potentially engage this network. In this pre-registered, triple-blind, sham-controlled trial (NCT03907644), we tested this intervention targeting the right frontoparietal network in people with opioid use disorder (OUD) to measure network engagement and behavioral outcomes. Sixty male participants with OUD were randomized to receive 20 min of active or sham 6 Hz tACS (HD electrodes over F4 and P4). Structural, resting-state, task-based fMRI drug cue reactivity, and repeated cue-induced craving assessments were collected immediately before and after stimulation. Pre-registered outcome measures were analyzed using time × group interaction models to examine (1) modulation of drug cue-related brain activity, (2) changes in craving, (3) alterations in functional connectivity, and (4) relationship between electric field, neural responses, and craving behavior. (1) A significant Time × Group interaction revealed decreased post-stimulation opioid cue-related activity in the active group relative to sham, involving key nodes in reward processing (ventral striatum, amygdala and ventral tegmental area) (FWE corrected α = 0.05) (2) subjective craving did not differ significantly between groups (3) Group by time generalized psychophysiological interaction analyses showed increased right frontoparietal network engagement (β = 2.63, p= 0.0308) following stimulation, and increased top-down inhibitory regulation of frontoparietal network on right ventral striatum (β = 1.99, p= 0.037) and left medial amygdala (β = 1.97, p= 0.039) (4) Electric field strength in the right frontal/parietal node predicted frontoparietal network engagement in the active group (r = 0.43, p= 0.02). Together, these findings demonstrate that theta-band frontoparietal tACS can modulate activity and task-dependent coupling within cortical-subcortical circuits in OUD, supporting network-targeted neuromodulation as a potential intervention for addiction.
Sex differences in insular cortex function in persistent alcohol drinking despite aversion in mice.
Fornari C, Ricci D, Couderc Y … +5 more , Guerrero-Márquez C, Namburi P, Penet C, Nicolas C, Beyeler A
Mol Psychiatry · 2026 Jun · PMID 42362767 · Publisher ↗
One major hallmark of alcohol use disorder (AUD) is the persistence of drinking despite negative consequences. Among indicators of AUD vulnerability, binge drinking has been identified as one of the strongest risk factor...
One major hallmark of alcohol use disorder (AUD) is the persistence of drinking despite negative consequences. Among indicators of AUD vulnerability, binge drinking has been identified as one of the strongest risk factors. Although the lifetime prevalence of both binge drinking and AUD has historically been higher in men than women, this gap has dramatically narrowed in the last decade. Additionally, sex differences in AUD and binge drinking have been found in clinical and preclinical studies. At the neurobiological level, the insular cortex plays an important role in AUD, with the anterior (aIC) and posterior (pIC) divisions supporting different functions. However, the contributions of the aIC and pIC sections in sexual dimorphism of alcohol binge drinking and the persistence of alcohol drinking despite aversion remain to be uncovered. Using the drinking in the dark model in mice, we validated that female mice have a higher binge ethanol intake compared to males. To evaluate persistent ethanol consumption despite aversion, we supplemented ethanol with the bitter compound quinine, and found a higher persistent drinking in females compared to males. Using fiber photometry recordings, we revealed that aIC activity was increased during binge and persistent ethanol consumption independently of sex, whereas pIC glutamatergic neuron activity was higher during persistent ethanol drinking, specifically in female mice. Using chemogenetics, we revealed that inhibition of aIC glutamatergic neurons reduced intake of bitter solutions independently of the solvent (ethanol or water) in both sexes. In addition, inhibition of pIC glutamatergic neurons exclusively reduced persistent ethanol drinking in females, while decreasing quinine consumption only in males. These findings suggest a sex-dependent function of the pIC in the persistence of ethanol consumption, providing a starting point in understanding sex-specific functions of the insular cortex in the neurobiology of AUD.
Widespread synaptic density loss in schizophrenia follows molecular and network architecture.
Chopra S, Worhunsky PD, Naganawa M … +17 more , Zhang XH, Segal A, Labache L, Orchard E, Cropley V, Wood S, Angarita GA, Cosgrove K, Matuskey D, Nabulsi NB, Huang Y, Carson RE, Esterlis I, Skosnik PD, D'Souza DC, Holmes AJ, Radhakrishnan R
Mol Psychiatry · 2026 Jun · PMID 42350786 · Publisher ↗
Converging neuroimaging, genetic, and post-mortem evidence highlights the fundamental role of synaptic density reductions in schizophrenia pathogenesis. However, the brain-wide spatial pattern of these alterations and th...
Converging neuroimaging, genetic, and post-mortem evidence highlights the fundamental role of synaptic density reductions in schizophrenia pathogenesis. However, the brain-wide spatial pattern of these alterations and the mechanisms underlying this patterning remain to be established. Here, using [C]UCB-J radiotracer positron emission tomography (PET) imaging in individuals with schizophrenia (n = 29) and healthy controls (n = 93), we find a prominent and widespread pattern of lower synaptic density (0.58 < Cohen's D < 1.47; p < 0.05) in patients. The left hemisphere is substantially more impacted than the right (Cohen's D = 1.14; p < 0.001), with frontal, temporal, cingulate, thalamic, striatal and hippocampal areas particularly affected. Synaptic density alterations were not spatially aligned with grey matter volume alterations indexed using anatomical Magnetic Resonance Imaging. Lower synaptic density in the left hemisphere is associated with higher normative concentrations of GABA, 5HT, mGluR5 and 5HT (r = 0.68; p = 0.022). Simulation-based network diffusion models identified regions that may represent the initial sources of pathology, nominating left inferior frontal areas (p < 0.05) as potential foci from which synaptic pathology initiates and then propagates to structurally connected and molecularly similar areas. Overall, our findings provide in vivo evidence for widespread synaptic density deficits in schizophrenia that are left-lateralised, independent of grey matter volume alterations, aligned to specific neurochemical systems, and suggest that such synaptic pathology may propagate in a pattern consistent with axonal networks.
Novel approaches in depression treatment: from rapid-acting antidepressants to personalized interventions.
Guidetti C, Fava M, Papakostas GI
Mol Psychiatry · 2026 Jun · PMID 42350785 · Publisher ↗
Major depressive disorder (MDD) and treatment-resistant depression (TRD) are prevalent and debilitating conditions. Over 50% of patients have inadequate response to first-line serotonergic antidepressants and are left wi...
Major depressive disorder (MDD) and treatment-resistant depression (TRD) are prevalent and debilitating conditions. Over 50% of patients have inadequate response to first-line serotonergic antidepressants and are left with suboptimal treatment options. Rapid-acting and individually tailored treatments for MDD remain major unmet needs. This review discusses promising rapid-acting treatments, including psychedelic and neuroplastogen compounds, currently under investigation for the treatment of MDD and TRD. Among these, psilocybin has advanced to late-stage trials. In addition, we examine the emerging role of repetitive transcranial magnetic stimulation (rTMS), including novel personalized interventions, such as the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, which has demonstrated rapid antidepressant effects and is now FDA-cleared for TRD, positioning it closest to clinical translation. We also highlight the ongoing ALTO-300 trial, which is evaluating an adjunctive treatment for MDD in patients identified by an EEG biomarker-representing another promising step toward personalized treatment. Finally, we review the results of a Phase 2 study reporting outcomes that vary by a specific genotype sequence, underscoring the potential for genetically guided personalized interventions. Despite these advances, key limitations, including unblinding in psychedelic trials, scalability challenges of intensive neuromodulation protocols, and the need for validated biomarkers, pose ongoing challenges for real-world implementation.
Protein epigenetic scores derived in neonatal saliva as biomarkers of childhood cognition.
Smikle R, Mckinnon K, Vaher K … +13 more , Turner H, Cruickshank H, Amir R, Chua YW, Conole ELS, Reynolds RM, Batty GD, Tsanas A, Murphy L, Whalley HC, Marioni RE, Cox SR, Boardman JP
Mol Psychiatry · 2026 Jun · PMID 42337013 · Publisher ↗
Preterm birth is closely associated with immune dysregulation in early life and subsequent learning and psychiatric disorders, but methods for stratifying infants at risk remain elusive. Protein epigenetic Scores (EpiSco...
Preterm birth is closely associated with immune dysregulation in early life and subsequent learning and psychiatric disorders, but methods for stratifying infants at risk remain elusive. Protein epigenetic Scores (EpiScores) are DNA methylation (DNAm)-based proxies of circulating proteins and can capture health-related exposures such as chronic inflammation. EpiScore of C-reactive protein (DNAm CRP) is associated with inflammatory burden in early life, atypical brain development following preterm birth and adult cognitive ability. To evaluate the utility of neonatal protein EpiScores for predicting childhood cognition, we examined associations of DNAm CRP and 42 other saliva-based EpiScores enriched for inflammatory proteins correlated with low gestational age, with cognition in a cohort of 231 children, including 154 preterm children assessed at 2 years and 127 preterm and term-born children assessed at 5 years. DNAm CRP was negatively associated with 5-year Mullen Scales of Early Learning Composite (ELC) (β = -0.273, p = 0.002). Association magnitudes were larger for children born earlier (DNAm CRP x gestational age, β = 0.181). DNAm CD209 was positively associated with 5-year ELC (β = 0.267, adjusted p < 0.005). Fourteen other EpiScores were nominally associated with either 2-year Bayley-III Cognitive composite or 5-year ELC (absolute β range 0.180 to 0.245, p < 0.05). For preterm children, associations of DNAm CCL18 with 2-year cognition (β = 0.182, p = 0.039) and of DNAm CRP (β = -0.318, p = 0.021) and DNAm CRTAM (β = -0.307, p = 0.008) with 5-year cognition remained significant after adjustment for inflammatory exposures. We demonstrate associations between a range of neonatal salivary EpiScores and childhood cognition, suggesting the clinical value of EpiScores as early life markers of cognitive ability in children at risk of impairment warrants further investigation.
Metabolomic signatures of brain aging: A multimodal and genetic study.
Li Z, Miao Y, Zhang X … +2 more , Ma Y, Jin L
Mol Psychiatry · 2026 Jun · PMID 42337012 · Publisher ↗
Accelerated brain aging is increasingly recognized as a transdiagnostic risk factor for neuropsychiatric and neurodegenerative disorders, yet its metabolic underpinnings remain poorly understood. Here we integrated multi...
Accelerated brain aging is increasingly recognized as a transdiagnostic risk factor for neuropsychiatric and neurodegenerative disorders, yet its metabolic underpinnings remain poorly understood. Here we integrated multimodal neuroimaging (MRI), plasma metabolomics, and genomic data from the UK Biobank to identify metabolic markers of brain aging and evaluate their causal relevance. Using 1079 imaging-derived phenotypes (IDPs) from 4333 healthy participants, we trained and validated machine learning models for brain age prediction, with a least absolute shrinkage and selection operator (LASSO) regression model achieving the best performance (mean absolute error = 3.26 years, R² = 0.68). Brain age gap (BAG) was then estimated in 37,458 participants. Association analyses in 21,780 individuals identified nine plasma metabolites significantly linked to BAG after Bonferroni correction, with glucose showing the strongest effect (β = 0.32, P = 9.90 × 10⁻¹²). Genome-wide association studies (GWAS) identified 392 BAG-associated single-nucleotide polymorphisms (SNPs) (P < 5 × 10⁻⁸), and two-sample Mendelian randomization (MR) provided evidence supporting a potential causal role of glucose in accelerating brain aging. Clinically, elevated plasma glucose was positively associated with seven brain disorders, including all-cause dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, stroke, depression, and anxiety, and negatively associated with cognitive performance, movement function, and mental health outcomes. Higher glucose concentrations were also associated with reduced regional brain volumes across 80 cortical, subcortical, and cerebellar regions. These findings implicate glucose metabolism as a modifiable pathway in brain aging, with implications for early intervention strategies aimed at preserving brain health across the lifespan.
Beyond amyloid and tau: synaptic and neurodegenerative biomarkers shape MCI progression.
Delaby C, Schraen-Maschke S, Paquet C … +9 more , Blanc F, Vidal JS, Hirtz C, Assou S, Allinquant B, Bombois S, Gabelle A, Hanon O, Lehmann S
Mol Psychiatry · 2026 Jun · PMID 42337011 · Publisher ↗
Accurate prediction of which patients with mild cognitive impairment (MCI) will progress to dementia remains a major challenge. Current biomarkers detect amyloid pathology with high accuracy but offer limited prognostic...
Accurate prediction of which patients with mild cognitive impairment (MCI) will progress to dementia remains a major challenge. Current biomarkers detect amyloid pathology with high accuracy but offer limited prognostic value for disease progression. We conducted a prospective analysis in the multicentre BALTAZAR cohort, all diagnosed with MCI at baseline and followed for 3 years. Paired cerebrospinal fluid (CSF) and plasma samples were analysed with the NULISA ultrasensitive multiplex platform quantifying more than 120 central nervous system biomarkers. Prognostic performance was assessed using area under the curve (AUC) and hazard ratios (HRs), both for individual markers and for elastic-net-derived biomarker combinations validated by bootstrap and survival analyses. During the 3-year follow-up, 36% of participants converted to dementia. Plasma p-tau biomarkers showed strong accuracy for detecting amyloid positivity (AUC > 0.90) but limited prognostic value for conversion (AUC < 0.75). In CSF, markers of neurodegeneration (tau, NfL) and synaptic dysfunction (NPTX2 encoding the Neuronal Pentraxin 2) predicted conversion with higher accuracy, exceeding p-tau217 performance. The best-performing CSF combination (IL-16, tau, NPTX2) achieved an AUC of 0.86 (95%CI 0.80-0.91) and an HR of 39.8 (95%CI 9.6-165.2). Plasma combinations (p-tau181 or p-tau217 with YWHAG encoding for 14-3-3 protein gamma, a member of the 14-3-3 protein family) provided only modest improvement, likely reflecting the absence of robust synaptic markers in blood. Prognostic assessment of MCI progression to dementia is best achieved through CSF biomarker combinations reflecting neurodegeneration and synaptic dysfunction, complemented by inflammatory markers. These findings emphasize the clinical and pathophysiological relevance of downstream processes beyond amyloid and tau, and support the implementation of multimarker panels for prognosis and therapeutic monitoring.
Superior frontal and hippocampal structures associated with onset versus recurrence of mood disorders in monozygotic twins.
Macoveanu J, Siebner HR, Sankar A … +3 more , Kessing LV, Vinberg M, Miskowiak KW
Mol Psychiatry · 2026 Jun · PMID 42337010 · Publisher ↗
Mood disorders involve complex neurobiological trajectories, making it difficult to identify predictors of their onset and progression. This prospective study disentangled markers of vulnerability from markers of illness...
Mood disorders involve complex neurobiological trajectories, making it difficult to identify predictors of their onset and progression. This prospective study disentangled markers of vulnerability from markers of illness recurrence by leveraging monozygotic twins discordant for mood disorders. We followed 136 monozygotic twins (66 affected [AT], 39 high-risk, and 31 low-risk unaffected twins [UT]; mean age 37.4 ± 9.1 years; 69.9% females) for 7.1 ± 0.8 years after baseline MRI. Cox regression examined associations between regional neuroanatomy (bilateral hippocampus, precuneus, anterior cingulate volumes; superior frontal gyrus [SFG] thickness) and: (1) time-to-first onset (UT) or (2) time-to-recurrence (AT), adjusting for age, sex, intracranial volume, and symptoms. In UT, thinner bilateral SFG and smaller left precuneus were associated with greater onset risk (HR = 1.1, p < 0.04). These regions showed an approximately linear relationship across structural quartiles, with progressively higher 7-year episode-free probability from Q1 (lowest measures) to Q4 (highest measures). In contrast, in AT, smaller precuneus and bilateral hippocampal volumes predicted higher recurrence risk (HR = 1.1, p < 0.037), following a threshold-like pattern, with markedly higher 7-year risk of a mood episode for individuals in Q1 (lowest volume) compared to the higher quartiles (Q2-Q4). Our findings indicate distinct neuroanatomical risk profiles: prefrontal thinning of SFG marks vulnerability to initial onset, potentially reflecting impaired cognitive control, while hippocampal atrophy predisposes to recurrence, possibly via stress-related neurotoxicity. These stage-specific biomarkers, identified under rigorous genetic control, highlight targeted prevention strategies: cognitive interventions preserving frontal integrity in high-risk populations, and hippocampal neuroprotection to sustain remission.
Transdiagnostic mapping of brain structural abnormalities and network-constrained gray matter atrophy patterns across affective and psychotic disorders.
Qin K, Zhu P, Chen X … +11 more , Sang L, Liu H, Chen H, Xiang J, Ran J, Deng X, Pan N, Ai C, DelBello MP, Singh MK, Chen W
Mol Psychiatry · 2026 Jun · PMID 42332027 · Publisher ↗
Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are severe psychiatric disorders with distinct and overlapping clinical and neurobiological features. Despite extensive evidence of brain str...
Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are severe psychiatric disorders with distinct and overlapping clinical and neurobiological features. Despite extensive evidence of brain structural abnormalities, the transdiagnostic neuropathological mechanisms remain poorly understood. A comprehensive literature search was performed for voxel-based morphometry (VBM) studies reporting altered gray matter volume (GMV) in MDD, BD or SZ. A transdiagnostic meta-analysis was conducted to identify common and disorder-specific GMV alterations using the Seed-based d Mapping toolbox. Disease epicenter and buffering mapping were further investigated using a normative functional connectome to understand the network-constrained GM atrophy patterns. A total of 221 studies (MDD: n = 66; BD: n = 59; SZ: n = 96) encompassing 10,485 patients and 12,128 healthy controls were included. Transdiagnostic GMV reductions were identified in the medial prefrontal cortex and superior temporal gyrus. Less atrophy in the limbic/paralimbic regions and temporoparietal junction were observed for MDD, whereas SZ patients exhibited more pronounced GMV reductions in these areas. The ventrolateral prefrontal cortex emerged as a shared disease epicenter and the precuneus as a common buffer across these affective and psychotic disorders. The visual and dorsal attention networks exhibited the most pronounced buffering effects, while epicenter effects were primarily concentrated within the limbic, frontoparietal, subcortical and default mode networks. These findings suggested that affective and psychotic disorders are characterized by both shared and unique network-constrained GM atrophy patterns, which might advance precision diagnostics and inform targeted therapeutic strategies in the future.
Deep brain stimulation of the nucleus accumbens for severe self-injurious behaviour in children: long-term outcomes from a first-in-human pilot trial.
Mithani K, Breitbart S, Dinger T … +10 more , Suresh H, LeBlanc-Millar A, Huber J, Kerr EN, Taylor MJ, Fasano A, Sauter S, Hagopian L, Gorodetsky C, Ibrahim GM
Mol Psychiatry · 2026 Jun · PMID 42332026 · Publisher ↗
Children with severe self-injurious behaviour (SIB) are at risk of permanent injury and lack effective treatment options. Neuromodulation of the nucleus accumbens (NAc), a key node in reward and behavioural regulation ci...
Children with severe self-injurious behaviour (SIB) are at risk of permanent injury and lack effective treatment options. Neuromodulation of the nucleus accumbens (NAc), a key node in reward and behavioural regulation circuits, may directly modulate the drivers of SIB. We report long-term outcomes from a first-in-human, single-centre trial of deep brain stimulation (DBS) targeting the NAc in children and adolescents with profound autism and treatment-refractory SIB (NCT03982888). Six participants (ages 7-14 years; mean 11.7) underwent bilateral implantation and were followed prospectively for at least 24 months (mean 32.5 months, range 25.8-56.0). One serious adverse event occurred: a device-related infection requiring hardware explantation, followed by relapse to baseline levels of self-injury. Subsequent re-implantation in this participant yielded rapid improvement in SIB, providing single-subject, causal withdrawal-rechallenge evidence of treatment-specific benefit. Across the cohort, NAc-DBS produced sustained reductions in SIB frequency and severity, repetitive and obsessive-compulsive behaviours, and clinically meaningful improvements in quality of life. The durability of these effects over multi-year follow-up suggests that circuit-targeted neuromodulation may modify the developmental course of severe behavioural pathology. These findings provide the first long-term evidence that modulation of reward circuitry can durably alter maladaptive behaviour in childhood neurodevelopmental disorders.
A new hope: locus coeruleus-norepinephrine system at the nexus of neuropsychiatric symptoms.
Korukonda A, Weinshenker D
Mol Psychiatry · 2026 Jun · PMID 42332025 · Publisher ↗
The earliest stages of Alzheimer's disease (AD) are frequently characterized by neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, compulsivity, appetite dysregulation, and sleep disturbances, often...
The earliest stages of Alzheimer's disease (AD) are frequently characterized by neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, compulsivity, appetite dysregulation, and sleep disturbances, often preceding measurable cognitive decline. Evidence from clinical and animal studies implicates hyperactivity of the locus coeruleus-norepinephrine (LC-NE) system as a mechanistic driver of these behaviors. Here, we review noradrenergic circuits that can potentially underlie psychiatric disturbances to identify therapeutic targets for preventing and delaying onset of AD. Given that this system influences attention, arousal, mood, and stress responses, LC-NE hyperactivity across circuitry involving amygdala, thalamus, hypothalamus, anterior cingulate cortex, prefrontal cortex, and olfactory areas can contribute to NPS features in early AD. Advances in neuroimaging and physiological measures of noradrenergic function have enabled in vivo tracking of LC integrity and NE transmission, offering the opportunity to detect LC-NE dysfunction early in disease progression and potentially implement targeted pharmacologic and neuromodulatory interventions to restore optimal LC-NE tone. Overall, dissection of LC-NE circuitry and its clinical translation hold promise for developing biomarker-driven, stage-specific interventions to reduce NPS burden and enhance the efficacy of disease-modifying therapies in AD.
Re-evaluating response rates, time to reorientation and inadequate seizure duration in magnetic seizure therapy for schizophrenia and major depression.
Jelovac A, Braithwaite R
Mol Psychiatry · 2026 Jun · PMID 42332024 · Publisher ↗
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Developmentally dynamic, non-convergent transcriptomic profiles in CNV models for schizophrenia risk.
French H, Yao S, Bast L … +6 more , Roig Adam A, Stümpges P, Memic F, Mulle J, Sullivan PF, Hjerling-Leffler J
Mol Psychiatry · 2026 Jun · PMID 42315919 · Publisher ↗
Schizophrenia is a complex psychiatric disorder with significant genetic and clinical heterogeneity. Although numerous rare copy number variations (CNVs) with high risk for schizophrenia have been identified, they show n...
Schizophrenia is a complex psychiatric disorder with significant genetic and clinical heterogeneity. Although numerous rare copy number variations (CNVs) with high risk for schizophrenia have been identified, they show no obvious overlap in gene content or function. We hypothesized that the downstream effects of schizophrenia-associated CNVs converge on shared molecular pathways. To test this, we profiled the prefrontal cortex of five schizophrenia-associated CNV mouse models - 15q13.3del, 3q29del, 1q21.1del, 22q11.2del, and 16p11.2dup - using single-cell RNA sequencing across two developmental stages: adolescence and adulthood. From 292,943 high-quality single-cell transcriptomes, we identified distinct age- and cell type-specific patterns of differential gene expression and biological pathway perturbations in each model. Rather than converging on a shared molecular mechanism, each CNV affected unique cellular pathways in a developmentally dynamic manner. Notably, genes dysregulated in deep-layer corticothalamic projection neurons from 15q13.3del and 16p11.2dup models, and intratelencephalic neurons from adult 22q11.2del mice, showed enrichment for schizophrenia-SNP heritability. These results support a model in which rare CNVs contribute to schizophrenia genetic risk through developmentally dynamic, distinct pathways rather than through a shared molecular mechanism.
Paternal cytokine administration alters sperm small ncRNAs and offspring brain and behavior.
Kiridena P, van de Garde N, Masson BA … +3 more , Gubert C, Reisinger SN, Hannan AJ
Mol Psychiatry · 2026 Jun · PMID 42315918 · Publisher ↗
Paternal pre-conceptual exposure to pathogenic infection can alter offspring phenotypes via changes to sperm epigenetics, including small non-coding RNAs (ncRNAs). This phenomenon occurs even in the absence of infection...
Paternal pre-conceptual exposure to pathogenic infection can alter offspring phenotypes via changes to sperm epigenetics, including small non-coding RNAs (ncRNAs). This phenomenon occurs even in the absence of infection when pathogen mimetics trigger paternal immune activation (PIA). While this implicates a shared component of the immune response, the specific mechanisms responsible remain unknown. Cytokines are a key component of innate immunity and are highly upregulated following exposure to both pathogens and their mimetics. Here we investigate whether paternal administration of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) recapitulates alterations to sperm small ncRNAs and offspring phenotypic changes from other models of PIA. C57BL/6J male mice were administered a single dose of IL-1β, TNF-α, or vehicle, prior to mating with naïve female mice, to produce offspring. Offspring from IL-1β-treated fathers exhibited altered fasting responses and female-specific alterations to stress-coping behavior. In response to paternal TNF-α, male offspring showed increased anxiety-like behavior. Analysis of paternal sperm small ncRNA revealed that IL-1β significantly downregulated several transfer RNA-derived small RNAs (tsRNAs) and P-element-induced wimpy testis (PIWI)-interacting RNA (piRNA) clusters. Surprisingly, paternal TNF-α only slightly altered small ncRNAs, downregulating a single piRNA cluster. These results partially recapitulate offspring phenotypic changes following paternal exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, in a COVID-19 mouse model) and polyinosinic:polycytidylic acid (poly I:C, a viral mimetic). Ultimately, we provide the first evidence that cytokines have intergenerational effects on brain and behavior, and that they contribute to altered offspring phenotypes in viral-like PIA. This study demonstrates that paternal cytokines are causally involved in a mechanism of epigenetic inheritance following PIA, and highlights the importance of PIA as a pre-conceptual factor that may modulate offspring health, including risk of neuropsychiatric disorders.
Early oligodendrocyte dysfunction signature in Alzheimer's disease: Insights from DNA methylomics and transcriptomics.
Fodder K, Smith HMG, Yaman U … +7 more , Piras IS, Murthy M, Hardy J, Lashley T, de Silva R, Salih DA, Bettencourt C
Mol Psychiatry · 2026 Jun · PMID 42315917 · Publisher ↗
Much research into the aetiology of Alzheimer's disease (AD) has focused on neuronal cell types, while studies on the contribution of glial cells, particularly oligodendrocytes (OLGs), are only starting to emerge. Altere...
Much research into the aetiology of Alzheimer's disease (AD) has focused on neuronal cell types, while studies on the contribution of glial cells, particularly oligodendrocytes (OLGs), are only starting to emerge. Altered brain DNA methylation, an epigenetic modification that provides the interplay between genetics and environmental cues to tightly regulate gene expression, is well documented in AD. Yet, cell-type-specific investigations remain limited. Here, we examine the role of DNA methylation and OLGs in AD, and how such changes may impact gene expression. We performed weighted-gene correlation network analysis (WGCNA) on multiple brain omics AD datasets across species: human DNA methylation data from 4 brain regions, human brain single-nuclei RNA sequencing data and mouse brain RNA sequencing data. We compared AD-associated network modules enriched for OLG genes across AD brain regions, as well as with other neurodegenerative disease DNA methylation datasets. We identified a DNA methylation signature associated with AD, enriched for OLGs, and preserved across brain regions representing early and late AD pathology stages. Genes within this signature showed altered expression in AD OLGs, confirming cell-type specificity and relevance to AD. This OLG signature was also preserved in transgenic mice with early Aβ pathology and in other neurodegenerative diseases without Aβ pathology. We reveal a consistent pattern of OLG dysfunction spanning early to late stages of AD, across DNA methylation and gene expression. Our findings highlight OLG-associated DNA methylation changes as important in AD pathogenesis, and possibly in other neurodegenerative diseases, opening new avenues for therapeutic development.
Opposing sensitive period effects of early and late childhood maltreatment on corticolimbic responses in fear conditioning.
Zhu J, Zhou L, Zou Y … +3 more , Zhang Y, Liu Y, Teicher MH
Mol Psychiatry · 2026 Jun · PMID 42310193 · Publisher ↗
The neural mechanisms underlying fear learning are critical for survival. Childhood maltreatment increases the risk of psychopathology by disrupting these processes, yet it remains unclear whether such effects reflect th...
The neural mechanisms underlying fear learning are critical for survival. Childhood maltreatment increases the risk of psychopathology by disrupting these processes, yet it remains unclear whether such effects reflect the cumulative burden of maltreatment types or arise from timing-specific exposures during sensitive developmental periods. In this study, 213 young adults (18-28 years) completed the Maltreatment and Abuse Chronology of Exposure (MACE), which retrospectively assesses the severity and timing of ten maltreatment types across childhood. During fMRI, participants underwent a Pavlovian fear-conditioning paradigm, allowing us to measure BOLD activation in the centromedial amygdala, basolateral amygdala, and hippocampus, as well as their functional connectivity with the ventromedial prefrontal cortex (vmPFC). Using machine-learning feature selection combined with a targeted maximum likelihood estimation (TMLE) framework, we identified the most influential type-by-age exposures and evaluated their effects on neural responses under standard causal assumptions. Two distinct windows of vulnerability emerged. Early maltreatment was associated with heightened threat-safety discrimination, reflected by stronger CS+-CS- separation in regional activation and vmPFC coupling, whereas late maltreatment was associated with blunted discrimination and reduced coupling, accompanied by relatively elevated CS- responding. Although directionally opposite, both patterns may represent adaptive phenotypes that confer heightened long-term vulnerability to psychopathology. These findings highlight sensitive periods during which maltreatment disproportionately alters corticolimbic dynamics, providing a developmental framework for timing targeted interventions to reduce mental-health risk in vulnerable youth.
Engineering functional ventral midbrain dopaminergic neurons in human organoids through WNT modulation and bioreactor culture.
Raji H, Bertoli F, Perez MJ … +3 more , Lam A, Volpicelli-Daley L, Deleidi M
Mol Psychiatry · 2026 Jun · PMID 42310192 · Publisher ↗
Human midbrain organoids (hMOs) derived from induced pluripotent stem cells provide a powerful system to model disorders involving dopamine (DA) dysfunction, including Parkinson's disease (PD) and neuropsychiatric condit...
Human midbrain organoids (hMOs) derived from induced pluripotent stem cells provide a powerful system to model disorders involving dopamine (DA) dysfunction, including Parkinson's disease (PD) and neuropsychiatric conditions. However, current differentiation protocols still fall short in recapitulating early specification, substantia nigra pars compacta (SNpc)-like identity, and the functional maturation of vulnerable DA neurons. Here, we established a differentiation strategy that combines tri-phasic WNT modulation with dynamic bioreactor culture to generate hMOs enriched in SNpc-like DA neurons. This approach significantly increases the yield of TH⁺/GIRK2⁺ and TH⁺/ALDH1A1⁺ DA neurons and promotes enhanced synaptic maturation, robust electrophysiological activity, and elevated DA release. Single-cell transcriptomics revealed that this strategy drives the emergence of SOX6/GIRK2 SNpc-like neurons, accompanied by upregulation of synaptic, metabolic, and maturation programs, alongside reduced cell stress and apoptotic signaling. Importantly, hMOs demonstrated vulnerability upon exposure to α-synuclein preformed fibrils, resulting in aggregate formation and DA neuron degeneration, supporting their use as a human model of PD-relevant pathology. Overall, this system provides a scalable and physiologically relevant approach to investigate molecular mechanisms underlying neurodegeneration and DA-related disorders.
Incidence, prevalence, and global burden of attention-deficit/hyperactivity disorder from 1990 to 2021 across 204 countries in individuals under age 20: data, with critical appraisal, from the 2021 Global Burden of Disease study.
Cortese S, Kim MS, Han JH … +4 more , Oh SS, Yon DK, Ii Shin J, Solmi M
Mol Psychiatry · 2026 Jun · PMID 42304068 · Publisher ↗
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition in children and young people worldwide. Robust estimates of its incidence, prevalence, and burden are essential for informing publ...
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition in children and young people worldwide. Robust estimates of its incidence, prevalence, and burden are essential for informing public health policy and planning. Using data from the Global Burden of Disease Study 2021 (GBD 2021), this global population-based analysis assessed ADHD among individuals under 20 years of age across 204 countries and territories from 1990 to 2021. The study examined incidence, prevalence, and disability-adjusted life years (DALYs) associated with ADHD. In 2021, there were an estimated 46,890,733 (95% uncertainty interval [UI]: 32,136,904-67,271,064) prevalent cases and 4,111,621 (2,775,203-5,954,941) incident cases globally in individuals under 20 years. ADHD accounted for 574,979 (294,277-977,557) DALYs, with a global prevalence rate of 1.78% (1.22-2.55%) and an incidence rate of 0.16% (0.11-0.23%). The global DALY rate was 21.8 (11.2-37.1) per 100,000 population. Prevalence and incidence were highest in Australia, with rates of 5.62% (4.16-7.46%) and 0.49% (0.34-0.66%), respectively. Between 1990 and 2021, global prevalence and incidence rates decreased modestly by 6.0 and 5.81%, respectively. Across all GBD regions, prevalence was higher in males than females (2.52 vs 0.99%) and increased with higher socio-demographic index levels. Overall, the GBD 2021 study provides the most comprehensive global estimates of ADHD burden in young people. These findings are important for guiding policymakers and stakeholders, although potential methodological limitations suggest that the prevalence, incidence, and burden of ADHD may be underestimated.
Inhibiting fear memory recall-induced oligodendrogenesis rescues PTSD-like behaviors.
Feng J, Huang NX, Liu K … +8 more , Fan YC, Chen JF, Zhao YB, Yu B, Fu QF, Mei F, Wang F, Xiao L
Mol Psychiatry · 2026 Jun · PMID 42304067 · Publisher ↗
Recurrent re-experiencing traumatic memory is known as a common symptom in post-traumatic stress disorder (PTSD) patients, and its severity is closely related to the progression and prognosis of PTSD. Notably, some indiv...
Recurrent re-experiencing traumatic memory is known as a common symptom in post-traumatic stress disorder (PTSD) patients, and its severity is closely related to the progression and prognosis of PTSD. Notably, some individuals with PTSD exhibit white matter abnormalities. Myelin constitutes a critical structure within white matter, and myelination in the adult brain has been demonstrated to actively regulate the consolidation of remote memories. However, the dynamics of myelin after re-experiencing traumatic stressors and their functional significance remain largely unexplored. Here, we developed a repeated fear recall mouse model to mimic re-experiencing symptoms in PTSD patients, and found that repeated fear recall can reinforce remote fear memory while cause anxiety-like behaviors and social preference deficits. This coincides with region-specific oligodendrogenesis, heightened reactivation of fear recall-associated engram cells, and an increase in dendritic spine density, demonstrated through cell-lineage tracing and labeling. We hypothesize that oligodendrogenesis driven by repeated fear recall is sufficient to regulate remote fear memory and behavioral abnormalities. Loss-of-function experiments, either inducing apoptosis of new oligodendrocytes (OLs) or cell-type-specific knocking out (cKO) oligodendroglial transcription factor 2 (Olig2), significantly attenuated the abnormal reinforcement of remote fear memory and ameliorated social deficits induced by repeated fear recall. Moreover, inhibiting oligodendrogenesis through Olig2 cKO relieved anxiety-like behavior. Notably, diminished newly formed OLs also decreases fear recall-induced neuronal activation and dendritic spine density in fear-related brain regions. More importantly, administering rapamycin, a potent inhibitor of oligodendrogenesis, during repeated fear recalls phenocopies the effects of anti-myelination on fear memory-related behavioral defects. In summary, our findings demonstrate that oligodendrogenesis induced by repeated fear recall is sufficient to drive the progression of PTSD-like behaviors, likely by modulating neuronal activity and dendritic spine density within the adult fear circuitry. Pharmacological treatments that inhibiting oligodendrogenesis during the recall phase represent a promising therapeutic strategy for preventing the pathological reinforcement of long-term fear memories, thereby averting the emergence of anxiety-like behaviors and social preference deficits in individuals with PTSD. Schematic image summarizing the major findings of the present study.
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