Transl Psychiatry [JOURNAL]
Sun
200 papers
Exploring offspring behaviour after prenatal COVID-19 vaccination in mice.
Otrokocsi L, Maácz F, Tod P … +2 more , Gölöncsér F, Sperlágh B
Transl Psychiatry · 2026 Jun · PMID 42297775 · Publisher ↗
Maternal immunisation allows the transfer of protective antibodies to the offspring, reducing the risk of severe infection during early life. While vaccination during pregnancy is clinically recommended, its long-term im...
Maternal immunisation allows the transfer of protective antibodies to the offspring, reducing the risk of severe infection during early life. While vaccination during pregnancy is clinically recommended, its long-term impact on neurodevelopment remains under investigation. Autism spectrum disorder (ASD) is a neurodevelopmental condition characterised by social and behavioural alterations. Here, we evaluated whether prenatal exposure to the COVID-19 mRNA BNT162b2 vaccine or influenza vaccine affects general and autism-related behavioural outcomes in juvenile (4 weeks) and adult (8 weeks) mouse offspring. We also assessed maternal and fetal immune responses by measuring cytokines, soluble P2X7 receptor, BDNF, CRP, and lipid peroxidation in maternal plasma and fetal brain tissue. Prenatal COVID-19 vaccination elicited a moderate maternal cytokine response (increased IL-6 and KC) without overt fetal brain inflammation. Mild, age- and sex-dependent behavioural changes were observed, including anxiety-related parameters in the elevated plus maze and altered locomotion in the open field at 4-8 weeks, however, no consistent or robust ASD-like behavioural phenotype emerged across ages. Fetal P2X7 receptor levels were elevated, while fetal CRP, BDNF, and TBARS remained unchanged. In adult offspring, BDNF was selectively reduced in the prefrontal cortex, whereas hippocampal BDNF and P2X7 receptor levels in both regions were unaffected. Although embryonic P2X7 receptor levels were transiently elevated following COVID-19 vaccination, these changes were not accompanied by fetal inflammation or persistent adult purinergic alterations. Prenatal influenza vaccination induced mild, age-dependent behavioural alterations, such as increased circling in juveniles and reduced sociability in females, without detectable maternal or fetal inflammatory responses or changes in fetal neurotrophic markers. In contrast, maternal poly(I:C) administration provoked robust systemic inflammation and pronounced fetal brain effects, including elevated cytokines, CRP, P2X7 receptor, and region-specific microglial density, accompanied by persistent reductions in adult BDNF expression. Overall, within the limits of this experimental design, prenatal COVID-19 vaccination did not produce long-lasting ASD-like phenotypes or widespread neurodevelopmental alterations, while influenza vaccination had limited and transient effects. These findings are consistent with the absence of widespread or persistent neurodevelopmental disruption in this experimental model, although further studies-including multiple doses, gestational timepoints, and cellular-level analyses-are warranted to fully elucidate mechanisms and long-term outcomes.
Excess EEG beta-band oscillations in Dup15q syndrome correlate with clinical severity.
Hipp JF, Chamberlain S, DiStefano C … +6 more , Frohlich J, Hernandez MC, Saravanapandian V, Vogel-Farley V, Goeldner C, Jeste SS
Transl Psychiatry · 2026 Jun · PMID 42297774 · Publisher ↗
Dup15q syndrome is a rare genetic neurodevelopmental disorder caused by copy number gains of 15q11.2-q13.1, which include UBE3A and three GABA-A receptor subunit genes among several other genes. The contribution of the d...
Dup15q syndrome is a rare genetic neurodevelopmental disorder caused by copy number gains of 15q11.2-q13.1, which include UBE3A and three GABA-A receptor subunit genes among several other genes. The contribution of the different genes to etiology remains elusive. Excess EEG beta-band power is a characteristic electrophysiological phenotype of this syndrome and a candidate biomarker of increased GABA-A receptor activity. Here we investigate the link between clinical and EEG phenotypes. We implemented a method to isolate oscillatory activity in the beta-band (16-32 Hz) from the background of the EEG power spectrum, i.e., locally referenced power (LRP) and applied it to EEGs from children with Dup15q syndrome (n = 52) and age-matched typically developing children (n = 14). We then investigated the relationship of LRP with cognitive ability (assessed with the Mullen Scales of Early Learning or the Differential Ability Scale), and adaptive behaviors (assessed with the Vineland Adaptive Behavior Scales). LRP was strongly elevated in individuals with Dup15q syndrome compared to typically developing children (effect size, Hedges' g = +1.84). LRP significantly correlated with both cognitive ability (developmental quotient; r = -0.48, p = 0.008) and adaptive functioning (Adaptive behavior composite score; r = -0.56, p = 0.002) in individuals without a history of epilepsy. Our results suggest that excess GABA-A receptor function is a relevant component of Dup15q syndrome pathophysiology and further substantiates the relevance of EEG beta-band power as a biomarker in Dup15q syndrome.
Phocaeicola vulgatus improves anxiety-like behavior by ameliorating amygdala neuroinflammation and the neurite impairment in IBS.
Wu J, He J, Zhang K … +9 more , Liu X, Yang P, Wang D, Xu Z, Qian W, Zhang L, Lei Z, Hou X, Tao B
Transl Psychiatry · 2026 Jun · PMID 42289401 · Publisher ↗
Anxiety is highly comorbid with disorders of gut-brain interaction, including irritable bowel syndrome (IBS). The gut microbiota is implicated in both conditions, yet the underlying mechanisms remain unclear. This study...
Anxiety is highly comorbid with disorders of gut-brain interaction, including irritable bowel syndrome (IBS). The gut microbiota is implicated in both conditions, yet the underlying mechanisms remain unclear. This study aimed to elucidate the neuropathological basis of anxiety in diarrhea-predominant IBS (IBS-D) and identify potential microbiota-based therapeutic targets. Here, Mendelian randomization analysis established a bidirectional causal relationship between IBS and anxiety. In our clinical cohort, 35.85% of IBS-D patients presented with comorbid anxiety, and GAD-7 anxiety scores correlated significantly with IBS symptom severity. Resting-state functional magnetic resonance imaging (rs-fMRI) revealed that IBS-D patients with comorbid anxiety exhibited significantly altered regional homogeneity (ReHo) in nine brain regions, with the most pronounced reductions observed in the bilateral amygdala. Moreover, bilateral amygdala ReHo could effectively differentiate these patients, with receiver operating characteristic (ROC) analysis yielding area under curve (AUC) of 0.746. To investigate the underlying pathology, we established a water avoidance stress (WAS) mouse model that successfully recapitulated the anxiety-like behaviors and visceral hypersensitivity observed clinically. Critically, these phenotypes were transmissible, as recipient mice colonized with microbiota from the WAS-induced IBS-D group also developed visceral hypersensitivity and anxiety-like behaviors. Phocaeicola vulgatus was determined as a key bacterial strain significantly depleted in both our IBS-D patient cohort and the WAS-induced IBS-D mice, with its abundance negatively correlating with anxiety levels. As anticipated, IBS-D patients with lower abundance of P. vulgatus exhibited reduced amygdala ReHo and Mendelian randomization analysis identified P. vulgatus as a protective factor against anxiety. Correspondingly, therapeutic supplementation with P. vulgatus ameliorated anxiety-like behaviors in WAS-induced IBS-D mice by attenuating neuroinflammation and restoring neuronal morphology in the amygdala. In conclusion, this study provides the first evidence that P. vulgatus can alleviate anxiety in IBS by targeting amygdala-centered neuropathology, presenting a novel psychobiotic strategy for treating emotional comorbidities in disorders of gut-brain interaction.
Characterizing non-hallucinogenic psychedelics beyond the head twitch response: phenotypic fingerprinting of lisuride and LSD.
King JL, Effinger DP, Basquez-Pfeifer C … +4 more , Wallingford JR, Calderon JR, O'Connell CK, Thompson SM
Transl Psychiatry · 2026 Jun · PMID 42288474 · Publisher ↗
The head-twitch response (HTR) is widely used as a preclinical assay for the hallucinogenic potential of compounds, with its utility based on 5HTR activation. Here, we examine how the polypharmacological agonists lisurid...
The head-twitch response (HTR) is widely used as a preclinical assay for the hallucinogenic potential of compounds, with its utility based on 5HTR activation. Here, we examine how the polypharmacological agonists lisuride and lysergic acid diethylamide (LSD) influence behavioral and physiological outcomes in mice to test whether the HTR reliably reflects overall psychoactivity. Lisuride (0.5 mg/kg) elicited no HTR yet impaired locomotion and coordination, evoked a pronounced stress response, disrupted cognitive function, and markedly reduced prefrontal cortex (PFC) electroencephalogram (EEG) power across several frequency bands. In contrast, LSD (0.1 mg/kg) produced a robust 5HTR-dependent HTR but had minimal impact on locomotion, coordination, stress responsivity, cognitive function, or PFC EEG power. None of these other behavioral or physiological effects of lisuride or LSD were mediated by 5-HT₂A receptors, as pretreatment with the selective antagonist MDL 100907 did not alter outcomes. These results reveal a striking dissociation: the compound that evoked no HTR produced broad behavioral, physiological, and cortical disruptions, while the compound that elicited robust HTRs had little effect. Our findings demonstrate that the HTR alone is not sufficient to identify psychoactivity and is best used in conjunction with other endpoints.
Preoperative gut microbial network alterations and BCAA-Related metabolic disturbance in postoperative delirium after cardiac surgery: a prospective matched multi-omic study.
Lyu C, Wang Z, Zhao R … +4 more , Zhao H, Liu S, Lian H, Wang X
Transl Psychiatry · 2026 Jun · PMID 42285959 · Publisher ↗
Postoperative delirium (POD) is a frequent neuropsychiatric complication after cardiac surgery, yet the biological basis of individual susceptibility remains unclear. In this prospective cohort study, 317 adults undergoi...
Postoperative delirium (POD) is a frequent neuropsychiatric complication after cardiac surgery, yet the biological basis of individual susceptibility remains unclear. In this prospective cohort study, 317 adults undergoing elective on-pump cardiac surgery were enrolled and followed for POD during the first 7 postoperative days. Thirty patients who developed POD were then matched 1:1 with 30 non-POD controls by age, sex, and primary diagnosis for multi-omic analyses. Preoperative fecal samples were collected from the first bowel movement after admission and before prophylactic antibiotic administration, and postoperative fecal samples were collected from the first postoperative bowel movement. Paired fecal samples underwent shotgun metagenomic sequencing, and perioperative serum samples underwent untargeted metabolomic profiling. Preoperatively, α- and β-diversity were comparable between groups, but patients who subsequently developed POD exhibited a less connected and less integrated microbial network structure. Postoperatively, gut microbial composition differed significantly between groups (PERMANOVA R² = 0.053, P < 0.001). Metagenomic profiling identified 35 differentially abundant species and 16 differentially enriched KEGG level 3 pathways, with POD-associated features showing inferred functional shifts toward amino-acid catabolism, including branched-chain amino acid (BCAA)-related pathways. Untargeted metabolomics demonstrated marked perioperative remodeling in both groups, but POD was associated with a 27-metabolite panel characterized predominantly by lower postoperative levels or impaired recovery, with pathway enrichment converging on valine, leucine, and isoleucine metabolism. Integrative analyses further linked POD-associated microbial taxa with amino-acid catabolic pathways and lower levels of BCAA-related serum metabolites. These findings suggest that POD is associated with preoperative alterations in microbial network organization and a postoperative microbiome-metabolome disturbance pattern centered on amino-acid metabolism, particularly the BCAA axis.
Optimizing tDCS cognitive outcomes in schizophrenia: the role of dopaminergic tone and antipsychotic load.
García-Fernández L, Romero-Ferreiro V, Muñoz-Gualan AP … +7 more , Cardona-Bejarano S, de Los Santos D, Ripoll Ayús I, Moleón-Ruiz Á, Martín-Bejarano García M, Wynn R, Rodriguez-Jimenez R
Transl Psychiatry · 2026 Jun · PMID 42285955 · Publisher ↗
Working memory deficits are a central cognitive impairment in schizophrenia and a key therapeutic target. Transcranial direct current stimulation (tDCS) has emerged as a potential cognitive enhancer, yet considerable int...
Working memory deficits are a central cognitive impairment in schizophrenia and a key therapeutic target. Transcranial direct current stimulation (tDCS) has emerged as a potential cognitive enhancer, yet considerable interindividual variability limits its clinical utility. Pharmacological modulation of dopaminergic signaling, particularly through antipsychotic medications, may influence neuroplasticity and thereby alter responsiveness to tDCS. This study investigated whether antipsychotic dose or pharmacodynamic profile affects tDCS-related working memory improvements in schizophrenia. In a randomized, double-blind, placebo-controlled trial, 120 clinically stable outpatients received active or sham bifrontal tDCS delivered over 10 consecutive weekdays. Working memory performance was assessed using the MATRICS Consensus Cognitive Battery. Antipsychotic regimens were categorized as full D2 antagonists or partial D2 agonists, and all doses were converted to olanzapine equivalents. Results showed a significant negative correlation between antipsychotic dose and tDCS-induced working memory enhancement (r = -0.197, p = 0.031), indicating diminished cognitive gains at higher doses. In contrast, no significant differences in working memory outcomes emerged between patients receiving full antagonists versus partial agonists. These findings suggest that overall dopaminergic blockade, rather than specific receptor-binding profiles, modulates cognitive responsiveness to tDCS. High antipsychotic doses may reduce neuroplastic capacity, thereby limiting the therapeutic potential of neuromodulation. The results highlight the need to consider antipsychotic load in the design and interpretation of cognitive enhancement trials and support the use of pharmacological burden as a stratification variable in precision-psychiatry approaches.
Predicting stress response trajectories: Differential contributions of limbic and prefrontal regions to cortisol and affective responses.
Lipka R, Kreuzpointner L, Bärtl C … +9 more , Giglberger M, Konzok J, Peter HL, Speicher N, Waller L, Kudielka BM, Wüst S, Walter H, Henze GI
Transl Psychiatry · 2026 Jun · PMID 42285949 · Full text
Why do individuals respond differently to stress? Since rodent studies indicated that stress regulation relies on limbic and medial prefrontal cortex (mPFC) outputs, we aimed to investigate whether data from these region...
Why do individuals respond differently to stress? Since rodent studies indicated that stress regulation relies on limbic and medial prefrontal cortex (mPFC) outputs, we aimed to investigate whether data from these regions could also predict cortisol and affect trajectories following psychosocial stress in humans. In this pre-registered study, 281 healthy adults (145 female) were exposed to ScanSTRESS. Repeated assessments of salivary cortisol and negative affect were used to identify response trajectories (i.e. groups of participants) using latent class mixture modelling (LCMM). LCMMs without brain predictors were compared to LCMMs including structural (volume, thickness) and functional (activation, exposure-time effect) predictors from the amygdala, hippocampus, or mPFC regions, using common fit indices including the Akaike Information Criterion. Results showed that cortisol LCMMs without brain predictors exhibited a single mean trajectory, indicative of homogeneous cortisol responses across the sample. Adding brain predictors resulted in three to four response trajectories, depending on region and outcome. Within identified models, cortisol 'hyper-response' trajectories were predicted by larger amygdala and hippocampus volumes. Cortisol 'non-responses' were predicted by greater amygdala activation and volume. 'Elevated baseline' cortisol was predicted by higher hippocampal activation. mPFC markers did not predict cortisol trajectories, however, medial orbitofrontal cortex parameters identified negative affect response profiles mirroring measures of long-term stress exposure and affect. Together, our findings suggest dissociated roles of limbic and mPFC regions in stress regulation: While limbic structures predicted cortisol responses, the mPFC shaped affective experience.
Association of glymphatic function with 40-Hz neural oscillations, systemic metabolic markers, and cognitive performance in healthy aging adults: An EEG and MRI study.
Lin S, Lu X, Liang Q … +5 more , Huang H, Chen S, Chen Q, Wei H, Qiu Y
Transl Psychiatry · 2026 Jun · PMID 42285933 · Publisher ↗
Aging-related cognitive decline is frequently concomitant with systemic metabolic dysregulation. However, the mechanisms linking age-related cognitive decline to systemic metabolic dysregulation remain poorly defined. We...
Aging-related cognitive decline is frequently concomitant with systemic metabolic dysregulation. However, the mechanisms linking age-related cognitive decline to systemic metabolic dysregulation remain poorly defined. We collected magnetic resonance imaging (MRI), electroencephalogram (EEG), and serum markers from 193 individuals (135 young adults [94 males] and 58 older adults [29 males]) in a multimodal dataset. Glymphatic system (GS) metrics were assessed indirectly using diffusion tensor image analysis along the perivascular space (DTI-ALPS) index and blood-oxygen-level-dependent cerebrospinal fluid (BOLD-CSF) coupling. EEG data were used to evaluate 40-Hz neural oscillatory dynamics. Partial correlation analyses and moderation analyses were performed to identify relationships among age, GS metrics, serum markers, cognitive performance, and 40-Hz oscillatory dynamics. The MRI metrics of GS activity declined with age in healthy adults. The power of 40-Hz neural oscillations across the whole brain showed a negative correlation with global BOLD-CSF coupling, similar correlations were also observed between regional 40-Hz power and corresponding regional BOLD-CSF coupling in the anterior, middle, and posterior regions of the brain. The MRI metrics of GS activity significantly associated with several serum markers and moderated the relationship between serum markers and cognitive performance. The results established an integrated neurophysiological framework of aging, metabolic dysregulation, gamma oscillation deficits, GS metrics decline, and cognitive decline. These findings emphasize the critical importance of maintaining normal GS function and preserving 40-Hz oscillatory activity in the current landscape of therapeutics targeting age-related cognitive deterioration.
Associations between adverse childhood experiences and progression to incident psychiatric disorders in older adults: A 22-year cohort study.
Fan HY, Zheng MR, Meng XX … +8 more , Zhang Q, Du ZC, Su Z, Cheung T, Ungvari GS, Ng CH, Xiang YT, Wang G
Transl Psychiatry · 2026 Jun · PMID 42276993 · Publisher ↗
The long-term impact of adverse childhood experiences (ACEs) on the development of psychiatric disorders in older adults remains unclear. This study examined associations between ACEs and incident psychiatric disorders i...
The long-term impact of adverse childhood experiences (ACEs) on the development of psychiatric disorders in older adults remains unclear. This study examined associations between ACEs and incident psychiatric disorders in older adults. Data from the 2000-2022 wave of Health and Retirement Study in the USA were analyzed. Time-varying Cox regression and multistate Markov models were applied to explore the impact of ACEs on transitions across five health states: healthy, physical conditions (PC), mental health symptoms (MS), comorbid PC & MS, and psychiatric disorders. Models were adjusted for demographic, behavioral, and disease-related factors. A total of 8628 participants were included, with a mean age of 64.75 years (SD = 8.01). During a mean follow-up duration of 16.8 years, 1429 developed psychiatric disorders (incidence: 9.85 per 1000 person-years). ACEs were significantly associated with higher risk of incident psychiatric disorders in a dose-response relationship. Participants with ACEs had higher transition percentages and intensities from healthy to less healthy states, notably from PC & MS to psychiatric disorders (percentages: 3.7 vs. 3.2%) and from the healthy state to MS (intensities: 0.130 vs. 0.104). They also spent less time in the healthy state and more time in comorbid states, with a 33% higher 22-year cumulative probability of psychiatric disorders (25.3 vs. 19.0%). ACEs appear to have enduring adverse impacts on mental health in later life by accelerating the progression to comorbidity and the development of psychiatric disorders. Early clinical screening and physical-mental health interventions are essential for prevention.
Divergent transcriptomic pathways underlie sex-biased cognitive rescue by developmental GSK3B inhibition in a mouse model of 22q11.2 deletion syndrome.
Passecker J, Chang CY, Dagunts A … +8 more , Aloimonos CM, Leitner L, Petryk A, Wagner FF, Myroshnychenko MV, Kupferschmidt DA, Gogos JA, Gordon JA
Transl Psychiatry · 2026 Jun · PMID 42276980 · Publisher ↗
Neuropsychiatric disorders such as schizophrenia frequently exhibit marked sex differences in onset, clinical features, and treatment response. However, the molecular and developmental bases of these differences remain p...
Neuropsychiatric disorders such as schizophrenia frequently exhibit marked sex differences in onset, clinical features, and treatment response. However, the molecular and developmental bases of these differences remain poorly defined. Here, we report a sex-dependent effect of developmental, paralog-selective GSK3B inhibition on working memory (WM) in the Df(16)A mouse model of 22q11.2 deletion syndrome (22q11.2DS), a genetic condition conferring high risk for schizophrenia. Pharmacological inhibition of GSK3B with BRD3731 rescued WM deficits and enhanced prefrontal cortex (PFC)-ventral hippocampus (vHPC) theta synchrony in male Df(16)A mice, but had no benefit in female mutants and impaired performance in wild-type (WT) females. Transcriptomic profiling of the postnatal PFC revealed previously unrecognized sex-by-genotype interactions in gene expression associated with the 22q11.2 deletion also implicating GSK3B-associated pathways. Notably, Gsk3b expression itself displayed opposing patterns in Df(16)A mice relative to WT mice, being elevated in males and reduced in females, potentially explaining the observed sex-specific behavioral and circuit responses. Our findings suggest that GSK3B is part of a broader, sexually dimorphic gene network that governs PFC circuit maturation and cognitive function. Specifically, our transcriptomic profiling delineates a postnatal window where the 22q11.2DS model exhibits these sexually dimorphic signatures. Notably, these signatures include many genes previously implicated in schizophrenia, autism, and intellectual disability, likely shaping the disorder's sex-specific pathophysiology. More broadly, this work underscores the importance of incorporating sex as a biological variable in translational research and supports precision psychiatry approaches that align interventions with sex-specific neurobiological profiles.
Value representation in youth psychopathology: evidence of a transdiagnostic risk mechanism for psychosis.
Millman ZB, Gold JM, Schiffman J … +9 more , Ellman LM, Walker EF, Powers AR, Woods SW, Silverstein SM, Mittal VA, Corlett PR, Strauss GP, Waltz JA
Transl Psychiatry · 2026 Jun · PMID 42270591 · Publisher ↗
Negative symptoms of schizophrenia are associated with deficits in representing the value of actions, observed in reinforcement learning (RL) tasks as impaired learning from gains but intact learning from losses. This RL...
Negative symptoms of schizophrenia are associated with deficits in representing the value of actions, observed in reinforcement learning (RL) tasks as impaired learning from gains but intact learning from losses. This RL profile contrasts with depression, where enhanced loss sensitivity is common. Whether a schizophrenia-like RL pattern characterizes youth at clinical high-risk (CHR) for psychosis - who show modest psychosis transition rates but high rates of co-occurring depression - remains unclear. We tested whether CHR youth show a schizophrenia-like RL profile and whether RL parameters relate differentially to negative vs. depressive symptoms by estimating RL in CHR (n = 292), clinical controls (CC; n = 241) with other psychopathologies, and healthy controls (n = 175). Participants completed symptom interviews, neuropsychological assessments, a dimensional psychosis risk calculator, and an RL task in which participants could seek gains or avoid losses. A computational gain-loss Q-learning model decomposed task behavior into components indexing value updating and value-guided choice. Although overall RL performance was similar across groups, in both CHR and CC youth, higher negative, but not depressive symptoms, were selectively associated with reduced win-stay behavior following gains. Computational parameters suggested this behavioral pattern reflected disrupted updating and expression of positive value representations. Lower win-stay rates were also linked to lower premorbid intelligence and higher psychosis risk calculator scores. Here, a schizophrenia-like RL profile was unrelated to depression but associated with multiple indicators of psychosis risk across clinical groups, suggesting a transdiagnostic psychosis risk mechanism distinct from affective disturbance.
Npas4 is involved in synaptic and cognitive function by regulating the transcription of Neuroligin-1 and N-cadherin.
Gui Y, Chen Y, Guo Q … +9 more , Luo Y, Yang F, Mahaman YAR, Wang JZ, Liu R, Luo H, Shu X, Wang X, Huang F
Transl Psychiatry · 2026 Jun · PMID 42270582 · Publisher ↗
Ischemic injury has been reported to induce mild to severe permanent deficits. Nevertheless, its recovery is often dynamic, depending on the plasticity of the injured neurons. The current study found that during the earl...
Ischemic injury has been reported to induce mild to severe permanent deficits. Nevertheless, its recovery is often dynamic, depending on the plasticity of the injured neurons. The current study found that during the early stage of cerebral ischemia (1 h), Npas4 expression was increased in the hippocampus of mice, thereby transcriptionally regulated the expression of Neuroligin-1 and N-cadherin to enhance long-term potentiation. Knocking down of Npas4 reduced the level of Neuroligin-1 and N-cadherin, sequentially prevented the enhanced neural plasticity in the early cerebral ischemia. Furthermore, the downregulation of Neuroligin-1 and N-cadherin also impeded the ischemia-induced enhancement in neural plasticity without affecting the expression of Npas4. Overexpression of Npas4 in the primary neurons increased the number of VAMP2-labeled synaptic vesicles, while interfering the expression of Neuroligin-1 and N-cadherin in the primary neurons with siRNA reduced the increase of VAMP2-labeled synaptic vesicles without affecting the Npas4 expression. Interestingly, the transcriptional level of Npas4, Neuroligin-1, and N-cadherin declined in multiple brain regions of Alzheimer's disease (AD) patients and 3 × TG AD mice. Moreover, overexpression of Npas4 increased the expression of Neuroligin-1 and N-cadherin, ameliorated the synaptic plasticity impairment of 3 × TG mice, and enhanced the cognitive function. These findings suggest a previously undiscovered biological mechanism of neural plasticity, driven by Npas4 upregulation of Neuroligin-1 and N-cadherin, which partially explain why the compensatory increase in Npas4 in the early stages of ischemic injury and the lack of Npas4 in AD progression, highlighting potential therapeutic strategies for cognitive deficits.
Intermittent fasting protects against stress-induced depression and demyelination via the gut microbiota-brain axis.
Ding X, Murayama R, Cai Y … +3 more , Yue Y, Yang JJ, Hashimoto K
Transl Psychiatry · 2026 Jun · PMID 42252286 · Publisher ↗
Chronic stress is a major risk factor for depression and disrupts myelin integrity in brain regions involved in emotional regulation. Although intermittent fasting (IF) improves metabolic and inflammatory states, its eff...
Chronic stress is a major risk factor for depression and disrupts myelin integrity in brain regions involved in emotional regulation. Although intermittent fasting (IF) improves metabolic and inflammatory states, its effects on stress-induced depression and demyelination remain unclear. Here, we investigated whether IF alleviates depression-like behaviors and myelin deficits in mice exposed to chronic restraint stress (CRS) and whether these effects involve modulation of the gut microbiota. Adult male C57BL/6 J mice underwent 14 days of CRS while maintained on either an ad libitum (AL) diet or an IF regimen. CRS induced robust depression-like phenotypes-characterized by increased immobility in the forced swimming test and reduced sucrose preference-without affecting locomotor activity, whereas IF significantly attenuated these behavioral abnormalities. Black-Gold II staining and myelin basic protein (MBP) immunofluorescence revealed marked demyelination in the corpus callosum, medial prefrontal cortex, and hippocampus of CRS mice, which was substantially reversed by IF. 16S rRNA sequencing demonstrated that IF reshaped gut microbial diversity and community composition under stress. Species-level analyses identified Prevotellamassilia timonensis and Muricoprocola aceti as positively associated with myelin integrity and behavioral improvement, whereas Anaeroplasma abactoclasticum showed negative associations. Functional pathway prediction further indicated that IF partially normalized stress-induced alterations in microbial metabolic functions. Collectively, these findings demonstrate that IF mitigates depression-like behaviors and preserves myelin integrity in CRS-exposed mice, potentially through gut microbiota-mediated mechanisms. IF may therefore represent a promising non-pharmacological strategy for alleviating stress-related neurobiological dysfunction.
Toxoplasma gondii infection is associated with changes in chronic outcomes in traumatic brain injury.
Spitz G, Baker TL, McDonald SJ … +12 more , Hicks AJ, Knott R, Sun M, Mitchell J, Gan G, Krishnadas N, O'Brien TJ, O'Brien WT, Law M, Ponsford JL, Rowe C, Shultz SR
Transl Psychiatry · 2026 Jun · PMID 42248867 · Publisher ↗
Traumatic brain injury (TBI) can lead to lasting neurological and emotional effects. Latent Toxoplasma gondii (T. gondii) infection, prevalent worldwide, may exacerbate these outcomes by altering immune and neurochemical...
Traumatic brain injury (TBI) can lead to lasting neurological and emotional effects. Latent Toxoplasma gondii (T. gondii) infection, prevalent worldwide, may exacerbate these outcomes by altering immune and neurochemical pathways. This cross-sectional observational study investigated whether chronic T. gondii infection is associated with structural brain differences and long-term outcomes in survivors of moderate-to-severe TBI ≥ 10 years post-injury. 89 TBI survivors (≥10 years post-injury) were recruited from a tertiary-centre database; 35 (39%) tested positive for latent T. gondii via plasma IgG. Thirty-two age- and sex-matched controls without TBI were included (25% T. gondii-seropositive). Nonparametric regression analyses adjusted for age, sex, and intracranial volume, with false discovery rate corrections applied. Primary outcomes were MRI-based measures of white matter microstructure, cortical thickness, and subcortical volumes. Secondary outcomes included neuropsychological assessments of anxiety, depression, cognition, and TBI blood biomarkers. Within the TBI group, T. gondii-positive individuals had reduced fibre density and increased diffusivity in the posterior corpus callosum, increased cortical thickness (insula, cuneus), and reduced brainstem volume. They also reported higher anxiety and mediation analysis showed brainstem volume partially mediated the link between infection and anxiety. Within controls, T. gondii infection was not significantly associated with anxiety, cognition, white matter microstructure, or blood biomarkers. However, controls with T. gondii infection did have increased cortical thickness in the left inferior temporal gyrus and reduced volume in the left caudate compared to their uninfected counterparts. Taken together, latent T. gondii infection may alter brain structure and exacerbate anxiety in chronic TBI. These findings support considering infection status in TBI prognostics and call for further research into its mechanistic and clinical implications.
Neighborhood opportunity, white matter, and cognition in a large pediatric neuroimaging study.
Yildiz-Ozhan N, Ku BS, Zekelman LR … +6 more , Zurrin R, Zhang F, O'Donnell LJ, Rathi Y, Seitz-Holland J, Cetin-Karayumak S
Transl Psychiatry · 2026 Jun · PMID 42248835 · Publisher ↗
Neighborhood opportunities are key influences on child development, yet existing research has largely emphasized socioeconomic indicators as proxies for environmental context. However, it remains unclear which specific c...
Neighborhood opportunities are key influences on child development, yet existing research has largely emphasized socioeconomic indicators as proxies for environmental context. However, it remains unclear which specific components of multidimensional neighborhood features are most strongly associated with tract-level white matter microstructure and cognition in children. Using data from 6141 children (ages 8-10 years) in the Adolescent Brain Cognitive Development (ABCD) Study and well-validated harmonized diffusion MRI, we examined multilevel associations between neighborhood opportunity, white matter microstructure, and cognitive performance. Neighborhood opportunity was measured using the Child Opportunity Index 2.0 (COI), which includes an overall score, three domain-level scores capturing Education, Social-Economic, and Health-Environment conditions, and 29 individual neighborhood indicators. Generalized additive models were used to characterize potentially non-linear associations while accounting for demographic and familial factors. Higher neighborhood opportunity was associated with greater fractional anisotropy (FA) in the Superior Longitudinal Fasciculus I (SLF-I), a fronto-parietal association tract implicated in higher-order cognitive functions. Higher neighborhood opportunity was also associated with better cognitive performance, with the strongest associations observed for Crystallized Cognition, reflecting accumulated knowledge and experience-based abilities. Mediation analyses indicated that SLF-I FA partially accounted for the association between neighborhood opportunity and cognitive performance. At the indicator level, access to high-quality education, higher neighborhood employment rates, and greater health insurance coverage emerged as the strongest correlates of neurocognitive outcomes. Together, these findings emphasize the value of multidimensional neighborhood measures and highlight specific, modifiable contextual factors that may represent targets for community-level interventions aimed at supporting neurocognitive development during childhood.
Cumulative mild stress during early life alters prefrontal astrocytic proteins and elevates peripheral S100B in young adult mice.
Kim J, Ko G, Kim JH … +1 more , Chang KA
Transl Psychiatry · 2026 Jun · PMID 42248833 · Publisher ↗
The prevalence of major depressive disorder (MDD) in young adulthood has increased in recent decades and represents a leading cause of psychological burden, highlighting the importance of prevention and early interventio...
The prevalence of major depressive disorder (MDD) in young adulthood has increased in recent decades and represents a leading cause of psychological burden, highlighting the importance of prevention and early intervention for depression in young adults. Early-life stress has been closely associated with the onset of depression in young adulthood, leading to adverse outcomes, including reduced quality of life, impaired social functioning, and socioeconomic burden. Among the various neuropathological features of depression, astrocytic abnormalities are increasingly recognized as key contributors. Therefore, we aimed to investigate the association between dysregulated astrocyte expression and depression in young adults. We utilized CPMS (cumulative mild prenatal stress, maternal separation and social defeat) mice as a young adult depression model, in which animals were exposed to a cumulative mild stress (CMS) paradigm during development, including prenatal stress, maternal separation, and social defeat. We further categorized CPMS mice into susceptible and resilient groups based on social interaction behavior. To explore the translational relevance of our findings, we subsequently analyzed blood samples from drug-naïve patients with MDD in young adulthood (mean age of 24 years). CPMS-susceptible mice of both sexes exhibited anxiety- and depression-like behaviors, accompanied by reduced expression of astrocytic markers in the prefrontal cortex. Furthermore, elevated S100B protein levels were observed in the blood of both CPMS mice and patients, showing a positive correlation with the severity of clinical symptoms. Together, these findings indicate that exposure to CMS during early life is associated with altered astrocytic protein expression and elevated circulating S100B, highlighting its potential relevance as a biomarker for depression in young adulthood.
Prenatal stress, excitatory-inhibitory imbalance, and ADHD risk: a hypothesis-driven perspective on psilocybin-induced neuroplasticity.
Ahmadian-Moghadam S, Roshan-Milani S, Saboory E
Transl Psychiatry · 2026 Jun · PMID 42248832 · Publisher ↗
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition in which prenatal stress and long-lasting disruptions of excitatory-inhibitory (E/I) balance have been implicated as key vulnera...
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition in which prenatal stress and long-lasting disruptions of excitatory-inhibitory (E/I) balance have been implicated as key vulnerability factors. Although established pharmacological and behavioral treatments are effective for many individuals, they are not universally successful and do not directly target upstream neurodevelopmental mechanisms. In this hypothesis-driven perspective, we examine whether psilocybin-induced neuroplasticity could theoretically modulate stress-related neurodevelopmental risk pathways relevant to ADHD. Rather than presenting psilocybin as an evidence-based intervention, we synthesize findings from related preclinical and clinical literatures to explore conceptual plausibility. Preclinical studies in non-ADHD models indicate that psilocybin can induce rapid and sustained synaptic plasticity, alter cortical E/I dynamics, and reverse stress-associated structural and functional alterations. Human clinical trials in adults-primarily in mood, trauma-related, and substance use disorders-demonstrate durable changes in emotional regulation, cognitive flexibility, and large-scale brain network organization, processes that overlap with neural systems implicated in ADHD. Research into the use of psilocybin for ADHD is in its early stages, with emerging, largely self-reported, and preliminary studies suggesting potential benefits for managing symptoms like inattention, impulsivity, and emotional dysregulation. We therefore frame psilocybin as a speculative (secondary/tertiary) approach that could, in principle, be explored to probe mechanisms of E/I rebalancing and neuroplasticity. Key mechanistic uncertainties-including the state-dependent effects of psilocybin on excitation and inhibition and the possibility of exacerbating existing imbalances-are explicitly discussed. Ethical and developmental considerations, particularly regarding vulnerable populations, are emphasized as critical constraints on translation. Finally, we propose a translational research roadmap encompassing preclinical prenatal-stress models, biomarker-driven pilot studies in ADHD, and multimodal outcome measures integrating neuroimaging, electrophysiology, and molecular indices. By clearly distinguishing established evidence from hypothesis, this perspective aims to stimulate rigorous and ethically grounded research rather than to advocate premature clinical application.
The sex-specific role of adrenal androgens in youth psychopathology.
Weisner FE, Serio B, Valk S … +5 more , Bläschke L, Degenhardt F, Hinney A, Hirtz R, Dinkelbach L
Transl Psychiatry · 2026 Jun · PMID 42243081 · Full text
Adolescence is a vulnerable period for the emergence of mental health problems. Adrenarche, an early stage of pubertal development marked by rising adrenal androgens, particularly dehydroepiandrosterone (DHEA), may influ...
Adolescence is a vulnerable period for the emergence of mental health problems. Adrenarche, an early stage of pubertal development marked by rising adrenal androgens, particularly dehydroepiandrosterone (DHEA), may influence emotional and behavioral development. However, longitudinal evidence linking early-adolescent endocrine influences to adolescent psychopathology remains limited. Using data from the Adolescent Brain Cognitive Development (ABCD) Study (up to N = 11 696), we analyzed whether salivary DHEA during early adolescence predicted later externalizing and internalizing symptoms during adolescence. Early-adolescent hormone levels were averaged across baseline and 1-year follow-up (age range = 8.9-12.4 years). Outcomes were measured via the Child Behavior Checklist (CBCL) at the 2-, 3-, and 4-year follow-ups (up to = 14.08 ± 0.68 years). Sex-stratified linear mixed models adjusted for age, race/ethnicity, BMI and physical activity. In males, higher DHEA levels were linked to fewer externalizing symptoms across follow-ups (e.g., β = -0.07 SD change of CBCL per SD-change of log-transformed DHEA levels (95% CI [-0.10, -0.04] at 3-year) and fewer internalizing symptoms at 3-year and 4-year follow-ups. Higher early-adolescent DHEA in males also reduced the probability of externalizing symptoms to reach clinical thresholds across follow-ups (e.g., adjusted Risk Ratio = 0.81 to reach clinical threshold for CBCL externalizing per SD increase in log-transformed DHEA; 95% CI [0.70, 0.93] at 3-year). In females, no hormone-symptom associations emerged. Sex-by-DHEA interaction effects tended to increase across follow-up years for both symptom domains. These findings suggest that early-adolescent adrenal endocrine influences may contribute to the development of sex-specific vulnerability during adolescence. Future studies should consider adrenarche as a sensitive period for hormonal effects on mental health.
A nucleus accumbens-projecting prefrontal cortex circuit underlies chronic social stress-induced depression-like behaviors.
Ma X, Kim H, Zhang L … +9 more , Chen P, Wei J, Cui Y, Chen L, Xu Y, Zhang J, Dai Z, Ferguson D, Qiu S
Transl Psychiatry · 2026 Jun · PMID 42243077 · Publisher ↗
Major depressive disorder (MDD) is a prevalent and debilitating psychiatric illness with limited treatment success. While chronic social stress is a well-established risk factor, the neural circuits that determine indivi...
Major depressive disorder (MDD) is a prevalent and debilitating psychiatric illness with limited treatment success. While chronic social stress is a well-established risk factor, the neural circuits that determine individual susceptibility or resilience to MDD remain poorly defined. Here, we identify a distinct subpopulation of layer 5 neurons in the medial prefrontal cortex (mPFC) that project to the nucleus accumbens (NAc) that are selectively activated by chronic social defeat stress (cSDS) in male mice. Using activity-dependent genetic tagging (TRAP), retrograde tracing, and electrophysiology recordings, we demonstrate that these stress-responsive mPFC-NAc neurons exhibit circuit-specific synaptic dysfunction-characterized by reduced excitatory postsynaptic currents, impaired local excitatory connectivity, and dendritic spine loss-in mice susceptible to stress, but not in resilient individuals. Optogenetic modulation further reveals a causal role for this pathway: activation of the mPFC-NAc circuit during cSDS promotes resilience, whereas inhibition increases susceptibility to stress. Together, these findings define a functionally distinct corticolimbic circuit that regulates depression-like behaviors and highlight a potential target for circuit-based interventions in MDD.
Comparison of acute effects of 3,4-methylenedioxymethamphetamine (MDMA) with and without a supplemental booster dose in healthy participants: a double-blind, randomized, placebo-controlled, crossover study.
Humbert-Droz M, Becker AM, Valenta J … +6 more , Rudin D, Luethi D, Vukalovic I, Eckert A, Liechti ME, Mueller L
Transl Psychiatry · 2026 Jun · PMID 42243076 · Publisher ↗
3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy (MDMA-AT) is being investigated as a treatment for several psychiatric disorders, particularly posttraumatic stress disorder. Phase 2 and 3 trials typically...
3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy (MDMA-AT) is being investigated as a treatment for several psychiatric disorders, particularly posttraumatic stress disorder. Phase 2 and 3 trials typically administered a first dose of MDMA followed by a second "booster" dose 1.5-2.5 h later, to extend the acute effect duration. However, the risks and benefits of the booster dose have not been systematically investigated. In this double-blind, randomized, placebo-controlled, cross-over study, we compared 120 mg MDMA followed by a 60 mg booster dose or placebo after 2 h, and placebo followed by placebo. The primary outcome was the overall duration of any subjective drug effects, measured by a Visual Analog Scale. Secondary outcomes included additional subjective effects, adverse effects, vital signs, and plasma concentrations of MDMA, oxytocin, and neurophysin I. Twenty-five healthy volunteers were included, and twenty-three (12 male, 11 female) completed all dosing sessions. The booster dose of MDMA prolonged the acute subjective effects of MDMA compared with the single dose (mean ± SD, 5.6 ± 1.8 h vs. 4.6 ± 1.2 h, p = 0.001), while no differences in subjective or autonomic peak effects were observed. Acute (0-9 h) and subacute (up to 3 days) adverse effects were more common after both MDMA conditions than placebo. These results indicate that acute MDMA effects can be prolonged by using a booster dose, as intended in clinical trials of MDMA-AT. Whether this translates into clinical benefit remains to be investigated.
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