Transl Psychiatry [JOURNAL]
Sun
200 papers
GluK1 kainate receptors in parvalbumin interneurons modulate cortico-hippocampal network dynamics during social behavior.
Rhee JK, Ojanen S, Paakkunainen T … +6 more , Vesikansa A, Kharybina Z, Haikonen J, Keskinen R, Taira T, Lauri SE
Transl Psychiatry · 2026 Apr · PMID 42062256 · Full text
The prefrontal cortex orchestrates complex behaviors by communicating with subcortical structures through synchronized oscillations. Here we show that ablation of GluK1 subunit-containing kainate receptors in parvalbumin...
The prefrontal cortex orchestrates complex behaviors by communicating with subcortical structures through synchronized oscillations. Here we show that ablation of GluK1 subunit-containing kainate receptors in parvalbumin interneurons (PV INs) disrupts oscillatory dynamics in the cortico-hippocampal circuits mediating social and cognitive behaviors. In control mice, the hippocampus-medial prefrontal cortex (HC-mPFC) circuit displayed elevated theta and gamma oscillation power as well as enhanced functional coupling during interaction with a familiar mouse. Similar circuit dynamics were not observed during interaction with a novel mouse, consistent with the idea that social recognition involves cortico-hippocampal communication. Mice lacking GluK1 in the PV INs (PV-Grik1) showed defects in cognitive flexibility and social discrimination as well as impaired neurochemical phenotype of PV INs in the HC and mPFC. Electrophysiological recordings in the PV-Grik1 mice revealed elevated theta and gamma oscillation power in both HC and mPFC along with enhanced functional coupling between these brain regions at rest. In contrast to the controls, no changes in the theta and gamma oscillation powers in the HC or mPFC or in the HC-mPFC coupling were detected in the PV-Grik1 mice during social interaction. Our data suggest that impaired functional dynamics in cortico-hippocampal circuits in the PV-Grik1 mice compromise social discrimination and shed light on the neurobiological mechanisms by which GluK1 dysfunction may contribute to neuropsychiatric disorders.
Sex differences in autism spectrum disorder: behavioral and sensory phenotypes in humans and mouse models.
Noriyama Y, Ishida R, Yamamuro K … +9 more , Kashida N, Okumura K, Okuda M, Ikehara M, Toritsuka M, Saito Y, Okada T, Iwata N, Makinodan M
Transl Psychiatry · 2026 May · PMID 42062255 · Full text
Sex differences in autism spectrum disorder (ASD) are increasingly recognized, not only in symptom presentation but also in underlying neurobiology and response to environmental factors. However, current diagnostic pract...
Sex differences in autism spectrum disorder (ASD) are increasingly recognized, not only in symptom presentation but also in underlying neurobiology and response to environmental factors. However, current diagnostic practices and animal models are male-centric, overlooking female-specific phenotypes and mechanisms. We conducted a multimodal, cross-species study to assess sex-dependent ASD phenotypes. In high-functioning adults with ASD and typically developing (TD) controls, we evaluated self-reported autistic traits, self-reported sensory sensitivity, and clinician-observed behaviors using standardized tools: Autism-Spectrum Quotient, Adolescent/Adult Sensory Profile, and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). In parallel, we assessed behavioral phenotypes in a paternal 15q11-q13 duplication mouse model (15q dup/+) using open-field, light-dark transition, and augmented reality-based behavioral assays. Among humans, individuals with ASD showed greater self-reported sensory sensitivity and autistic traits than TD individuals. Within the ASD group, female participants reported greater self-reported sensory sensitivity and exhibited lower clinician-rated impairments (ADOS-2) than male participants, despite comparable self-reported autistic traits. No sex differences were found among TD individuals. In contrast, female 15q dup/+ mice exhibited heightened light-related sensory reactivity and reduced exploratory behavior under bright light. These findings suggest that sex differences in light-related sensory reactivity may be more readily detected through behavioral measures in animal models. Our findings underscore the importance of considering sex as a biological and behavioral variable in ASD research. Cross-species, phenotype-oriented approaches that integrate human and animal data may uncover subtle phenotypic variations and enhance sex-informed diagnostics and interventions.
From gut to brain: effects of fecal microbiota transplants from humans to rats on hippocampal gene regulation - a study on anorexia nervosa.
Korten NM, Blischke L, Thelen AC … +14 more , Schulze Eckel A, van Egmond M, Verspohl V, Neumann M, Kneisel L, Tran M, Beyer C, Herpertz-Dahlmann B, Keller L, Bang C, Andreani NA, Seitz J, Trinh S, Voelz C
Transl Psychiatry · 2026 Apr · PMID 42062245 · Full text
Fecal microbiota transplantation (FMT) has emerged as a novel approach for understanding anorexia nervosa (AN), a complex eating disorder characterized by severe underweight, fear of weight gain and distorted body image....
Fecal microbiota transplantation (FMT) has emerged as a novel approach for understanding anorexia nervosa (AN), a complex eating disorder characterized by severe underweight, fear of weight gain and distorted body image. Patients with AN show alterations in the gut microbiome, brain structure, and inflammatory processes, indicating the importance of the microbiome‒gut‒brain axis in AN pathology. This study aimed to investigate whether FMT from patients with AN into antibiotic-treated rats could transfer a phenotype associated with the disease inducing AN-like symptoms and hippocampal alterations. Female Wistar rats received antibiotics followed by FMT from healthy controls, patients with AN, or water. Gut microbiota effects were assessed through 16S rRNA gene sequencing, alongside post-mortem analyses of glial cells, neurogenesis markers, and inflammatory markers. The results revealed dysregulated microbial diversity after antibiotic treatment, which was partially restored after FMT. Successful transfer of human bacterial species was observed, but AN-like symptoms and changes in glial/neuronal counts were not detected. Notably, a decrease in hippocampal Bdnf expression was detected in the antibiotic control group, which was reversed by healthy control stool transplantation but not in the AN-transplanted group. Similar patterns were observed for neuroinflammation and Mki67, a marker of cell neogenesis. These findings suggest potential links between microbial changes, neuroinflammation and neuroplasticity in the hippocampus with the potential to correct deficits with FMT. Future studies should extend these findings by exploring the combination of FMT and starvation phases to better understand the roles of specific microbial populations in neuroinflammatory processes and, ultimately, clinical outcomes in AN.
Correction: Change in striatal functional connectivity networks across 2 years due to stimulant exposure in childhood ADHD: results from the ABCD sample.
Kaminski A, Xie H, Hawkins B … +1 more , Vaidya CJ
Transl Psychiatry · 2026 Apr · PMID 42056089 · Full text
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Cornichon Homolog-3 (Cnih3) deletion impairs spatial memory, operant learning, and fentanyl self-administration behavior.
Lintz T, Liu A, Aal TA … +5 more , Park A, Dearman JJ, Agrawal A, Nelson EC, Moron JA
Transl Psychiatry · 2026 Apr · PMID 42056073 · Full text
Opioid misuse remains rampant as new synthetic opioids reach the market. Large-scale genetic tools like the GWAS identify previously unrecognized targets and biomarkers in opioid misuse with the hopes of combating the op...
Opioid misuse remains rampant as new synthetic opioids reach the market. Large-scale genetic tools like the GWAS identify previously unrecognized targets and biomarkers in opioid misuse with the hopes of combating the opioid epidemic. One such target is the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) auxiliary protein Cornichon Homolog-3 (human analog: CNIH3, mouse analog: Cnih3), which determines AMPAR subunit composition and kinetics: important factors in opioid use. Though CNIH3 was identified as a gene of interest in OUD, its role in opioid use and related behavior has not been studied. Using mice with Cnih3 deletion, we characterize the role of Cnih3 in a battery of behaviors that encompass well-being, affect, spatial and social memory, operant learning, reversal learning, and opioid use itself. We find that Cnih3 deletion moderately impairs spatial memory in the novel object recognition task, as well as operant learning in a sucrose self-administration paradigm. Cnih3 deletion also delays acquisition of fentanyl IVSA in females and blunts fentanyl intake during IVSA in both sexes. We use principal component analysis to pinpoint the dimensions in which Cnih3 deletion impacts the behaviors tested in an unbiased manner. These findings, combined with initial GWAS findings, identify Cnih3 as a behaviorally relevant protein in opioid-related plasticity.
Serum metabolites associated with depression and anxiety in the Hispanic Community Health Study/Study of Latinos.
Qiu X, Zhang Y, Purushotham Y … +10 more , Qi Q, Yu B, Bressler J, Perreira KM, Parada H, Daviglus ML, Vega AC, Isasi CR, Gallo LC, Sofer T
Transl Psychiatry · 2026 Apr · PMID 42049717 · Full text
Omics signatures for psychiatric conditions have been under-investigated. In this study, we used data from a representative observational cohort study of Hispanic/Latino adults to identify serum metabolites associated wi...
Omics signatures for psychiatric conditions have been under-investigated. In this study, we used data from a representative observational cohort study of Hispanic/Latino adults to identify serum metabolites associated with symptoms of depression or anxiety and to develop and assess metabolite risk scores (MRSs) of these phenotypes. We conducted a metabolome-wide association study of 768 metabolites with depression and anxiety symptoms, using two separate assay batches measured from baseline samples collected between June 2008 and July 2011 for discovery (batch 1: n = 4002 adults) and replication (batch 2: n = 2178 adults). We estimated the associations via survey-based generalized linear regression, and applied Least Absolute Shrinkage and Selection Operator (LASSO) regression for metabolite selection and for obtaining MRS weights. In analyses adjusted for age, sex, field center and Hispanic/Latino background, we identified five metabolites of replicated associations with depression symptoms and six metabolites with anxiety symptoms. Key pathways related to the identified metabolites included arginine and proline, vitamin A, phospholipid, fatty acid and tyrosine metabolism. MRSs were associated with higher depression symptom score (1.07 points, 95% CI: 0.67 - 1.46, per 1 SD increase in depression MRS) and anxiety symptom score (1.05 points, 95% CI: 0.67 - 1.43, per 1 SD increase in anxiety MRS) in the replication dataset. Our study supports the associations between serum metabolites and symptoms of depression and anxiety in Hispanic/Latino adults. The developed MRSs may facilitate earlier and more objective screening of individuals for depression and anxiety apart from traditional risk factors.
Loss of connexin 36 elicits abnormalities in thalamocortical network activity relevant to neuropsychiatric disorders.
McNally JM, Carey S, Uygun DS … +2 more , Thankachan S, Basheer R
Transl Psychiatry · 2026 Apr · PMID 42034628 · Full text
Neuronal gap junctions, or electrical synapses, are extensively expressed in the mammalian forebrain and play a key role in synchronizing network activity. Connexin 36 (Cx36) is the primary gap junction protein in mature...
Neuronal gap junctions, or electrical synapses, are extensively expressed in the mammalian forebrain and play a key role in synchronizing network activity. Connexin 36 (Cx36) is the primary gap junction protein in mature GABAergic neurons, but its contribution to thalamocortical oscillations and cognitive processes remains unclear. Here, we examined the effects of Cx36 deletion on sleep/wake regulation, spontaneous and evoked EEG activity, and behavior in mice. While Cx36 knockout (KO) mice displayed largely intact sleep architecture, spectral analysis revealed impaired gamma and beta band activity and reduced sigma power surges preceding NREM-REM transitions. Spindle density was preserved, but spindle amplitude and duration were reduced. Cx36KO mice exhibited blunted gamma responses to ketamine, impaired 40 Hz auditory steady-state responses, and reduced mismatch negativity with attenuated ERP amplitudes and altered evoked power. Behaviorally, Cx36KO mice showed impaired social habituation and reduced investigation-induced gamma activity. These findings demonstrate that Cx36-containing gap junctions are essential for maintaining thalamocortical synchrony and support translational EEG biomarkers relevant to schizophrenia and other psychiatric disorders. Cx36 may therefore represent a novel therapeutic target for modulating dysfunctional network activity in neuropsychiatric disease.
Transdiagnostic associations between subjective gesture behaviour and objective performance in schizophrenia and depression.
Pavlidou A, von Känel S, Maderthaner L … +8 more , Malifatouratzis A, Chapellier V, Viher PV, Bachofner H, Stegmayer K, Hein G, Adorjan K, Walther S
Transl Psychiatry · 2026 Apr · PMID 42031739 · Full text
Social communication deficits are common across mental-health disorders, yet little is known about how individuals perceive their own gesture behaviours. Gaining insight into this, particularly across different disorders...
Social communication deficits are common across mental-health disorders, yet little is known about how individuals perceive their own gesture behaviours. Gaining insight into this, particularly across different disorders, could enhance our understanding of social communicative impairments and disruptions in self-awareness. The current study included 274 participants: N = 113 with schizophrenia, N = 65 with depression and N = 96 healthy controls where we compared self-reported gesture behaviours in social and non-social contexts. These self-reports where further explored in relation to objective-measures of gesture performance and expert-rating scales of symptom severity and social functioning. Both patient groups self-reported impairments compared to controls, but with disorder-specific profiles. Specifically, people with schizophrenia uniquely reported reduced gesture perception and use, while both patient groups reported diminished social gesture production. The schizophrenia group also reported elevated social perception relative to the other groups. The depression group consistently rated themselves higher than the schizophrenia group across domains. Furthermore, only the schizophrenia group showed distinct associations: self-reported social perception was negatively associated with self-reported gesture perception, but positively associated with self-reported social production. Notably, only schizophrenia showed a significant link between self-reported difficulties in social gesture production and objective gesture performance deficits. These findings suggest that disruptions in self-awareness of gesture behaviours manifests differently across disorders and underscore the value of integrating self-report measures together with objective assessments to capture the complexity of social-communicative impairments. This will help in designing tailored interventions aimed at enhancing social communication and awareness in diverse mental-health disorder populations.
Inflammation as a mediating pathway between social defeat and mental health in humans: A systematic review.
Sharma S, Taylor M, Sadiq Z … +6 more , Kashyap T, Shao H, Sulaiman Z, Wang Y, Kumarendran B, Griffiths SL
Transl Psychiatry · 2026 Apr · PMID 42031703 · Full text
INTRODUCTION: Social Defeat (SD), an animal-derived concept characterised by experiences of subordination, may influence biological mechanisms affecting mental health. Despite evidence linking inflammation to mental diso...
INTRODUCTION: Social Defeat (SD), an animal-derived concept characterised by experiences of subordination, may influence biological mechanisms affecting mental health. Despite evidence linking inflammation to mental disorders and animal studies suggesting SD's inflammatory effects, to date, no review has comprehensively examined these relationships in human populations. This systematic review synthesises evidence from human studies examining human SD, inflammation, and mental health, with particular attention to inflammation as a potential mediating pathway in these relationships, to better inform understandings of mental health disparities across marginalised communities. METHODS: Embase, MEDLINE, and PsycInfo were searched for eligible observational human studies published from database inception to September 2025. Studies were screened by two reviewers, while a single reviewer extracted data and evaluated study quality and risk of bias. Narrative synthesis revealed overarching themes and patterns. RESULTS: 13 heterogenous studies met the inclusion criteria, predominantly examining social isolation, peer victimisation, discrimination, and childhood adversity. Interleukin-6 (IL-6) and C-Reactive Protein (CRP) with depression were the primarily assessed inflammatory and mental health outcomes. Most studies found SD-inflammation-mental health associations, although some inconsistencies emerged. Sex and SD type arose as potential mediators. However, results were limited by the range of moderate-to-high quality and low-to-high risk of bias across studies. CONCLUSION: Various forms of human SD experiences may independently alter immunological profiles and mental health outcomes, providing translational support for animal studies linking SD to inflammatory changes. The mediating role of SD in the relationship between inflammation and mental health remains inconclusive, however. While longitudinal studies may help elucidate the directionality of associations, this study reiterates that SD prevention is paramount for achieving sustainable mental health improvements.
Delivery of HSP70 mRNA via exosomes ameliorates sleep deprivation-induced cognitive impairments in mice.
Kang Z, Zhu G, Su C … +3 more , Zhong X, Lin J, Lin Y
Transl Psychiatry · 2026 Apr · PMID 42031702 · Full text
Chronic sleep deprivation impairs cognition and triggers neuroinflammation, but effective molecular therapies are lacking. Heat shock protein 70 (HSP70) offers neuroprotection, though its delivery across the blood-brain...
Chronic sleep deprivation impairs cognition and triggers neuroinflammation, but effective molecular therapies are lacking. Heat shock protein 70 (HSP70) offers neuroprotection, though its delivery across the blood-brain barrier remains a challenge. This study investigates exosomes as a vehicle to enhance brain delivery of HSP70 for treating chronic sleep deprivation. We engineered HEK293T cells to stably express HSP70 mRNA and the brain-targeting RVG-Lamp2b fusion protein, generating HSP70@Exo exosomes. These were characterized via transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. In vitro uptake and HSP70 expression were assessed in neural progenitor cells (NPCs). In vivo efficacy was evaluated in a sleep-deprived mouse model using behavioral tests and molecular analyses of inflammatory and neurotrophic markers. HSP70@Exo exosomes efficiently delivered HSP70 mRNA to NPCs, increasing intracellular HSP70 protein. In vivo, systemic administration restored memory performance, reduced hippocampal TNF-α, IL-6, and IL-1β levels, and increased IL-10. Treatment also elevated brain-derived neurotrophic factor and phosphorylated CREB, indicating enhanced neurotrophic signaling. These effects surpassed those of non-targeted or empty exosomes. Engineered exosomes enabled effective brain-targeted HSP70 mRNA delivery, reversing cognitive and inflammatory consequences of sleep deprivation. To our knowledge, this is the first demonstration of RVG-modified exosomes successfully delivering mRNA (rather than siRNA or miRNA) for the treatment of sleep deprivation-induced deficits. HSP70@Exo offers a promising, noninvasive therapeutic strategy for sleep-related neurodegenerative conditions and highlights the potential of exosome-based mRNA delivery systems.
Characterising the clinical associations of hallucinogen persisting perception disorder: a retrospective cohort study.
Butler M, Moore E, Rucker JJ … +6 more , Lynch-Kelly K, Hafeez D, Prideaux E, Nicholson TR, Edwards M, Pollak TA
Transl Psychiatry · 2026 Apr · PMID 42031693 · Full text
Hallucinogen persisting perception disorder (HPPD) is characterised by episodes of altered perception linked to past psychoactive drug use, accompanied by distress and functional impairment. To date, clinical characteris...
Hallucinogen persisting perception disorder (HPPD) is characterised by episodes of altered perception linked to past psychoactive drug use, accompanied by distress and functional impairment. To date, clinical characterisation has been limited in scale. Using TriNetX, a global federated health research network of electronic health records, we conducted a retrospective cohort study comparing clinical associations in individuals with HPPD versus population and psychedelic-using controls. Cumulative incidences of psychiatric and medical disorders were compared. Cox proportional hazards models assessed risk factors for developing HPPD, and odds ratios (ORs) were used to evaluate associated conditions following diagnosis. We identified 25,778 individuals diagnosed with HPPD. Prior to diagnosis, high rates of comorbidities were observed, including depressive episodes (29.2%), anxiety disorders (26.2%), chronic pain (15.9%), headache syndromes (14.7%), post-viral fatigue (12.3%), ADHD (6.6%), and fibromyalgia (6.7%). Anxiety and functional somatic syndromes were significantly more common in the HPPD group than in psychedelic-using controls (p < 0.001). Anxiety (OR 1.5) and post-viral fatigue (OR 1.9) predicted HPPD development in psychedelic users. HPPD diagnosis was associated with increased risk of subsequent functional somatic syndromes (OR 2.0) and psychiatric disorders (OR 1.4) versus psychedelic-using controls. This largest-to-date study of HPPD highlights its psychiatric and somatic complexity, with strong associations with anxiety and functional somatic syndromes. Several methodological limitations are acknowledged. Further research should explore overlapping pathophysiological mechanisms linking HPPD, visual disorders (e.g. visual snow syndrome), anxiety, and functional somatic syndromes.
Identification of susceptibility modules and genes through WGCNA and ceRNA network analysis in neuropathic pain-induced anxiodepression.
He Y, Xu Y, Xing F … +7 more , Shi X, Zhang F, Xing M, Liu Y, Zhang W, Wei X, Yuan J
Transl Psychiatry · 2026 Apr · PMID 42026034 · Full text
Neuropathic pain (NP) is frequently comorbid with anxiety and depression, yet the underlying molecular mechanisms in the brain remain poorly understood, hindering the development of targeted therapies. This study aimed t...
Neuropathic pain (NP) is frequently comorbid with anxiety and depression, yet the underlying molecular mechanisms in the brain remain poorly understood, hindering the development of targeted therapies. This study aimed to identify key transcriptional networks and regulatory pathways in the anterior cingulate cortex (ACC) associated with NP-induced anxiodepression. We analyzed transcriptomic data (GSE92718) from the ACC of a mouse model of chronic NP. By comparing differentially expressed genes at a time point manifesting anxiodepressive-like behavior (8-week post-injury) against those with pain alone (2-week), we constructed a weighted gene co-expression network (WGCNA). A key module (blue module) significantly correlated with the anxiodepressive phenotype was enriched for synaptic signaling (glutamatergic/GABAergic), neuroplasticity, and key pathways like MAPK and Ras. Within this module, we identified 7 pivotal lncRNAs and 5 hub mRNAs (Flt1, Slc38a2, Bmpr1b, Pdgfra, Gng2) via integrated lncRNA-mRNA-pathway and protein-protein interaction network analyses. Furthermore, we established a competing endogenous RNA (ceRNA) network, revealing a core regulatory axis comprising 3 hub lncRNAs, 5 hub mRNAs, and 40 miRNAs. The aberrant expression of the five hub mRNAs in the ACC was specifically validated in mice with anxiodepressive phenotypes using RT-PCR. Our findings unveil a critical ceRNA network and implicate dysregulated synaptic genes in the ACC as key drivers of NP-induced anxiodepression, providing novel insights into its molecular basis and highlighting potential diagnostic biomarkers and therapeutic targets.
Augmenting extinction with counterconditioning strengthens and sustains neural safety representations in PTSD.
Cooper SE, Keller NE, Bauer EA … +8 more , Lambert SR, Hennings AC, Azar AA, Bibb SA, Nemeroff CB, Cisler JM, Lewis-Peacock JA, Dunsmoor JE
Transl Psychiatry · 2026 Apr · PMID 42026031 · Full text
Because extinction forms the empirical foundation of exposure therapy, strategies to enhance extinction could lead to more effective interventions for posttraumatic stress disorder (PTSD). Here, we used functional MRI to...
Because extinction forms the empirical foundation of exposure therapy, strategies to enhance extinction could lead to more effective interventions for posttraumatic stress disorder (PTSD). Here, we used functional MRI to compare immediate and long-term efficacy of enhanced versus standard extinction in 54 adults with (n = 32) and without (n = 22) PTSD. In both control and PTSD groups, counterconditioning-an enhanced form of extinction that replaces threat with positive outcomes-was more effective than standard extinction. It reduced threat-related neural activity and promoted reinstatement of safety (extinction) patterns in the ventromedial prefrontal cortex (a region involved in learning and retrieving safety associations). However, the PTSD group continued to reinstate both threat- and safety-related neural patterns in the dorsal anterior cingulate cortex (a region involved in learning and retrieving threat associations). These findings represent novel evidence that enhanced extinction outperforms standard extinction in promoting more rapid and persistent neural representations of safety in PTSD.
Concurrent maternal stress and THC exposure alters maternal regulation and downstream adolescent corticolimbic programs.
Olusakin J, Dewan M, Kashyap A … +6 more , Franco D, Kumar G, Lujan MA, Mark KS, Cheer J, Lobo MK
Transl Psychiatry · 2026 Apr · PMID 42026029 · Full text
Cannabis use during pregnancy is increasing, often to alleviate stress and anxiety, yet the impact of prenatal cannabis exposure alone, or in combination with psychosocial stress on maternal regulation and downstream off...
Cannabis use during pregnancy is increasing, often to alleviate stress and anxiety, yet the impact of prenatal cannabis exposure alone, or in combination with psychosocial stress on maternal regulation and downstream offspring neurodevelopment remains unclear. Here, we developed a translational rodent model combining prenatal Δ⁹-tetrahydrocannabinol (THC) exposure with chronic psychosocial stress using the maternal witness defeat stress (MWDS) paradigm. Pregnant C57BL/6 mice were exposed to MWDS from gestational day (GD) 3-12 and received daily subcutaneous THC (2 mg/kg) or vehicle until birth. All exposure groups exhibited disrupted maternal caregiving and adverse postnatal outcomes, with combined THC and stress exposure producing the most pronounced maternal impairments. To assess downstream consequences, adolescent male and female offspring were evaluated for behavioral and molecular alterations. Prenatal stress and combined exposures were associated with increased anxiety-like behavior and reduced motivated behavior in both sexes, while THC alone primarily impacted female self-care and social behavior. Transcriptomic profiling of the prefrontal cortex (PFC) and nucleus accumbens (NAc) of adolescent offspring using a custom NanoString panel revealed sex- and region-specific gene expression changes across exposure groups. Prenatal THC, stress, and combined exposures altered molecular pathways related to mitochondrial function, synaptic organization, and glial signaling. Comparative analysis with a perinatal fentanyl model identified shared transcriptional substrates involved in synaptic signaling and circadian regulation. Collectively, these findings demonstrate that concurrent prenatal stress and THC exposure disrupt maternal regulation, with associated and enduring neurodevelopmental signatures in offspring.
Paving the way for precision treatment of psychiatric symptoms with functional connectivity neurofeedback.
Taylor JE, Oka T, Murakami M … +9 more , Motegi T, Yamada T, Kawashima T, Kobayashi Y, Yoshihara Y, Miyata J, Murai T, Kawato M, Cortese A
Transl Psychiatry · 2026 Apr · PMID 42020355 · Full text
Treatment for Major Depressive Disorder (MDD) remains relatively homogeneous, despite patients having heterogeneous subsets of symptoms with differing underlying neural aberrations. Demonstrating potential for a more ind...
Treatment for Major Depressive Disorder (MDD) remains relatively homogeneous, despite patients having heterogeneous subsets of symptoms with differing underlying neural aberrations. Demonstrating potential for a more individualised treatment approach, we recently showed that normalisation of a neural network and a corresponding reduction in related symptoms can be achieved using real-time fMRI functional connectivity neurofeedback (FCNef). Specifically, we showed that brooding rumination but not anxiety symptoms decreased as functional connectivity between the dorsolateral prefrontal cortex (DLPFC) and posterior cingulate cortex/precuneus (PCC) normalised with FCNef. However, the robustness of this effect, how localised it is in the brain, and the best parameters for optimising therapeutic outcomes remained unknown. We therefore ran additional participants (final N = 68) in our FCNef protocol. We replicated our original findings and ran new analyses that better highlighted the precision of this effect to rumination symptoms. For the first time we also demonstrated that connectivity between the Executive Control and Default-Mode networks reduced significantly with FCNef. Finally, we manipulated core FCNef parameters between participants and found that the most effective protocol involved consecutive training days with greater external reward. These results highlight the potential of FCNef for precision medicine in psychiatry and underscore the importance of optimising parameters to enhance feasibility of BMI-based clinical interventions.
Behavioral and transcriptomic markers of susceptibility to escalate fentanyl intake.
Keady J, Charnigo R, Shaykin JD … +8 more , Prantzalos ER, Xia M, Denehy E, Bumgardner C, Miller J, Ortinski P, Bardo MT, Turner JR
Transl Psychiatry · 2026 Apr · PMID 42020354 · Full text
The "loss of control" over drug consumption, known as escalation of intake in opioid use disorder (OUD), is well-established in preclinical rodent models. However, little is known about how antecedent behavioral characte...
The "loss of control" over drug consumption, known as escalation of intake in opioid use disorder (OUD), is well-established in preclinical rodent models. However, little is known about how antecedent behavioral characteristics, such as valuation of hedonic reinforcers prior to drug use, influence fentanyl intake trajectories. Moreover, it is unclear if distinct escalation phenotypes are driven by transcriptomic markers predictive of OUD susceptibility. Male and female Sprague-Dawley rats (n = 72) were trained in a sucrose reinforcement task using a progressive ratio schedule. Individual differences in responsivity to sucrose were hypothesized to predict escalation of fentanyl intake. Rats underwent daily 1-h acquisition sessions for i.v. fentanyl self-administration (2.5 µg/kg; FR1) for 7 days, followed by 21 6-h escalation sessions, then tissue from prefrontal cortex was collected for RNA sequencing and qPCR. Latent growth curve and group-based trajectory modeling were used, respectively, to evaluate the association between sucrose reinforcement and fentanyl self-administration and to identify whether distinct escalation phenotypes can be linked to gene expression patterns. Sucrose breakpoints did not predict fentanyl acquisition nor change during escalation but did predict fentanyl intake on the first day of extended access. Permutation analyses found no associations between behavior and single gene expression, either overall or within our ascertained phenotypes. However, weighted genome correlation network analysis (WGCNA) and gene set enrichment analysis (GSEA) determined several gene modules linked to escalated fentanyl intake, including genes coding for voltage-gated potassium channels, calcium channels, and excitatory synaptic signaling. Transcription factor analyses identified EZH2 and JARID2 as potential transcriptional regulators associated with escalated fentanyl intake. Further, these modules were enriched for genome-wide association study (GWAS) term categories relating to substance use disorders. Escalation of opioid intake largely differs from motivation for natural rewards like sucrose. Further, the gene networks associated with fentanyl escalation suggest that engagement of select molecular pathways were associated with "addiction prone" behavioral endophenotypes, potentially representing druggable targets for OUD. Our extended in silico analysis found that gene networks associated with the "addiction prone" high escalating rats were enriched for genes with known risk alleles for substance use disorders and identified transcription factors that may regulate these networks, highlighting the importance of integrating findings from translational preclinical models, supporting patient-centered treatment options for OUD.
Establishment and validation of an Alzheimer's disease diagnostic model on the basis of exhaled volatile organic compound characteristics.
Liu P, Xu Y, Che P … +7 more , Wang Y, Zhang Y, Ji D, Wang C, Ma X, Sun M, Zhang N
Transl Psychiatry · 2026 Apr · PMID 42014693 · Publisher ↗
Exhaled volatile organic compounds (VOCs) have been investigated in some diseases, including cognitive impairment, in pilot studies. The present study aimed to explore the role of exhaled VOCs in identifying and differen...
Exhaled volatile organic compounds (VOCs) have been investigated in some diseases, including cognitive impairment, in pilot studies. The present study aimed to explore the role of exhaled VOCs in identifying and differentiating patients with Alzheimer's disease (AD). The identification cohort included 241 participants: 99 AD patients (dementia=74, mild cognitive impairment (MCI) = 25), 59 non-AD dementia patients, and 83 cognitively unimpaired controls (CUCs). Proton transfer reaction time-of-flight mass spectrometry (PTR-TOFMS) was employed to detect exhaled VOCs. The differences in VOCs between the AD and CUC groups and between the AD dementia and non-AD dementia groups were compared separately. Furthermore, machine learning models for discriminating AD from CUC as well as AD dementia from non-AD dementia were established. The AD diagnostic model was further validated in an independent cohort of 44 AD patients (dementia=33, MCI = 11) and 35 CUCs. Moreover, we explored the possible metabolic pathways of AD-specific exhaled VOCs with the Human Metabolome Database (HMDB). We detected 60 different VOCs between the AD and CUC groups, among which the top ten were CHS, CHNO, CHO, CHFNO, CHNO, CHN, CHN, CHN, CH, and CH (P < 0.001). The AD diagnostic model had an accuracy of 0.93 in the identification cohort according to internal validation and 0.75 in the validation cohort for external validation. The model for discriminating AD dementia patients from non-AD dementia patients had an accuracy of 0.90. Fourteen of the 60 AD-specific VOCs were retrieved from the HMDB, from which the three most significant metabolic pathways were identified, namely, butyrate metabolism, pyruvate metabolism, and glycolysis/gluconeogenesis. These results indicate that exhaled VOC measurement may be a promising approach for diagnosing and differentiating AD, but further validation is needed.
A case-series of oral acetate supplementation for gut microbiota alteration and metabolic improvement in patients with affective disorders on psychotropics.
Al KF, Wammes M, Warren M … +6 more , Lee JE, Walton DM, O'Connor C, Cameron L, Burton JP, Osuch EA
Transl Psychiatry · 2026 Apr · PMID 42014676 · Full text
Mental illnesses affect one in five Canadians and often require psychotropic medications. While effective, many psychotropic medications can cause weight gain and metabolic side effects. The gut microbiota, influenced by...
Mental illnesses affect one in five Canadians and often require psychotropic medications. While effective, many psychotropic medications can cause weight gain and metabolic side effects. The gut microbiota, influenced by short-chain fatty acids like acetate, plays a role in mental health via the gut-brain axis and may be disrupted as a result of medication use. This case-series explored the feasibility of acetate supplementation contained in delayed-release capsules as an intervention to alter the gut microbiota and reduce metabolic side effects in people taking psychotropic medication for mood and anxiety disorders. Eleven participants aged 22-32 with medication-related weight gain were evaluated at baseline, across three months of delayed-release acetate supplementation, and at one-month follow-up. Adherence was high, with no serious adverse events. Six participants showed signs of metabolic improvements, including clinically-meaningful changes in cholesterol and weight. Mood and anxiety symptoms meaningfully improved in two participants. 16S rRNA gene sequencing revealed alterations in the gut microbiota at both the individual and group levels following the intervention, including increased relative abundance of butyrate-producing bacteria and functional changes potentially influencing cholesterol metabolism. Microbiota differences were also noted between participants with and without metabolic improvements, both pre- and post-intervention, suggesting a potential "responder" phenotype. These findings support further exploration of the effectiveness of delayed-release acetate as a safe adjunctive therapy to offset metabolic concerns and gut microbiome changes in people on psychotropic medication. Larger studies with longer follow-up are needed to confirm these effects and validate responder subgroups.
Subcallosal cingulate functional connectivity in depression: a systematic review of brain stimulation-induced changes and pretreatment connectivity predictors.
Henensal A, Attali D, Aubry JF … +1 more , Plaze M
Transl Psychiatry · 2026 Apr · PMID 42014673 · Full text
Major depressive episode (MDE) is a common mental disorder that severely impacts patients' lives and carries a high suicide risk. About 30% of patients are resistant to oral antidepressants, necessitating alternative app...
Major depressive episode (MDE) is a common mental disorder that severely impacts patients' lives and carries a high suicide risk. About 30% of patients are resistant to oral antidepressants, necessitating alternative approaches such as neurostimulation. The subcallosal cingulate (SCC), characterized by hyperactivity and altered functional connectivity (FC) in MDE, has emerged as a key target for interventions like deep brain stimulation (DBS) and transcranial focused ultrasound stimulation (TUS). Other techniques, including repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT), may influence SCC activity indirectly via network-level effects. We searched multiple databases for studies investigating changes in SCC connectivity following various neurostimulation techniques in depression. We included 28 studies using resting-state functional MRI to investigate SCC FC changes following neurostimulation for depression with different modalities: ECT, DBS, rTMS, tDCS, TUS. Results showed high variability across studies. rTMS targeting the DLPFC modulated SCC FC with the OFC, precuneus, and default mode network (DMN), while other targets affected connectivity with the hippocampus and supramarginal gyrus. Stronger baseline anticorrelation between SCC and DLPFC predicted better rTMS response. ECT studies reported heterogeneous effects, involving the temporal pole and vmPFC. TUS targeting SCC increased FC with the DLPFC, whereas TUS to the DLPFC enhanced FC between SCC subregions and mPFC or cerebellum. Findings remain heterogeneous, likely due to methodological inconsistencies, including variability in SCC ROI definitions and stimulation protocols. Standardizing analysis methods is essential to improve reproducibility and clarify the SCC's role in treatment response.
Thalamocortical functional connectivity alterations and peripheral immune transcriptomic dysregulation in major depressive disorder patients with suicidal ideation.
Wang M, Wei J, Yan Y … +5 more , Dou Y, Zhao L, Ni R, Yang X, Ma X
Transl Psychiatry · 2026 Apr · PMID 42014385 · Full text
Suicidal ideation (SI) in major depressive disorder (MDD) presents a serious clinical concern, yet its underlying biological mechanisms remain poorly understood. Using an exploratory, multimodal design, this study includ...
Suicidal ideation (SI) in major depressive disorder (MDD) presents a serious clinical concern, yet its underlying biological mechanisms remain poorly understood. Using an exploratory, multimodal design, this study included 98 MDD patients with SI (MDD_SI), 61 without SI (MDD_nSI), and 233 healthy controls (HC), and collected functional MRI and peripheral blood transcriptomic data. Network-based statistics of resting-state functional connectivity (FC) identified brain network differences among the three groups, followed by graph-theoretical analysis of derived hub regions. Differential module connectivity (MDC) analyses of blood transcriptomic modules were performed to identify group-level differences, and exploratory correlation analyses were performed to examine associations between brain network topology and transcriptomic alterations. A functional network centered on the caudal temporal thalamus (cTtha) showed significant group differences (MDD_SI > MDD_nSI >HC; p < 0.001), with increased nodal efficiency of the left cTtha in both the MDD_SI (p = 0.043) and MDD_nSI (p < 0.001) groups compared with the HC group. Modules differentiating MDD_SI from MDD_nSI were enriched in antiviral immune responses and epigenetic regulation (darkred, MDC = 1.508, p = 0.04; yellow, MDC = 0.93, p = 0.01), while SI-specific alterations involved mitochondrial energy dysregulation and nSI-specific alterations involved vascular and translational pathways. Notably, one immune-related gene module was significantly correlated with left cTtha betweenness centrality (r = 0.274, p = 0.021), degree centrality (r = 0.262, p = 0.027), and nodal efficiency (r = 0.235, p = 0.048) in the MDD_SI group. This study indicates that MDD and SI are associated with cTtha-centered functional network alterations and peripheral transcriptomic dysregulation, and that, within MDD, SI may show a potential link between cTtha-centered brain network disruption and immune transcriptomic dysregulation. These results should be interpreted cautiously given the exploratory design, binary SI assessment, and modest effect sizes.
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