Biological Psychiatry

GABAergic deficit is associated with key neuropsychiatric disorders, such as major depressive disorder (MDD), anxiety, schizophrenia, and autism spectrum disorder (ASD). However, it is not known whether these disorders are causal to or a result of GABAergic dysfunction. We previously showed that the Solute carrier 38 member 1 (Slc38a1) accumulates glutamine in subpopulations of GABAergic neurons and sustains neurotransmitter GABA synthesis. Genetic inactivation of Slc38a1 in mice caused lowered GABA levels, altered synaptic vesicle morphology, slowed {gamma}-oscillations, and reduced cortical processing and plasticity, selectively at GABAergic synapses. We now demonstrate a significant reduction in learning and memory performance in the Morris water maze and increased signs of despair in the forced swim test in Slc38a1-/- mice compared to Slc38a1+/+ mice, implicating cognitive impairments and depressive-like behavior. Examination in the open field maze also indicates anxiety and/or reduced interest in exploration. There are no signs of impaired sociability or recognition of social novelty in the three-chambered test, speaking against involvement in schizophrenia- or ASD-like disorders. Metabolic phenotyping and measurement of the locomotion do not segregate the Slc38a1 genotypes, suggesting that the cognitive impairments, depressive-like behavior and anxiety are brain-dependent. Our data is further supported by a pathologic variant of Slc38a1 in a family with depression and suicidal behavior. Altogether, we demonstrate that dysfunction of Slc38a1-dependent GABA synthesis and the ensuing impaired {gamma}-oscillations underpin the pathogenesis of neurocognitive deficits, anxiety and depression.

Major Depressive Disorder (MDD) frequently follows a recurrent trajectory of episodes and remissions, often culminating in treatment-resistance. Molecular differences defining state-specific changes during episode and remission have been explored. However, progressive differences--defined here as cross-sectional linear trends across clinical stages from first to recurrent episodes or remissions, reflecting increasing illness burden over time--remain poorly understood, limiting sustained therapeutic outcomes. Here, we analyzed RNA-seq data from postmortem sgACC to identify progressive differences across MDD episodes or remission relative to state-specific differences, using an integrative assessment of molecular and cellular specificity, genetic-risk, disease-comorbidity and potential therapeutic targets. Differential expression analysis showed greater overlap between progressive and state-specific differences during remission than episode. Pathway enrichment highlighted disruptions in extracellular-matrix pathways shared by state-specific and progressive episodes, while metabolic and catalytic pathways were restored during remission. Cell-type-specific analyses showed that progressive changes were linked to superficial-layer intra-telencephalic neurons, whereas state-specific changes were enriched in pyramidal neuron subtypes and deeper layer SST-positive interneurons. Genome-wide association-informed enrichment analysis further linked these transcriptomic changes to genetic risk factors and symptom dimensions. Anhedonia was associated with both state-specific episode and progressive-remission signatures, suggesting that it is a persistent trait-like feature of MDD. Finally, an integrative pharmacological analysis revealed shared molecular mechanisms between pro-disease and therapeutic targets, highlighting pleiotropic effects of key pathways depending on disease state and dosage. Together, these findings provide a novel perspective on biological underpinnings of MDD progression over episodes or remissions and identify pharmacological targets that account for pathological and/or compensatory/therapeutic processes.

Antidepressant efficacy varies widely, yet the circuit-level mechanisms that distinguish treatment responders from non-responders remain poorly understood in humans. Here, we used high-resolution neuroimaging of hippocampal-amygdala networks during an emotional mnemonic discrimination task that taxes hippocampal pattern separation to examine how antidepressant mechanism of action and perceived treatment response shape emotional memory circuitry (N = 117). Participants included individuals taking single-action antidepressants (selective serotonin reuptake inhibitors), multi-action antidepressants (serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, or polypharmacy), and unmedicated controls matched on current depression severity. Antidepressant mechanism and treatment response were associated with distinct patterns of activity in hippocampal subfields (dentate gyrus (DG)/CA3 and CA1) and amygdala subnuclei, including the basolateral amygdala (BLA) and central amygdala (CEA), during emotional mnemonic discrimination. Among non-responders, the relative balance of hippocampal activity differed by antidepressant mechanism: those taking single-action antidepressants showed greater DG/CA3 than CA1 activity, whereas those taking multi-action antidepressants showed the opposite pattern. This suggests mechanistically specific differences in hippocampal computations associated with ineffective treatment. These effects were localized to the anterior hippocampus, with no significant effects observed in posterior regions. In contrast, responders exhibited stronger DG/CA3-BLA coactivation during negative mnemonic discrimination, a pattern absent in non-responders and unmedicated controls. Antidepressant-associated differences in amygdala subnuclei activity persisted beyond current symptom severity, suggesting medication-related modulation of emotional memory circuits rather than effects driven solely by depression severity. These findings provide evidence in humans that antidepressant use is associated with altered hippocampal-amygdala circuitry in a manner that depends on both pharmacological mechanism and treatment efficacy. Identifying circuit-level signatures of treatment response may inform mechanistically guided approaches to antidepressant selection and monitoring.

BackgroundThe single nucleotide polymorphism (SNP) rs1053230 within the kynurenine 3-monooxygenase (KMO) gene encodes either an arginine (CGC) or cysteine (TGC) at amino acid residue 452. The rs1053230 genotype is associated with alterations in KMO expression and activity, and impaired cognition. Additionally, KMO intronic SNP rs2275163 is associated with schizophrenia endophenotypes. However, the direct functional consequences of these SNPs on KMO function have never been investigated. MethodsHere we performed the first in vitro cell-based examination of the rs1053230 genotype on KMO expression, activity, cellular localisation and KMO-protein interactions, as well as examination of the effects of rs1053230 on schizophrenia-relevant clinical measures. We also examined the effects of rs2275163 genotype on KMO pre-mRNA stability and alternative splicing. ResultsHEK293T cells expressing KMO-Arg452 or KMO-Cys452 with a red fluorescent protein (RFP) tag produced equivalent levels of KMO mRNA, protein and enzymatic activity, and localised to mitochondria to the same extent. However, cycloheximide-mediated inhibition of protein translation revealed a striking reduction in protein stability of KMO-Arg452-RFP. KMO-RFP-trap pull-down followed by tandem liquid-chromatography-mass spectrometry (LC-MS/MS) identified dramatic differences in protein partners between KMO variants. Indeed, gene ontology-term enrichment analysis revealed that terms associated with synaptic function were more highly enriched amongst KMO-Cys452 interacting proteins. rs1053230 genotype was found to associate with chronic, trait-like depressive mood symptoms in patients. rs2275163 genotype had no effect on KMO pre-mRNA. ConclusionsDifferences in protein stability and protein-protein interactions may underlie the mechanisms by which the KMO rs1053230 genotype influences neuronal function, leading to cognitive differences in psychiatric conditions.

Background: Schizophrenia, bipolar disorder, and depression share substantial genetic liability. However, the molecular mechanisms underlying this shared architecture remain poorly characterized. In particular, the role of circulating proteins as potential mediators and therapeutic targets is not well understood. Methods: Based on large-scale genome-wide association studies, we constructed a latent psychiatric common factor using genomic structural equation modeling. We then performed proteome-wide Mendelian randomization to estimate the associations between circulating proteins and this shared liability, based on four independent proteomic cohorts. Protein-psychiatric common factor associations were prioritized through comprehensive sensitivity analyses and colocalization. We additionally performed tissue- and single-cell expression enrichment analyses and a systematic druggability assessment. Results: We identified 36 circulating proteins with evidence of association with the psychiatric common factor that withstood multiple sensitivity analyses. Several proteins showed distinct tissue-specific expression patterns, with enrichment in brain, immune, or liver tissues, highlighting convergent neuroimmune and systemic pathways. For instance, genetically predicted higher levels of MAPK3, FES, MRE11A, HS6ST3, OLFM1, BTN3A1, BTN3A2 and BTN3A3 were associated with increased psychiatric risk, whereas higher levels of CD40, ITIH3, and ITIH4 were associated with decreased risk. Druggability assessment identified CD40, MAPK3, FES, MRE11A and BTN3A1 as established or potential therapeutic targets. Conclusions: By integrating genetic, proteomic, and transcriptomic data, this study identifies circulating proteins that associated with the shared genetic effects on three major psychiatric disorders. These findings provide biologically grounded candidates for therapeutic targeting and offer insights into shared disease mechanisms.

The past decade has seen tremendous progress in the identification of genes associated with complex neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. Expression patterns of these genes in single cell data strongly implicate excitatory and inhibitory neurons; however, there are limited data on the brain regions involved - a critical question for neurobiology. Spatial transcriptomics provide an opportunity to perform systematic multiregional analyses to provide insights into this question. Here, we have generated a spatial transcriptomics dataset encompassing the diverse anatomical territories of the adult mouse brain sagittal midsection. We compare neuropsychiatric gene enrichment by applying Gene Fraction Enrichment Score (GFES), a novel statistic method that controls for differing neuronal proportions across regions. ASD-associated genes identified by exome sequencing were most enriched in the thalamus followed by the cortex. Schizophrenia genes from genome-wide association studies were also enriched in the thalamus, along with the hippocampus and cortex. These findings add to the evidence that the thalamus plays a major role in neuropsychiatric disorders whilst supporting roles for the cortex and hippocampus. The results highlight shared and distinct patterns for pleiotropic brain disorders that could elucidate common underlying mechanisms and circuitry.

Relapse after treatment for various mental health disorders has been linked to tendency for reductions in responding to increase over time or following re-exposure to motivating stimuli. Here we show that, in rats, responding reduced through non-contingent outcome delivery does not recover in these ways, and that this learning depends on an intact lateral orbitofrontal cortex. These findings suggest that contingency degradation overwrites original learning which may support the development of relapse-resistant behavioural interventions.

Hypomanic tendencies are associated with elevated goal-directed behavior, creativity, charisma, sociability, and entrepreneurial drive, but also with mood instability, irritability, impulsive persistence, and elevated risk for bipolar disorder and other psychopathology. Existing models often emphasize unidimensional constructs such as reward sensitivity or behavioral activation, yet these approaches incompletely capture the dynamic and often contradictory nature of the hypomanic temperament. We propose the Limbic Overload Hypothesis of Hypomanic Vulnerability, a dynamic biosocial framework suggesting that hypomanic tendencies reflect a persistent pattern of elevated engagement despite potential loss, coupled with reduced integration of negative emotional experience into subsequent behavioral regulation. Over time, this pattern may contribute to progressive "limbic overload," characterized by increasing emotional dysregulation, hypersensitivity to salient experiences, and vulnerability to psychopathology. Integrating evidence from personality research, affective neuroscience, and preliminary neuroimaging findings, we propose a dynamic cortico-limbic model linking prefrontal-limbic coordination, loss tolerance, emotional updating, and social reinforcement cycles. Preliminary pilot data suggest that individual differences in hypomanic tendencies are reflected not simply in baseline cortico-limbic organization, but in dynamic neural reconfiguration across pre-task resting-state [->] task [->] post-task resting-state transitions during loss-related decision making. Specifically, elevated hypomanic tendencies were associated with persistently elevated tolerance of potential losses and reduced integration of negative emotional information into subsequent behavioral regulation. We further propose that social connectedness and cognitive-emotional integration may mitigate progressive limbic overload and contribute to resilience. Together, this framework generates experimentally testable predictions regarding the neural, behavioral, and social processes underlying hypomanic vulnerability and resilience.

Transcranial magnetic stimulation (TMS) targeting the left dorsolateral prefrontal cortex is known to progressively reduce symptoms of depression. However, the neural mechanisms supporting this effect are poorly understood. To address this gap, we analysed longitudinal EEG recordings from 70 people undergoing TMS therapy and fitted an established dynamic network model of resting-state activity. Greater baseline symptom severity was associated with reduced occupancy of and fewer transitions into an anterior default mode brain state, alongside increased activity in a posterior default mode state. During treatment, decreases in anterior default mode state engagement following TMS predicted symptom improvement in the latter half of the intervention. Brain state activity exhibited structured, cyclical dynamics, with slower cycles linked to greater baseline severity. These findings suggest that symptoms of depression are characterised by gradual alterations in brain state dynamics, highlighting a central and dissociable role of default mode brain states in the persistence and remission of symptoms.

The behavioral features of autism spectrum disorders (ASD) span multiple domains, yet the relationships among them remain incompletely characterized. Using phenotypic data from the Simons Foundation Powering Autism Research (SPARK), the largest autism cohort to date (N = 197,187), we characterized associations among motor (DCDQ), repetitive behavior (RBS-R), social-communication (SCQ), and psychopathology (CBCL) measures. Broad positive correlations were observed across all domain pairs, with the strongest effects for RBS-R sensory and obsessive/repetitive features. Covariate-adjusted {surd}{Delta}R2 analyses, controlling for age, sex, and nonverbal IQ, revealed heterogeneous but structured association profiles, with the largest unique contributions observed for CBCL thought problems, social problems, and internalizing outcomes. Principal component analysis (PCA) confirmed that these dimensions dominated a shared covariance structure. Split-half replication and out-of-sample ridge regression both demonstrated strong reproducibility of these profiles. Adjustment for anxiety/depressive symptoms attenuated many associations, particularly those involving sensory and repetitive predictors, though substantial cross-domain structure remained, revealing a reproducible behavioral fingerprint linking motor, sensory-repetitive, social-communicative, and cognitive dimensions in ASD, one that is internally consistent across analytic approaches and only partially explained by co-occurring anxiety and depression.

D1-type receptor (D1R)-mediated dopaminergic signaling within the nucleus accumbens shell (NAcSh) is essential for forming adaptive circuit changes that embed persistent memories associated with drug seeking and craving. While D1R is expressed in both NAcSh neurons and astrocytes, the specific contribution of astrocytic D1R to drug-related circuit plasticity remains poorly understood. Here, we demonstrate in mouse NAcSh slices that D1R agonists increase astrocytic Ca2+ activity, an effect that is attenuated by astrocyte-specific D1R knockdown. Furthermore, selective knockdown of astrocytic D1R in the NAcSh prior to cocaine self-administration inhibits cocaine-induced generation of silent synapses, therefore hampering the associated remodeling of NAcSh circuits. Behaviorally, knockdown of NAcSh astrocytic D1R expedites the extinction of cocaine seeking and reduces cue-induced reinstatement. These results identify astrocytic D1R as a fundamental component of NAcSh dopamine signaling during cocaine experience that remodels synaptic connections and neural networks underlying drug seeking and relapse.

Thirty-five percent of people with schizophrenia-related disorders (SRD) form a high-inflammation subgroup defined by elevated anti-gliadin antibodies (AGA+) and inflammatory proteins and associated with an increased severity of negative symptoms. However, the immune mechanisms mediating these effects remain poorly defined. Here, we characterized transcriptional signatures of peripheral immune cells in AGA+ SRD (n=7) compared to AGA-negative (AGA-) SRD (n=3) and healthy controls (HC; n=5), using single-cell RNA-sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs). AGA+ SRD was associated with increased abundance of T-helper-17 cells (Th17), T-follicular helper-1 (Tfh1), CD5+ B cells, plasmacytoid dendritic cells (pDCs), and several CD8+ T cell subsets, including memory and Natural Killer-T-like activated subsets. In parallel, AGA-SRD exhibited a higher abundance of several monocyte subsets compared to either AGA+ SRD or HC. Pathway analysis revealed upregulation in AGA+ SRD of JAK/STAT, type I Interferon, and IL-6 signaling pathways in distinct subset of activated T-cells. Collectively, these results define a unique T cell predominant inflammatory signature in AGA+ SRD, as well as potential targets for therapeutic intervention.

BackgroundResponding appropriately to threats is critical for survival. Dysregulated defensive responses are core features of psychiatric illnesses including panic disorder and post-traumatic stress disorder. Carbon dioxide (CO2) inhalation evokes defensive behaviors in both humans and mice. Here we investigated the role of acid-sensing ion channels (ASICs) in CO2-evoked jumping in mice. MethodsDefensive behaviors (jumping and freezing) were assessed in response to CO2 inhalation and basolateral amygdala (BLA) acidification. We tested the role of ASICs using global knockout mice and Asic1aloxP/loxP mice transduced with AAV-CMV-Cre or AAV-CaMKII-Cre in the BLA. Effects of CO2 on single neuron firing and local field potentials were studied via BLA microwire arrays. ResultsASIC1A disruption increased CO2-evoked jumping while reducing freezing, paralleled by increased BLA c-Fos induction. Acidification of the BLA recapitulated these effects. Virus-mediated ASIC1A disruption in BLA did not resolve the locus of ASIC1A action in jumping. CO2 inhalation suppressed firing in most BLA neurons, though a small number increased firing. ASIC1A disruption enhanced CO2-induced suppression of narrow waveform neurons (putative interneurons), and facilitated excitation of wide waveform neurons (putative principal neurons). Additionally, CO2 produced concentration-dependent broadband power suppression with selective theta enhancement, effects that were augmented by ASIC1A disruption. ConclusionsTogether, these findings suggest that ASIC1A promotes interneuron activity during acidosis and that its loss may reduce inhibition of principal neuron output, shifting defensive responses from freezing toward jumping. These results advance our understanding of how brain pH and ASICs regulate defensive behavior, with potential implications for understanding dysregulated defensive responses.

Chronic stress induces structural and functional changes in the brain, increasing susceptibility to major depressive disorder and other mental illnesses. Myelination deficits are a key pathological feature of stress-related disorders, yet the molecular mechanisms linking chronic stress to oligodendrocyte dysfunction remain poorly understood. Here, we used single-nucleus multiome sequencing to map gene expression and chromatin-accessibility remodeling in the hippocampus of mice exposed to chronic unpredictable mild stress (CUMS), a model that simulates key features of human daily stressors. CUMS induced broad molecular reprogramming across hippocampal cell populations, with stress-responsive gene networks significantly enriched for depression-associated genes. The oligodendrocyte lineage showed heightened vulnerability, with CUMS preferentially disrupting immature OPC/intermediate states and impairing OPC migration, OPC-to-ODC lineage progression, intercellular communication, and myelination. Integrated multiomic analysis identified stage-specific cis-regulatory elements and stress-sensitive gene regulatory networks, converging on SOXD transcription factors, particularly SOX5 and SOX6, as key regulators of OPC dysfunction. SOX6 ChIP-seq confirmed direct SOX6 binding at regulatory elements associated with genes controlling OPC morphogenesis, migration, and glutamatergic signaling. CUMS reduced SOX6 protein levels and SOX6-associated regulatory network activity in OPCs, whereas OPC-specific enhancer-driven restoration of SOX6 rescued stress-induced defects in OPC migration and myelination. Together, these findings define a stress-sensitive SOXD/SOX6 regulatory mechanism linking chronic stress to oligodendrocyte lineage dysfunction and myelination deficits, identifying SOX6 as a functional regulatory node with therapeutic potential for stress-related brain pathology.

Schizophrenia is a severe psychiatric disorder associated with altered dopaminergic signaling and hippocampal circuit dysfunction. Although antipsychotic medications remain the standard treatment, many are limited by incomplete efficacy and adverse effects. Cariprazine, a dopamine D2/D3 receptor partial agonist, has a favorable clinical profile, but its effects on neuronal excitability and network activity remain incompletely understood. Here, we integrated nationwide real-world clinical data with in vitro electrophysiology, computational modeling, and molecular analyses to define the neuronal actions of cariprazine. Among Hungarian patients diagnosed with schizophrenia and receiving index-drug monotherapy with one of the three prespecified D2/D3 targeting antipsychotics, haloperidol was associated with worse survival and a higher cumulative incidence of first registered suicide attempt than cariprazine or aripiprazole in matched observational cohorts. In primary mouse hippocampal cultures, multielectrode array recordings showed that acute cariprazine treatment moderately reduced spontaneous firing in a dose-dependent manner and prolonged burst intervals while largely preserving network synchronization. These effects were milder than those of haloperidol and aripiprazole. Whole-cell patch-clamp recordings revealed cell-type-dependent effects, with reduced intrinsic excitability and increased firing irregularity mainly in regular- and stuttering-type neurons. Conductance-based modeling identified enhanced Kv1-mediated D-type potassium currents as sufficient to reproduce these effects. Consistent with this mechanism, chronic cariprazine treatment altered Kv1.2 protein distribution without changing Kcna2/Kcna3 or Drd1/Drd2/Drd3 transcript expression. These findings identify modulation of intrinsic excitability via Kv1/D-type potassium currents as a candidate cellular mechanism of cariprazine and provide a translational link between real-world evidence and circuit-level drug effects.

Dopamine signaling plays critical roles in postnatal brain development, yet the molecular consequences of early dopaminergic disturbance remain incompletely understood. Here, we investigated transcriptomic alterations in the prefrontal cortex (PFC) and striatum (STR) of mice subjected to early postnatal dopaminergic disturbance by 6-hydroxydopamine (6-OHDA) treatment. Using bulk RNA sequencing (RNA-seq) and weighted gene co-expression network analysis (WGCNA), we identified 369 differentially expressed genes (DEGs) in the PFC, 493 DEGs in the STR, and 32 co-expression modules with region-specific expression patterns. Functional enrichment analyses showed that PFC DEGs were associated with cortical development, plasma membrane signaling, and transcriptional regulation, whereas STR DEGs were enriched for striatal development, locomotion, extracellular matrix organization, and amphetamine response. Co-expression network analysis further identified module-specific enrichments related to developmental, synaptic, metabolic, immune-related, and transcriptional programs. DEG sets from both regions also overlapped with genes implicated in attention-deficit/hyperactivity disorder (ADHD) and other neuropsychiatric disorders. Together, these findings reveal region-specific cortico-striatal transcriptomic remodeling following early postnatal dopaminergic disturbance and identify molecular programs that may link developmental dopaminergic perturbation to later behavioral phenotypes. HighlightsO_LIEarly dopaminergic disturbance reshapes cortico-striatal transcriptomes C_LIO_LIPFC changes were linked to developmental and transcriptional programs C_LIO_LISTR changes were linked to locomotion and extracellular matrix programs C_LIO_LINetwork analysis revealed region-specific developmental and synaptic programs C_LI

Circular RNAs (circRNAs) remain an underexplored layer of transcriptomic regulation in psychiatric disorders. We quantified circRNA expression from 1,022 [518 neurotypical, 365 schizophrenia (SCZ) and 139 bipolar disorder (BIP)] postmortem cortex samples from PsychENCODE consortium cohorts and integrated these profiles with matched linear RNA and genotype profiles. We identified 23 SCZ-associated and 3 BIP-associated differentially expressed circRNAs (FDR<0.05; FDR-circDEG). We trained genetically regulated circRNA expression (circGReX) models using neurotypicals and applied them to SCZ and BIP GWAS to perform Transcriptomic Wide association analysis (TWAS) which identified 22 and 4 circGReX trait associations (circGTAs), respectively. Pathway enrichment of circDEGs and circGTAs implicated neuronal and synaptic processes for both disorders. In UK Biobank, circGReX-imaging associations were predominantly negatively correlated with SCZ and BIP circGTAs, but positively correlated with Alzheimers disease circGTAs. circKLHL24 isoforms showed the most prominent imaging associations. Many co-expression modules containing our FDR-circDEGs were enriched for psychiatric and neurodegenerative risk genes, including our identified circGTAs, and these modules were enriched for cognitive and neurodevelopmental traits. To conclude, circRNAs represent a distinct regulatory layer in psychiatric disorders, linking genetic risk to synaptic biology, brain structure and cognition through disease-specific expression, TWAS prioritization, and imaging associations.

Background: Obsessive-compulsive disorder (OCD) is characterized by disturbing thoughts (obsessions) that initiate anxiety-reducing thoughts or behaviors (compulsions). For patients with treatment-resistant OCD (tr-OCD), neuromodulation techniques, like capsulotomy (a lesion in the anterior limb of the internal capsule) and deep brain stimulation (DBS), have emerged as interventions that likely regulate connectivity between the prefrontal cortex (PFC) and subcortical targets. Three patients (Cap-DBS1-3) underwent a failed capsulotomy followed by successful DBS. Here, we aimed to understand the brain connections disrupted by failed capsulotomy vs modulated by successful DBS. Methods: We used diffusion-weighted magnetic resonance imaging (dMRI) tractography in a control cohort with tr-OCD (n=12) and in two of the Cap-DBS patients themselves to determine connectivity profiles of the capsulotomy, volume of tissue activated (VTA), and potentially necessary tracts (VTA minus capsulotomy tracts). We used whole-brain, PFC-focused, and subcortically-focused tractography algorithms to fully explore the space of possible connections. Results: Capsulotomy regions-of-interest (ROIs) connected with a variety of PFC and subcortical regions. VTA ROIs and potentially necessary tracts had limited and inconsistent PFC connectivity but substantial subcortical connectivity. While correlated to the average OCD connectome (r = 0.214, 95% CI [0.177, 0.251]; r = 0.756, 95% CI [0.739, 0.772]), the Cap-DBS connectomes had many edges that were stronger (z-score > 3). Conclusions: The connectivity profile of potentially necessary tracts for successful DBS treatment after failed capsulotomy revealed a surprising proportion of subcortical regions and inconsistent PFC involvement, highlighting an often-ignored set of connections that may be critical to effective DBS.

Autism spectrum disorder and related neurodevelopmental disorders (NDDs) affect males at two-to-four times the rate of females, yet the environmental contributors to this sex-differentiated vulnerability remain poorly understood. Here, using a clinically translatable postpartum rat model, we show that synthetic oxytocin (OT) administered for postpartum hemorrhage (PPH) prophylaxis ( PPH-OT), a universally administered obstetric medication, undergoes lactational transfer, confirmed by stable isotope-labeled OT and LC-MS/MS, without altering maternal behavior or neonatal cortical OT receptor expression. In offspring, PPH-OT altered ultrasonic vocalizations during dyadic interaction and caused a male-specific reduction in social approach, without affecting other behavioral domains. Sex-stratified RNA-sequencing of the medial prefrontal cortex (mPFC) revealed pronounced transcriptional dimorphism: males showed 1,732 differentially expressed genes versus 693 in females, and a sex-by-treatment interaction contrast identified 1,229 formally sex-differentiated genes. Male mPFC downregulated genes were significantly enriched for high-confidence NDD risk genes across three independent databases -- SFARI score-1 (highest confidence autism genes; OR = 4.56, p = 0.015), DBD autism (OR = 10.34, p = 7.3x10-{superscript 1}{superscript 2}), and SysNDD autosomal dominant (OR = 9.78, p = 8.4x10-) -- including core regulators of cortical circuit assembly (Grin2a, Grin2b, Reln, Tbr1, Mef2c, and Tcf4), an enrichment pattern largely restricted to males. Hypothalamic transcriptional changes were pronounced but showed no enrichment for NDD risk genes, establishing mPFC specificity. These findings identify PPH-OT as a candidate environmental modifier of male neurodevelopmental vulnerability and provide a pressing rationale for prospective investigation of neurodevelopmental outcomes in PPH-OT-exposed children.

Apathy is a leading driver of functional disability in schizophrenia, yet effective mechanism-based therapies are lacking. We evaluated whether cerebellum-ventral tegmental area functional connectivity (CB-VTA FC) meets the criteria for clinical translation as a therapeutic neuromodulation target. Using resting-state fMRI in three independent repeated-imaging cohorts (healthy controls, early psychosis or chronic schizophrenia patients, minutes-months inter-scan intervals), CB-VTA FC was always stable and individual-specific (stability r=0.52-0.69; differential identifiability {Delta} r=0.21-0.35; all p<10-5). In paravermal cerebellar territories, it tracked apathy severity in two patient cohorts (early psychosis, Crus I/II: n=99; r97=0.36, p=2.65 {middle dot} 10-4; chronic schizophrenia, Lobules VIIB/VIIIA: n=87 scans [65 patients]; t85=4.06, p=1.1 {middle dot} 10-4). In a meta-analysis of 39 randomized controlled transcranial magnetic stimulation trials (n=1,624; 867 active), connectivity of neighboring areas to stimulation site predicted negative symptoms improvement. CB-VTA FC thus emerges as a stable, individual-specific, and symptom-related therapeutically relevant circuit, constituting a mechanism-informed precision neuromodulation target in schizophrenia, ready for prospective clinical trials.