Biological Psychiatry

Anorexia nervosa is a severe psychiatric disorder characterized by persistent food restriction and often excessive physical activity, implicating dysfunction in neural circuits governing motivation, reward, and behavioral persistence. The nucleus accumbens (NAc) is a central component of these circuits, yet synaptic and cellular adaptations within this region during anorexia-like states remain poorly defined. Using the activity-based anorexia (ABA) paradigm in adult female mice, we examined glutamatergic signaling and intrinsic neuronal properties in the NAc shell. ABA exposure produced rapid weight loss, reduced food intake, and progressively increased running-wheel activity. Biochemical analyses of NAc shell tissue revealed elevated membrane-associated GluA2 AMPA receptor protein. Consistent with this finding, whole-cell patch-clamp recordings from medium spiny neurons showed increased amplitude of spontaneous excitatory postsynaptic currents. ABA also enhanced intrinsic neuronal excitability, reflected by greater firing in response to depolarizing current injections. Together, these convergent biochemical and electrophysiological results demonstrate that ABA induces coordinated postsynaptic strengthening and increased intrinsic excitability in NAc shell medium spiny neurons. These adaptations suggest a sustained increase in accumbal output that may bias motivational circuit function and contribute to excessive activity and suppressed feeding during anorexia-like conditions, paralleling glutamatergic plasticity observed in other compulsive disorders, including substance use disorder.

BackgroundSynaptic function is increasingly recognized as a core property of genes implicated in psychiatric disorders. Defining the specific synaptic molecular systems underlying genetic risk is critical step toward therapeutic advances. Synaptic processes rely on rapid protein production driven by local translation of mRNA in context-specific synapses. Synaptic mRNA metabolism, transport and local translation is regulated by RNA-binding proteins (RBPs). Here, we hypothesized that genetic risk converges on localised transcripts with synaptic function and aimed to identify RBP regulatory systems that capture this shared schizophrenia genetic risk. MethodsWe use recent human and mouse bulk and single-synapse transcriptomic and proteomic datasets to test for enrichment of schizophrenia genetic risk among mRNAs stratified by localization and synaptic function employing gene set association (MAGMA) and heritability enrichment (S-LDSC) analyses. Prioritized transcripts were further analyzed for RBP control through motif enrichment analysis (Transite) of the 3UTRs of these transcripts. Candidate RBPs were then evaluated based on the strength of genetic association among their predicted binding targets. ResultsWe demonstrate that genes encoding localised mRNAs with synaptic function show significantly greater genetic association than other synaptic genes. We identified a subset of RBPs, RBFOX1/2/3, CELF4, HNRNPR, and nELAVL, whose motifs are enriched in localised synaptic mRNAs and whose targets are enriched for schizophrenia risk variants. These RBPs are prioritized as candidate regulatory systems through which genetic risk may converge on the transport, splicing and translation of localised transcripts with synaptic function. ConclusionsOur results highlight potential regulatory systems through which genetic variation influences synaptic mechanisms and provide a scalable framework for refining the link between genetic association and post-transcriptional regulation in neuropsychiatric disorders.

Transcriptome and proteome sequencing of brain tissue homogenate has helped unravel processes underlying schizophrenia (SCZ). However, most studies have lacked granularity at the cell type level and have focused on individual brain regions, rather than examining expression dynamics across multiple regions or illness-relevant circuitries. We used laser capture microdissection to collect excitatory neuron-enriched samples from hippocampal subregions CA1 and presubiculum (SUB), and from dorsolateral prefrontal cortex (DLPFC), a circuit prominently implicated in schizophrenia. Using RNA sequencing and quantitative proteomics, we show significantly superior discrimination of brain regional identity in the transcriptomic (>90% accuracy) and proteomic data (>97% accuracy) compared with gene-level expression data (<70% in bulk). Patients with SCZ show hippocampal-specific differential protein phosphorylation. SCZ risk co-expression gene-sets that replicate across transcript and protein networks are enriched for transmembrane transporters in the DLPFC and CA1 and postsynaptic processes in the SUB. We demonstrate a strong directional connectivity effect of SCZ risk in that excitatory synaptic genes in CA1 unidirectionally predict gene expression in SUB. Finally, parallel CA1 snRNA-seq results suggest that in SCZ excitatory efferents in CA1 are affected by interactions with glia and by downregulation of inhibitory neuropeptide inputs. Our study proposes molecular mechanisms by which hippocampal communication, previously associated with SCZ at the macroscopic level, may be altered at the inter-field and interregional circuit level.

Roughly one-third of patients with major depressive disorder (MDD) fail to respond to standard treatments and develop treatment-resistant MDD. For these patients, alternative therapies ofer additional options but yield inconsistent outcomes. Progress has been limited by the absence of objective, brain-based biomarkers to guide target selection or track therapeutic response in real time. Instead, clinicians rely on behavioral assessments that evolve slowly over weeks to months, obscuring the underlying neural dynamics of symptom changes. Here, we test whether the aperiodic exponent of intracranial EEG (iEEG) local field potentials can serve as a neurophysiological marker of depression symptom severity. We leveraged a large iEEG cohort (N = 20) undergoing invasive monitoring for refractory epilepsy, yielding over 1,800 contacts spanning cortical and subcortical zones. For each contact, we estimated the aperiodic exponent (thought to reflect aspects of cortical excitability) of the power spectrum across 10-100 Hz within local brain regions and across distributed cortical association networks. Depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II) immediately before intracranial resting state recordings. With respect to the BDI-II scale, participants were identified as experiencing minimal (BDI-II [&le;] 13) or elevated depression symptoms (BDI-II [&ge;] 14). Associations between symptom severity (BDI-II total score and Somatic-Afective, Cognitive, and Anhedonia subscales) and region- or network-level exponents were modeled with ordinary least squares (OLS) regression. The whole-brain, mean aperiodic exponent for each participant discriminated symptom status (AUC = 0.82). At the regional level, the orbitofrontal cortex, anterior cingulate cortex, insula, and amygdala showed higher exponents in the elevated depression symptom group (d = 1.18-1.71; p = 0.032-0.004). A post-hoc classification analysis across these four regions misclassified one participant per group (AUC = 0.86; 95% CI 0.64-1.00). In continuous analyses, BDI-II scores correlated positively with exponents in these same four regions (pFDR = 0.019-0.027; partial r=0.61-0.70) and at the network level in the Salience network (pFDR = 0.024; partial r = 0.63) and Default (pFDR = 0.046; partial r = 0.55) network. The Salience network significantly tracked Anhedonia symptoms (p = 0.004; partial r = 0.62). Here we report that intracranial aperiodic exponents within fronto-limbic and insular circuits, overlapping with networks implicated in contemporary accounts of depression pathophysiology, diferentiate depressive symptom status and scale with severity. These findings support the aperiodic exponent as a candidate neurophysiological marker of current depression symptom burden, with potential relevance for individualized neuromodulation in MDD.

Schizophrenia is one of the most complex brain disorders, arising from multidimensional pathophysiological processes that span genetic vulnerability, neurotransmitter dysregulation, structural brain damage, and large-scale brain network dysfunction. Large-scale neuroimaging studies have consistently demonstrated the critical role of frontal brain regions in schizophrenia. Despite substantial progress, the precise localization of structural damage within these regions and the neurobiological mechanisms linking such alterations to disease pathology remain poorly understood. In this study, we included a total of 115 subjects from two sites of the B-SNIP dataset, comprising 60 healthy controls and 55 individuals with schizophrenia. We employed diffusion tensor imaging (DTI) to precisely characterize specific structural alterations in the frontal brain regions associated with schizophrenia. Our findings reveal significant microstructural abnormalities in the forceps minor, a major commissural white-matter tract that serves as a critical interhemispheric bridge between the bilateral frontal lobes. Network-level mapping further demonstrates that the forceps minor is closely integrated with large-scale brain networks, particularly the default mode network, and maintains strong structural connectivity with orbitofrontal regions-both of which are known to exhibit dysfunction in schizophrenia. Moreover, converging evidence suggests that the forceps minor plays an important role in the regulation of social behavior, a core domain of impairment in schizophrenia. Collectively, these findings identify the forceps minor as a promising structural imaging biomarker for schizophrenia and provide novel insights into the microstructural mechanisms underlying the disorder.

BackgroundNeurodevelopmental disorders, including autism spectrum disorder, involve widespread transcriptional dysregulation. Copy number variations at 16p11.2 are among the strongest genetic risk factors for autism spectrum disorder, yet the molecular mechanisms by which these copy number variations contribute to neurodevelopmental pathology remain unclear. ResultsWe identify significant genetic associations between autism spectrum disorder susceptibility and the HIST1 histone gene cluster through genome-wide analysis. Transcriptomic profiling across post-mortem brain tissue, patient-derived neural progenitor cells, neurons, and cerebral organoids reveals consistent upregulation of linker histone variants H1.2 and H1.5 in idiopathic autism spectrum disorder and 16p11.2 hemi-deletion carriers, but not in schizophrenia or bipolar disorder. Functional assays demonstrate that dysregulated H1 expression disrupts gene networks involved in synaptic signaling, chromatin remodeling, and neural differentiation. Mechanistically, we link H1 upregulation to MAZ, a transcription factor encoded within the 16p11.2 locus. MAZ binds the promoter regions of H1 genes and represses their transcription. Knockdown of MAZ leads to H1 overexpression. H1 upregulation alone is sufficient to alter the expression of autism spectrum disorder-associated genes. ConclusionsOur findings define a MAZ-dependent regulation of H1 dosage as a critical chromatin-mediated mechanism contributing to transcriptional pathology in 16p11.2-associated autism spectrum disorder.

The dorsolateral prefrontal cortex (dlPFC) controls many cognitive and emotional processes that are disrupted in schizophrenia (SCZ). However, the spatial location of molecular changes associated with SCZ within the dlPFC remains poorly characterized. dlPFC cell types are spatially organized across six layers into microcircuits that mediate dlPFC function. While SCZ has been linked to regionally-defined cell types, spatially-resolved transcriptomics (SRT) can more directly map molecular associations of disease. We integrated protein detection for perineuronal nets, neurons and vasculature with SRT to investigate how gene expression varies across different cellular microenvironments in the human dlPFC from neurotypical control (n=31) and SCZ (n=32) brain donors. We mapped transcriptional alterations in synaptic, neuroimmune and metabolic pathways to neuropil and glia-enriched domains including the white matter. Integrative analyses linked laminar alterations predominantly to non-neuronal populations, and in situ profiling further resolved these changes at cellular resolution, indicating intracellular transcriptional changes that may underpin SCZ-associated alterations. By mapping SCZ-associated ligand-receptor pairs, we curated altered patterns of cell-cell communication that may coordinate local signaling dynamics across specialized tissue microenvironments. Finally, analyses that integrate SCZ genetic risk further highlight the significance of neuron-glia interactions, suggesting that neuronal genetic liability may signal through non-neuronal alterations across cortical domains. This multimodal atlas provides a spatial-anatomical framework for linking genetic risk to transcriptional phenotypes in the human cortex, delineating SCZ-associated gene expression landscapes across layers, single cells, and microenvironments. The data is available as a browsable PsychENCODE resource to support broad utilization that can inform mechanistic studies investigating SCZ pathology and risk.

BackgroundDepression is biologically heterogeneous, and first-episode depression (FED) carries a high risk of recurrence that is poorly captured by symptom-based assessment. Early identification of patients likely to relapse, as well as reliable identification of those unlikely to relapse, is needed to support personalized intervention and efficient allocation of care. MethodsWe developed a neurocomputational framework to infer recurrence risk from resting-state fMRI functional connectivity. The framework combines a Convolutional Filtering Autoencoder (CFAE) with a k-medoids clustering algorithm (FED-kMC) to derive neurofunctional FED subtypes, followed by a Manifold Sheaves-based Ensemble Support Vector Machine (MST-LVSVM) to estimate individual-level recurrence risk and define an interpretable decision boundary. Circuit-level analyses were then used to localize connectivity pathways associated with high relapse risk. ResultsThe framework identified two neurofunctionally distinct FED subtypes with divergent recurrence trajectories and achieved an external validation accuracy of 82.61% for recurrence risk prediction. Circuit analyses highlighted dysfunction within the Medial Superior Frontal Gyrus-Hippocampus and Angular Gyrus-Precuneus pathways as neural correlates of high relapse risk, together with a decision boundary enabling early-stage risk stratification. ConclusionsIntegrating connectome-derived, circuit-level information with subtype-aware machine learning may support proactive identification of FED patients at elevated recurrence risk and facilitate targeted early interventions, bridging connectome-level analysis and clinical decision-making.

The medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) form a highly interconnected circuit involved in emotional regulation, stress reactivity, and cognitive processing. While prior research has established the anatomical and functional interactions between these regions, the precise organization and molecular identity of VTA neurons involved in unidirectional and bidirectional mPFC connectivity remains poorly defined, particularly under stress. We combined dual anterograde and retrograde viral tracing in male and female mice to label VTA neurons according to their connectivity with the mPFC. This approach identified three distinct subpopulations including mPFC-projecting, mPFC-receiving, and bidirectionally-connected neurons which accounted for nearly half of the labelled VTA population. Each group displayed molecular heterogeneity, with most cells expressing dopaminergic (TH) and glutamatergic (VGLUT2) transcripts rather than single dopaminergic or GABAergic (GAD1) markers. Acute and chronic stress exposure revealed sex- and circuit-specific patterns of c-Fos activation. In males, acute and chronic stress generated opposing rostrocaudally organized activation profiles, whereas females showed a more uniform increase in activity. Spatial clustering analyses further revealed that stress induces distinct hotspot organization within the VTA, with chronic stress promoting cohesive hotspot organization and consistent local enrichment of bidirectionally connected neurons despite a limited global activation. Together, these findings uncover a molecularly diverse mPFC-VTA circuitry with bidirectional connectivity that undergoes sex-dependent spatial and functional rearrangement under stress, providing new insights on circuit-level mechanisms of stress-related disorders.

BackgroundPeripheral inflammation is implicated in the pathophysiology of schizophrenia, but how inflammatory signals map onto the large-scale brain organization remains incompletely understood. MethodsWe applied a supervised multimodal fusion approach guided by interleukin-6 (IL-6) to gray matter volume (GMV) and resting-state regional homogeneity (ReHo) from a population-based discovery cohort in the UK Biobank. Brain components related to IL-6 were identified and then projected onto an independent schizophrenia cohort to examine their relevance to the disease. Imaging-transcriptomic analyses using the Allen Human Brain Atlas characterize the molecular substrates underlying the disease-relevant pattern. ResultsTwo ReHo components were significantly associated with plasma IL-6, while no GMV components showed robust IL-6 correlations. One of the components (ReHo IC4) exhibited a conserved functional pattern characterized by enhanced visual synchrony and reduced synchrony in the medial prefrontal cortex. This pattern remained unchanged in both the healthy controls and patients. In contrast, another component (ReHo IC8) showed increased synchrony in the default mode network and reduced synchrony in sensorimotor networks, and its loadings were significantly elevated in patients with schizophrenia. Imaging-transcriptomic analysis revealed the molecular architecture of this disease-amplified pattern. The default mode region was enriched in synaptic signaling pathways, while the sensorimotor region was linked to mitochondrial bioenergetic processes; both patterns significantly enriched with gene sets related to schizophrenia. ConclusionsThis study identified an IL-6-associated functional brain pattern that is amplified in schizophrenia, linking peripheral inflammation to disease-specific network dysregulation. The findings provide a systems-level framework for understanding how peripheral inflammation interacts with large-scale brain network activities in schizophrenia.

Schizophrenia spectrum disorders (SSD) are characterized by altered brain structure, reflecting widespread dysconnectivity across brain-specific networks. However, the role of hierarchical organization on cortical morphometric networks in shaping clinical outcomes over the course of the disease remains unclear. Connectome-derived gradients have increasingly been used to investigate spatial transitions in brain organization. Here, we computed cortical and subcortical Morphometric INverse Divergence (MIND) similarity networks from 1293 structural MRI data of 193 healthy controls (HC) and 350 individuals with SSD followed for up to 20 years. MIND features were calculated for each subject-specific network by computing regional averages and performing gradient decomposition. We found that MIND in SSD was longitudinally associated with treatment duration and medication. These associations were co-localized with hierarchical axes of cortical organization and schizophrenia epicenters. Moreover, psychiatric symptoms were associated with these alterations in structural similarity, which were also related to treatment duration. Collectively, these findings advance our understanding of how brain organization, treatment duration, and medication shape clinical symptoms throughout the course of SSD.

Mutations in the synaptic scaffold protein SHANK3 represent one of the most frequent genetic causes of autism spectrum disorder (ASD), yet the circuit mechanisms through which SHANK3 dysfunction leads to behavioral alterations remain incompletely understood. The anterior insular cortex (aINS) is a key integrative hub involved in socio-emotional processing, anxiety regulation, and social cognition, a group of behaviors frequently disrupted in ASD. Here, we investigated whether selective deletion of SHANK3 signaling in glutamatergic neurons of the aINS is sufficient to produce ASD-relevant behavioral and circuit phenotypes. Using conditional Shank3flox4-22 mice combined with stereotaxic viral delivery of Cre recombinase under the CaMKII promoter, we selectively deleted Shank3 in glutamatergic neurons of the aINS. Behavioral phenotyping revealed increased anxiety-like behavior, enhanced repetitive behavior, and impaired social memory, while sociability and locomotor activity were largely preserved. These behavioral alterations were accompanied by genotype-dependent differences in neuronal activity revealed by calcium imaging, indicating disrupted activity dynamics in insular glutamatergic neurons following Shank3 deletion. To assess the broader relevance of these findings, we evaluated the behavioral profile of BTBR T+ Itpr3tf/J mice, a model of idiopathic ASD, in the same battery of behavioral tests. Several behavioral alterations observed following insular Shank3 deletion partially overlapped with those present in BTBR mice, supporting the relevance of aINS Shank3 in ASD-related phenotypes. Together, these findings identify glutamatergic neurons of the aINS as a critical locus through which Shank3 dysfunction can disrupt socio-emotional, cognitive, and repetitive behaviors. Our results highlight the aINS as a key circuit node contributing to ASD-related behavioral alterations and provide mechanistic insight into how synaptic scaffold disruption leads to circuit dysfunction and produces behavioral alterations.

Several neurodevelopmental disorders (NDDs) are characterized by impairments in social behavior and affective dysregulation. Converging evidence implicates the endocannabinoid system in the control of both behaviors. However, the brain region-specific contribution of cannabinoid receptor type 1 (CB1R) signaling to these NDD-relevant phenotypes remains unclear. The anterior insular cortex (aINS) is a key integrative hub involved in socio-emotional processing and social novelty recognition. Whether CB1Rs within this region are sufficient to regulate behavioral domains disrupted in NDDs remains unclear. Here, we employed a Cre-dependent viral strategy to selectively restore CB1R mRNA expression in the aINS of global CB1R-deficient mice. Region-specific rescue of CB1R in the aINS normalized social novelty discrimination and reduced anxiety-like behavior as compared to mice lacking CB1R, while leaving basal sociability and locomotor activity unaffected. In addition, insular CB1R re-expression modulated repetitive-like behaviors without broadly altering other behavioral domains. These effects were observed in the absence of off-target expression, supporting the specificity of the genetic manipulation. Our findings demonstrate that CB1R mRNA expression within the aINS is sufficient to regulate distinct socio-emotional and repetitive behavioral domains. These results identify the aINS as a critical CB1-dependent modulatory node and provide mechanistic insight into how region-specific endocannabinoid signaling contributes to behavioral phenotypes relevant to NDDs.

Psychosis is increasingly understood as a disorder of disrupted cortical excitation-inhibition balance, yet robust non-invasive translational biomarkers remain lacking. The resting-state fMRI Hurst exponent (HE) and EEG aperiodic spectral exponent are promising complementary biomarkers, with lower values in each proposed to reflect a shift towards cortical hyperexcitability, but they have not been jointly examined in psychosis, and the spatial and molecular architecture of HE alterations remains poorly defined. We therefore tested for convergent systems-level signatures across independent cohorts and modalities, using resting-state fMRI (107 patients, 53 controls) and EEG (547 patients, 363 controls). Whole-brain and regional HE were estimated using wavelet methods, and EEG aperiodic exponents were quantified using spectral parameterisation. Compared with healthy controls, individuals with psychosis showed reduced whole-brain HE and widespread regional reductions. Regional HE case-control differences were associated with cortical gene-expression patterns, with enrichment for potassium channel and GABA receptor pathways, and correlated with noradrenergic, muscarinic, serotonergic, glutamatergic and dopaminergic receptor density maps, but not with cortical thickness or symptom or cognitive measures. In the independent EEG cohort, psychosis was similarly associated with a reduced aperiodic spectral exponent. Together, these findings provide cross-modal evidence for altered cortical resting-state dynamics in psychosis, consistent with a shift towards cortical hyperexcitability. Integration with receptor-density and transcriptomic maps implicates biologically plausible molecular pathways and supports HE and EEG aperiodic activity as scalable translational biomarkers in psychosis.

Stress exposure early in life is an established risk factor for adult psychiatric illness, yet these disorders - including anxiety disorders and depression - show significant sex-dependence in prevalence, symptomatology, and treatment response. The biology underlying these differences remains largely unexplored and may contribute to the clinical heterogeneity in anxiety and depression. Here, we characterize the lasting impact of developmental stress on adulthood neurobiology and behavior in mice by combining analyses of multiple levels of brain function, including whole-brain c-Fos mapping, manganese-enhanced MRI and transcriptomics with advanced behavioral phenotyping. Across levels of investigation, we find distinct and often opposite effects of developmental stress depending on sex. These results together showcase the strong influence of sex on how early life adversity affects the onset of stress-related disorders. This work emphasizes the necessity of considering sex when investigating developmental and neurobiological underpinnings of stress-related disorders and displays a vast range of lasting effects of developmental stress on the brain, which provides a valuable resource for future studies aiming to improve psychiatric treatments.

New treatments for depression are needed that combine robust efficacy with improved scalability. Although psilocybin has demonstrated antidepressant effects in Phase 3 clinical trials, some of its psychedelic effects limit tolerability, necessitating administration in highly supervised clinical settings, and thus motivating development of serotonergic therapeutics that preserve antidepressant efficacy while reducing the acute psychedelic experience. We combined psilocybin with a phosphodiesterase-9 inhibitor (PDE9i), which raises cyclic GMP levels, and observed substantial reduction in the mouse head twitch response (HTR) -- a proxy for 5-HT2A receptor-mediated psychedelic-like behavior in rodents -- suggesting attenuation of acute psychedelic effects. Significantly, rescue of chronic stress-induced depressive-like behavior by psilocybin was maintained with the coadministration of PDE9i. Proteomic analysis of medial prefrontal cortex (mPFC) synaptosomes showed that the combination of PDE9i and psilocybin enhanced synaptogenesis pathways relative to psilocybin alone, while reducing pathways involved in G protein-coupled receptor (GPCR) signaling. Together, these results suggest that the combination of PDE9i and psilocybin may be a promising direction for psychedelic treatment, and point towards molecular pathways that dissociate acute psychedelic and antidepressant responses.

Fear extinction processes are central to the pathology and treatment of anxiety disorders. Emerging evidence implicates rapid eye movement (REM) sleep in the consolidation of extinction memory. Separately, converging theory and empirical work suggest that vagally mediated heart rate variability (VmHRV) serves as a peripheral index of cortico-subcortical regulatory capacity relevant to extinction circuitry. On this basis, we tested the hypothesis that VmHRV during REM sleep would be associated with the retention of extinction memory in individuals with generalized anxiety disorder (GAD). Participants underwent a validated two-day fear conditioning and extinction paradigm. Subjective extinction retention (sERI) was quantified during a recall test 24 hours after learning and ambulatory polysomnography was recorded on the intervening night. As hypothesized, higher REM VmHRV was significantly associated with better extinction retention. This association remained robust after controlling psychotropic medication use and REM density. In contrast, VmHRV during SWS or wakefulness, as well as other REM sleep measures, were not associated with extinction retention. These findings identify REM VmHRV as a significant predictor of extinction memory retention in GAD, extending prior findings in trauma-exposed individuals. We propose that reduced vagal tone indexes compromised prefrontal inhibitory control over amygdala and noradrenergic circuits, thereby impairing REM sleep-dependent consolidation. These results position VmHRV during REM sleep as a potential transdiagnostic biomarker of extinction memory processing and suggest that interventions enhancing vagal tone could improve treatment outcomes in anxiety disorders.

Metabotropic glutamate 2/3 receptors (mGluR2/3) have been implicated in depression, anxiety, learning, and memory. However, their causal role in reward-related behaviors remains unclear. Here, we examined the effects of intraperitoneal administration of LY341495, a selective mGluR2/3 antagonist, on reward-related behaviors in mice. In a head-fixed temporal conditioning task, mice received a 10% sucrose solution every 10 seconds. After training, mice exhibited anticipatory licking and pupil dilation aligned with expected reward delivery, indicating successful reward prediction. LY341495 dose-dependently reduced licking behavior without disrupting temporal prediction, as normalization analyses revealed reduced gain but preserved timing. LY341495 also induced overall pupil dilation and attenuated reward-proximity pupillary responses. To determine whether reduced licking reflected general motor impairment, we assessed spontaneous locomotion in a freely moving open-field task. LY341495 did not affect locomotor activity or excretion, suggesting intact general motor and autonomic function. To further evaluate orofacial motor function, we measured ultrasonic vocalizations (USVs) during a social interaction task. LY341495 did not significantly alter USVs, indicating preserved mouth-related motor function independent of licking. In contrast, LY341495 dose-dependently reduced food intake in a freely moving feeding task. Moreover, social preference testing revealed that LY341495 reduced social interaction, suggesting impaired processing of non-food rewards. Together, these findings demonstrate that mGluR2/3 signaling regulates reward-seeking behaviors independently of general locomotor or orofacial motor function. These results provide new insights into glutamatergic mechanisms underlying reward processing and may have clinical implications for obesity, eating disorders, and psychiatric conditions involving motivational dysfunction.

Schizophrenia spectrum disorders (SSDs) are clinically and neurobiologically heterogeneous. Normative modeling addresses heterogeneity of structural brain alterations by focusing on individual-level deviations, but their clinical relevance in SSDs remains controversial. We mapped the relationship between individual gray matter volume (GMV) deviations and schizophrenia diagnosis and symptoms. Normative models of GMV were established using cross-sectional, T1-weighted magnetic resonance imaging data from a large, multi-site, healthy reference cohort (N = 7957). Deviations were derived for SSD patients (n = 379) and healthy controls (n =149). Patients showed a significantly more negative average deviation compared to controls and regional deviations predicted diagnostic status with adequate performance (AUC = 0.79). A more negative deviation was associated with higher symptom severity and lower cognitive functioning in SSD. Negative deviations were scattered across the brain, with the largest alterations in the salience network. Our findings strengthen the potential of normative modeling to disentangle the heterogeneous underpinnings of SSD and provide further evidence for individualized structural deviations, particularly in the salience network, as promising markers of illness severity in SSDs.

Mutations in SCN2A, which encodes the voltage-gated sodium channel Nav1.2, are associated with a wide spectrum of neurodevelopmental and neuropsychiatric disorders, including epilepsy, autism spectrum disorder (ASD), and schizophrenia. Although dysfunction of SCN2A-dependent neural circuits has been implicated in these disorders, the circuit mechanisms underlying social behavioral abnormalities remain poorly understood. Here, we investigated the neural circuit basis of social behavioral deficits associated with Scn2a dysfunction, focusing on the nucleus accumbens (NAc), a key hub in cortico-limbic circuits that regulates emotional and motivational behaviors. Using conditional genetic and chemogenetic approaches in mice, we examined the roles of dorsal telencephalic excitatory neurons, including those in the cerebral cortex, hippocampus, and amygdala, as well as parvalbumin-positive fast-spiking interneurons (PV FSIs) in the NAc. Mice with Scn2a haploinsufficiency in dorsal telencephalic excitatory neurons (Scn2afl/+/Emx1-Cre) exhibited reduced sociability in the three-chamber social interaction test. Similarly, chemogenetic inhibition of NAc PV FSIs decreased sociability without affecting locomotor activity or anxiety-like behavior. Scn2afl/+/Emx1-Cre mice also showed a trend toward reduced prepulse inhibition of the acoustic startle response. Notably, dopamine release into the NAc in the Scn2afl/+/Emx1-Cre and systemic Scn2a heterozygous knockout (Scn2a+/-) mice was largely comparable to that in control mice. Together, these findings indicate that reduced activity of dorsal telencephalic excitatory neurons or NAc PV FSIs is sufficient to impair sociability independently of mesolimbic dopamine hypofunction. Our results highlight a potential role of cortico-accumbal circuits in social behavioral deficits associated with SCN2A dysfunction.