Biological Psychiatry

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.

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.

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.

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.

Transcranial magnetic stimulation (TMS) shows promise in autism spectrum disorder (ASD), but variable outcomes may reflect suboptimal targeting. We developed a functional-connectivity (FC)-guided individualized TMS approach by identifying an ASD-relevant effective region and selecting superficial targets. In a multi-site mega-analysis of Autism Brain Imaging Data Exchange I data (298 ASD, 348 controls), the region with the greatest regional homogeneity (ReHo) abnormality was defined as the effective region. Individualized dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobule (IPL) targets were localized as sites with strongest FC to this region. Group differences, symptom associations, and a six-patient case series were examined. The posterior cingulate cortex (PCC) showed the greatest ReHo abnormality and was implicated in theory-of-mind (ToM) circuitry. PCC-guided targets showed weaker FC in ASD in the right IPL, correlating with Autism Diagnostic Interview social scores; left DLPFC FC differences lacked symptom associations. In the case series, individualized PCC-IPL-guided TMS reduced ToM-related symptoms and Childhood Autism Rating Scale scores. PCC-IPL FC-guided TMS is a biologically informed intervention for modulating ToM circuitry in ASD.

Schizophrenia (SCZ) is increasingly linked to neuroimmune dysregulation and impaired synaptic plasticity, yet the cellular mechanisms connecting inflammatory signaling to neural dysfunction remain poorly understood. Using human induced pluripotent stem cell (iPSC)-derived cortical spheroids (hCS) and astrocytes from patients with SCZ and matched controls, we investigated the effects of GABAA receptor modulation on immune signaling and neuroplasticity. Inflammatory stimulation induced robust interferon-responsive transcriptional programs, prominently involving the antiviral effector MX1 and related interferon-stimulated genes. Computational deconvolution and cell type-specific analyses identified astrocytes as key mediators of these responses. Muscimol, a non-classic psychedelic and GABAA receptor agonist, suppressed inflammatory gene expression, reduced secretion of proinflammatory cytokines, and attenuated interferon-associated signaling. In addition, muscimol induced neuroplasticity-associated transcriptional programs, including upregulation of NTRK2 and ELK1 in hCSs, and restored impaired glutamate uptake in iPSC-derived SCZ astrocytes. These effects were blocked by GABAA receptor inhibition, confirming receptor-dependent mechanisms. Proteomic analyses of hCS cultures, and independent human dorsolateral prefrontal cortex datasets revealed baseline dysregulation of GABAergic and neurotrophin signaling in SCZ, supporting translational relevance. Together, these findings demonstrate that GABAA receptor activation by muscimol suppresses inflammatory signaling while promoting neuroplasticity in hCSs, and identify astrocytes as central regulators of interferon-dependent neuroimmune dysfunction in SCZ. These results establish non-classic psychedelic compounds as potential modulators of neuroimmune-plasticity coupling and suggest that targeting astrocyte GABAergic signaling may represent a therapeutic strategy for restoring neural homeostasis in SCZ.

Major depressive disorder (MDD) is a common psychiatric illness with a high proportion of patients being nonresponsive to therapy. Selective serotonin reuptake inhibitors (SSRI) are widely prescribed for treating depression. Chronic SSRI administration is needed for therapeutic effects, a process implicating in part, increased neurogenesis in the hippocampus. Recent genome wide association studies (GWAS) identified the DrD2 locus, which encodes the dopamine D2 receptor (D2R) as a major risk factor in MDD. Here we demonstrate that behavioural effects associated with chronic administration of the SSRI drug fluoxetine and its accompanying neurogenic effects require D2R. Administration of fluoxetine to congenital D2R-knockout mice, or co-administration of the antidepressant with the antipsychotic D2R antagonist drug haloperidol prevented the neurogenic effects of fluoxetine. Furthermore, while acute behavioural responses to fluoxetine did not require D2R, this receptor was essential for the behavioural effects of chronic fluoxetine. The neurogenic impact of chronic fluoxetine was further associated with beta-arrestin 2-mediated signalling and the hippocampal regulation of the pro-neurogenic factor BDNF. These results support a role of D2R in regulating the therapeutically relevant chronic effects of fluoxetine on mood, BDNF signalling, and associated hippocampal neurogenesis. Furthermore, our findings suggest an unappreciated interaction between genetic risk for MDD and treatment responsiveness as well as a negative interaction between SSRIs and antipsychotic drugs in the regulation of hippocampal neurogenesis.

BackgroundPsychosis has been conceptualised as a continuum extending from healthy individuals with psychotic-like experiences to clinical populations with schizophrenia. It is unclear which biological mechanisms found in chronic schizophrenia extend across the psychosis continuum to healthy individuals with high positive schizotypy (HS). In this study, we used computational modeling to test whether changes in effective connectivity and excitation/inhibition (E/I) balance reported in schizophrenia are also found in HS. MethodsA total of 2425 individuals from the general population were screened for HS. A subset (N=141) was invited for in-depth phenotyping. Resting-state functional magnetic resonance imaging (rsfMRI) and proton magnetic resonance spectroscopy (1H-MRS) were recorded in n=69 HS individuals and n=72 group-matched controls with low schizotypy (LS). We used dynamic causal modeling to estimate effective connectivity between bilateral primary auditory cortex (A1), superior temporal gyrus (STG), and inferior frontal gyrus (IFG). ResultsBilateral backward connectivity from IFG to STG was significantly reduced in HS compared to LS. Widespread cortical disinhibition in the auditory cortex-IFG network correlated with more severe positive schizotypy scores and impulsive nonconformity. Reduced excitability in the same network was correlated with stronger cognitive disorganisation. ConclusionsOur results favour a psychosis-continuum hypothesis, suggesting that reduced top-down drive from frontal cortex and compensatory allostatic upregulation of cortical excitability, as observed in chronic schizophrenia, also extend to groups with sub-clinical psychotic symptoms. Frontal cortex dysfunction may serve as a biologically interpretable biomarker of psychosis risk and a target for preventative interventions.

BackgroundPerinatal mood and anxiety disorders (PMADs) are among the most common and consequential complications of pregnancy. The perinatal period is also characterized by profound hormonal fluctuations and large-scale brain plasticity. However, the mechanisms linking these neurobiological changes to psychiatric risk are poorly understood. Prospective, clinically informed studies are needed to identify quantitative biomarkers and clarify pathways linking perinatal neurobiology to PMADs risk. MethodsThis report describes the design of a prospective, longitudinal cohort study integrating multimodal neuroimaging, biofluid sampling, and deep clinical phenotyping to enable precision characterization of neurobiological trajectories of PMADs risk. Twenty-five individuals at elevated risk for PMADs will be recruited prior to conception and followed across six in-person timepoints spanning the menstrual cycle, pregnancy, and early postpartum, with additional remote follow-ups through the first postpartum year. Data collection includes high-resolution structural MRI, functional brain mapping using multi-echo resting-state fMRI, diffusion MRI, arterial spin labeling, ultra-high field MR-based techniques for measuring glutamate (GluCEST and 1HMRS), biofluid sampling, and comprehensive clinical, behavioral, and cognitive assessments. Structured clinical interviews assess categorical diagnoses while dimensional symptom measures capture heterogeneity and transdiagnostic features of perinatal psychopathology. Longitudinal analyses will model nonlinear trajectories of brain and symptom change across the perinatal period as well as evaluate whether preconception network features and menstrual cycle-related brain changes are associated with subsequent perinatal symptom emergence. DiscussionThis cohort study establishes a longitudinal, multimodal framework for investigating neurobiological changes across the transition to pregnancy in individuals at elevated risk for PMADs. By anchoring pregnancy-related brain changes to preconception and menstrual cycle-related variability within the same individuals, this study is designed to evaluate associations between preconception hormone sensitivity, pregnancy-induced neuroplasticity, and PMADs risk. The resulting dataset will provide a deeply phenotyped longitudinal resource for investigating brain-behavior relationships across the perinatal period. Findings are expected to inform future larger-scale studies aimed at advancing mechanistic understanding of PMADs, improving individualized risk stratification, and supporting development of personalized preventive and neuromodulatory interventions.

Despite autism's prominent genetic etiology and early-life origins, parsing genetic effects contributing to the condition into those that operate directly (via allelic transmission to offspring) vs. indirectly (via influencing prenatal environment) remains challenging. We examined this using a novel design leveraging 3-generation family linkage in Danish national registers. The cohort included all children born in Denmark from 1998-2015 and their relatives identified through 3-generation family linkage. The analytic sample comprised full maternal cousin pairs, including parallel (children of mother's sister) and cross cousins (children of mother's brother). Exposures were diagnoses in the index mother previously associated with offspring autism; the outcome was autism diagnosis in cousins of the index child. We used Cox proportional hazards models to estimate associations separately in parallel and cross cousins, followed by comparisons of these hazard ratios to infer mechanisms. Several maternal diagnoses (e.g., postpartum hemorrhage, personality disorders, epilepsy) were associated with autism in both parallel and cross cousins, consistent with shared direct genetic effects. Other conditions (e.g., false labor, recurrent major depressive disorder, other anxiety disorders, systemic connective tissue involvement) showed stronger associations in parallel than cross cousins, supporting additional indirect genetic effects operating through the prenatal environment. Adjustment for the same diagnosis in the cousin's own mother did not substantially change estimates, providing no evidence for an additional role of non-genetic mechanisms associated with the diagnosis. These findings suggest that both direct and indirect genetic effects contribute to observed links between maternal health and offspring autism, highlighting etiologic heterogeneity and highlighting a registry-based family design to separate these pathways without genetic data.

BackgroundLarge-scale T1-weighted MRI studies have established grey-matter abnormalities in bipolar disorder (BD), with our group contributing to consensus findings. However, structural connectivity, particularly within emotion- and reward-related circuits, remains poorly understood. Diffusion-weighted MRI (dMRI) enables investigation of white-matter pathways, yet prior work is constrained by small samples, methodological heterogeneity, and unclear medication effects. We conducted the largest dMRI network analysis in BD, relating symptom burden and polypharmacy to tractography-derived connectivity and graph-theoretic metrics. MethodsCross-sectional structural and diffusion MRI scans from 449 individuals with BD (35.7{+/-}12.6 years) and 510 controls (33.3{+/-}12.6 years), aged 18-65, were analyzed across 16 ENIGMA-BD sites. Standardized segmentation/parcellation and constrained spherical deconvolution tractography generated individual structural connectivity matrices. Graph-theoretic metrics of global and subnetwork organization were related to symptom severity and medications. ResultsBD showed widespread network alterations (lower density and efficiency, longer path length, and higher betweenness centrality), altered microstructural organization in a limbic-basal ganglia circuit, and abnormal streamline counts in a default-mode/salience/fronto-limbic-basal ganglia network. Longer illness duration, later onset, and psychosis history were associated with greater abnormalities in network architecture, whereas more manic episodes were associated with greater fronto-limbic connectivity. Antidepressant (particularly SSRI), anticonvulsant, and antipsychotic use related to poorer global and fronto-limbic connectivity; no clear lithium effects emerged. ConclusionsAs the largest structural connectivity study in BD, we reveal widespread disruption in reward and emotion-regulation networks influenced by illness severity and medication use. Results show that multisite harmonization is feasible and highlight ENIGMA-BD as a scalable framework for identifying reproducible neurobiological markers.

Identifying the neural circuits engaged and reshaped by chronic stress is critical for understanding how adaptive responses shift to maladaptive behaviors that contribute to stress-related disorders. Our previous work demonstrates that chronic unpredictable stress (CUS) induces a persistent increase in the firing activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC). This hyperactivity is due, in part, to a reduction in GABAergic synaptic transmission onto POMC neurons, indicating a disruption in inhibitory control. However, the sources of GABAergic inputs responsible for this effect of chronic stress are unknown. Although AgRP neurons provide local GABAergic input onto POMC neurons and are suppressed by chronic stress, chemogenetic activation of AgRP neurons during stress exposure failed to reduce POMC neuron hyperactivity. GABAergic projections originating from the dorsomedial hypothalamus (DMH) represent another source of inhibitory input to POMC neurons. We found that CUS decreased the firing activity of DMH GABAergic neurons with sex differences, with females exhibiting greater vulnerability to stress-induced suppression. Chemogenetic activation of these neurons during chronic stress markedly attenuated POMC neuron hyperactivity in both sexes, indicating that DMH GABAergic neurons function as a critical upstream regulator of POMC neuron activity under chronic stress. These findings suggest that reduced inhibitory input from DMH GABAergic neurons, rather than local GABAergic AgRP neurons, drives POMC neuron hyperactivity. The weakening of the DMHGABA[->]ARCPOMC circuit activity may represent a novel mechanism underlying maladaptive stress responses and a potential therapeutic target for stress-related disorders.

Opioid and methamphetamine use disorders (OUD and MUD) are characterized by enduring neural adaptations within brain reward circuitry, yet the cell-type-specific post-transcriptional mechanisms underlying these changes remain poorly understood. While microglia are essential for maintaining central nervous system homeostasis and modulating neuroinflammatory responses to drugs of abuse, their alternative splicing (AS) programs have not been defined in the context of addiction. This study characterized the microglial AS landscape in the mouse dorsal striatum during morphine and methamphetamine intravenous self-administration (IVSA), as well as following a 21-day period of abstinence. Analysis of RNA-sequencing data using rMATS and DEXSeq revealed that both drugs significantly dysregulate core splicing machinery, with skipped exons (SE) emerging as the most prevalent splicing event. Notably, morphine exposure induced a robust persistent splicing signature, comprising 736 exonic regions in 221 genes that remained altered through abstinence, whereas methamphetamine-induced changes were primarily reversible. Functional annotation predicted that approximately 27.5% of these events induce frameshifts, potentially impacting critical microglial pathways such as autophagy (Wdr81), chromatin remodeling (Chd4, Kmt2c), and RNA processing (Hnrnpl, Mbnl2, Tia1). These findings identify previously unrecognized post-transcriptional neuroimmune mechanisms and suggest that persistent splicing dysregulation in microglia may contribute to the long-term pathophysiology of OUD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/716002v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1c30f01org.highwire.dtl.DTLVardef@10e16d7org.highwire.dtl.DTLVardef@1fd80dforg.highwire.dtl.DTLVardef@17c80f_HPS_FORMAT_FIGEXP M_FIG C_FIG

Scratching provides transient relief from itch, yet the neural circuit mechanisms that transform scratching into itch relief remain poorly understood. Midbrain dopaminergic neurons and their downstream targets in the lateral shell of the nucleus accumbens (NAc LaSh) are implicated in itch-scratch processing. Previous studies show that pharmacological manipulation of dopamine D1 and D2 receptors in the NAc LaSh alters scratching behavior, but the specific contributions of D1R- and D2R-expressing neurons during acute and chronic itch remain unclear. Here, we show that NAc LaShD1R and D2R neurons bidirectionally regulate scratching behavior across itch states. NAc LaShD1R neurons activity promotes scratching bouts, whereas NAc LaShD2R neurons preferentially facilitate scratch termination. Anterograde viral tracing revealed distinct brain-wide projection patterns of NAc LaShD1R and D2R neurons, which we functionally tested using projection-specific optogenetic manipulations. We found that NAc LaShD2R neurons terminate scratching by inhibiting neurons in the lateral parabrachial nucleus (LPBN), a key hub for itch processing. Furthermore, dopamine levels in the NAc LaSh were elevated during chronic itch compared with acute itch, suggesting enhanced dopaminergic signaling contributes to persistent scratching. Together, these findings identify circuit mechanisms linking reward pathways to itch regulation.

The cerebellum rapidly integrates with cerebral networks during infancy and shows consistent structural and functional alterations in Autism Spectrum Disorder (ASD), suggesting that early cerebellar development may be consequential for later behavioral and psychiatric outcomes. Yet, little is known about the effect of ASD genetic liability on cerebello-cerebral functional connectivity in infancy or whether effects may differ by biological sex. Here, we leveraged neonatal functional magnetic resonance imaging, genetic, and behavioral follow-up data from the Developing Human Connectome Project (dHCP) to examine the relationship between ASD polygenic scores (PGS) and functional connectivity of cerebellar regions associated with sensorimotor and social-cognitive functions in 198 term-born neonates (mean age: 9.7 days). We report widespread sex differences in neonatal cerebello-cerebral connectivity that are regionally specific across cerebellar subdivisions. Across the full sample, elevated ASD PGS predicted alterations in cerebello-cerebral connectivity, with hemisphere-dependent differences in sensorimotor cerebellar connectivity with temporal cortex, and hyperconnectivity between the right social-cognitive seed and posterior cingulate. Notably, elevated ASD PGS predicted opposing patterns of cerebello-cerebral connectivity in males and females, including male hyperconnectivity between the right sensorimotor cerebellum and default mode areas, and female hyperconnectivity between the right social-cognitive seed and sensorimotor cortex. Connectivity associated with elevated ASD PGS showed nominal, sex-specific associations with 18-month language ability, attention problems, and emotional reactivity. Our findings show that ASD PGS influences the functional configuration of the cerebellum at birth and suggest that underlying cerebellar connectivity profiles associated with ASD may partially underlie distinct behavioral presentations in males and females.

Recent evidence suggests that psychosis involves glutamatergic dysfunction and altered activity/connectivity within corticolimbic circuitry. While altered relationships between corticolimbic glutamatergic metabolite levels and resting-state functional connectivity (FC) have been described in schizophrenia and first-episode psychosis (FEP), whether these disruptions are also present prior to psychosis onset remains unclear. We measured Glx (glutamate + glutamine) levels in the anterior cingulate cortex (ACC) and hippocampus with magnetic resonance spectroscopy (MRS), and resting-state FC between corticolimbic regions of interest (ACC, hippocampus, amygdala and nucleus accumbens (NAc)) in antipsychotic-naive participants at clinical high-risk for psychosis (CHR-P, n=22), compared to healthy controls (HC, n=23) and FEP participants (n=10). Primary analyses compared corticolimbic Glx-FC interactions between CHR-P and HC groups. FEP individuals were included in secondary Glx comparisons but were excluded from FC analyses due to insufficient sample size after quality control. There was a significant interaction between group and ACC Glx for FC between the NAc and the bilateral amygdala and hippocampus (p-FDR=0.021), which was driven by a significant negative association in the CHR-P group (p-FDR=0.005). Complementary seed-to-whole-brain analyses revealed additional negative associations between ACC Glx and FC with the left middle temporal gyrus, and between hippocampal Glx and FC with the parahippocampal and temporal fusiform cortices in CHR-P individuals, which were absent in HC. FEP showed higher Glx than HC across both regions (p=0.015), but there were no significant Glx differences between CHR-P and HC. These data suggest that increased risk for psychosis is associated with altered relationships between corticolimbic connectivity and glutamatergic function.

Craving is a hallmark feature of substance use disorders (SUDs) and a major risk factor for relapse, yet reliable biomarkers that enable individual-level prediction remain scarce. Here, we applied connectome-based predictive modeling (CPM) to resting-state functional magnetic resonance imaging (fMRI) data in a transdiagnostic sample of individuals with cannabis, opioid, or tobacco use disorder (n = 78). Using CPM, we identified a distributed functional brain network that reliably predicted self-reported craving. Computational lesion analyses revealed key contributions from the right medial orbitofrontal cortex, right dorsal posterior cingulate cortex, and left lateral medial frontal gyrus. Importantly, the craving network generalized across two independent datasets. In alcohol-dependent patients (n = 41), the identified craving network, along with its positive and negative subnetworks, predicted distinct cognitive and motivational components of craving. In a second external dataset of smokers (n = 28), the craving network predicted both nicotine craving after abstinence as well as intra-individual changes in craving between sated and craving states. Together, these findings provide evidence for a robust, transdiagnostic craving signature in SUDs. Future work should assess the networks predictive utility for longitudinal outcomes such as relapse risk and treatment response.

Cognitive functions in adults are mainly attributed to experience-dependent plasticity. Nonetheless, the developmental encoding of memory deficits is still inadequately addressed. Here, we demonstrate that early-life stress (ELS) reprograms the hippocampal epitranscriptome by enhancing N6-methyladenosine (m6A) deposits during early development leading to memory deficit in adulthood. We observed a shift toward hypermethylation of transcripts including coding and non-coding RNAs (lncRNAs) following maternal separation. We also observed that these transcripts encoding proteins necessary for translational regulation, ribosome biogenesis and mitochondrial function. This epitranscriptomic change is driven by ELS-induced downregulation of the m6A demethylase FTO (Fat mass and obesity-associated protein). We observe that the overexpression of FTO in young adult mice selectively rescues memory deficits without ameliorating elevated anxiety. Further, the knockdown of FTO in primary hippocampal neuron, mimicking ELS - induced reduction of its expression, leads to reduced translation as detected by puromycin labelling. Taken together, our study demonstrated previously uncharacterized mechanism of ELS-induced epitranscriptomic change linked with memory deficit via the regulation of protein synthesis.