Neuropsychopharmacology

The 7-nicotinic acetylcholine receptor (7nAChR) has driven extensive research over the past three decades for its pro-cognitive potential. It is the leading druggable target for the cognitive deficits associated with schizophrenia and has motivated major pharmaceutical and clinical efforts to ameliorate similar impairments in other neurological disorders, such as Alzheimers disease (AD). Yet, a systematic evaluation of the role played by 7nAChR in cognition, and its mechanistic underpinnings, is still lacking. Here we report that 7nAChRs on principal and inhibitory forebrain neurons are largely inconsequential to mouse behavior, including in domains that are most sensitive to schizophrenia-related cognitive impairments. By contrast, loss of 7nAChR from astrocytes produces profound behavioral alterations that are cognitive domain-specific, are time-of-day dependent, coincide with reduced levels of the N-methyl D-aspartate receptor (NMDAR) co-agonist D-serine, and are fully restored by D-serine supplementation. Further, an 7nAChR partial agonist previously evaluated in Phase III trials for cognitive enhancement in schizophrenia and AD fails to augment behavior in mice lacking astrocytic 7nAChRs. Together, these findings identify astrocytes and D-serine/NMDAR signaling as a central mechanism through which 7nAChR, a major drug target, promotes cognitive behavior.

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.

Traumatic brain injuries (TBIs) are more than mere lesions and generate a persistent secondary pathology. This, combined with functional reorganization of circuits post-injury, may explain the increased risk for psychiatric disorders in patients with TBI. In the current studies, we demonstrate that frontal TBI changed the Pavlovian behavioral response to reinforcer-predicting cues and reduced the motivational value of cues. TBI also chronically impaired decision-making on a gambling-like task with reinforcer-paired cues. To investigate how these changes occur, we evaluated the nucleus accumbens (NAc) core. At a subacute time point (14 days), we confirmed reduced input to the NAc with optogenetics and evaluated electrophysiological and transcriptional changes. TBI increased neuronal excitability and the single nucleus RNA sequencing profile indicated a substantial stress and inflammatory response, but also high indicators of plasticity, particularly in D1- and D2-positive medium spiny neurons. To evaluate how these subacute changes transitioned to chronic NAc dysfunction, we measured immunohistochemical surrogates of activity post-mortem and recorded calcium activity from the NAc after TBI during Pavlovian conditioning. TBI reduced histological markers of activity and reduced cue-evoked calcium activity. Overall, these data indicate that substantial reorganization of the NAc occurs following frontal brain injury. A primary effect of this is to reduce the salience of environmental cues linked to outcomes. The inability to properly process outcomes could contribute to broader psychiatric symptoms after TBI, including impairments in decision-making, behavioral flexibility, and impulsivity but also presents a potential treatment target.

Progress in pharmacological treatment development for neurodevelopmental disorders is hindered by a misalignment between targeted mechanisms, outcome measures, and trial designs. This study was initiated as a post-trial access pathway for bumetanide and later expanded with treatment-naive participants. Within this framework, we implemented a parent-cocreated sensory outcome measure set (PROMset) in an unmasked, multiple-baseline single-case experimental design with randomized baseline periods of 2-12 weeks, followed by 6 months of bumetanide treatment (up to 1.5 mg twice daily). Participants (7-19 years) had atypical sensory reactivity and a diagnosis of ASD, ADHD, epilepsy, or TSC. The primary outcome was a PROMset comprising seven PROMIS item banks assessing anxiety, depressive symptoms, sleep disturbance, fatigue, sleep-related impairment, cognitive function, and peer relationships. Secondary outcomes included SSP, SRS-2, RBS-R, and ABC. Of 113 enrolled participants (mean age 13.2 [SD 2.7], 64% male), 102 completed the trial and 95 had analyzable PROMsets. At baseline, PROMset scores showed substantial impairment across domains (mean deviation =9.0 T-score points, p<.001) and correlated with sensory reactivity (SSP; r=-0.40, p<.001). Individual-level analyses showed improvement in 24-41% of participants per PROM domain, most frequently in anxiety and depressive symptoms (41% and 38%; mean across-case Cohen's d=-1). Overall, 83% improved on at least one domain. Group-level analyses showed improvement across all secondary outcomes (p<.001), with superiority over historic placebo for RBS-R and SSP. Integrating PROMsets with individualized trial designs can reveal clinically meaningful changes, supporting a more sensitive and patient-centered framework for treatment evaluation in heterogeneous populations.

Substance use disorders run in families, yet the mechanisms underlying intergenerational transmission remain unclear. We investigated indirect genetic effects, pathways through which parental genotypes influence offspring phenotypes via the family environment, for alcohol use disorder (AUD), nicotine dependence (ND), and related quantitative outcomes, and aimed to identify family environmental factors through which such effects may operate. Using transmitted and non-transmitted polygenic scores (PGS) constructed for problematic alcohol use, tobacco use disorder, and general addiction liability, we analyzed 5972 European-ancestry adult offspring with at least one genotyped parent from the population-based Lifelines cohort (Netherlands). Offspring outcomes included lifetime DSM-5 AUD diagnosis, AUD symptom count, maximum drinks in 24 hours, Fagerstrom Test for Nicotine Dependence score, and cigarettes per day. AUD findings were meta-analyzed with data from the Brisbane Longitudinal Twin Study (N = 1368; Australia). We also examined parent-of-origin effects and mediation by parental substance use and socioeconomic status using structural equation modeling. Transmitted PGS robustly predicted all AUD and ND outcomes ({beta} = 0.07-0.16; OR = 1.20 for AUD diagnosis). Non-transmitted PGS, indexing indirect genetic effects, were negligible for all clinical syndrome outcomes. The only significant indirect genetic effect was on cigarettes per day ({beta} = 0.03, p = 0.01), mediated by parental smoking behavior but not socioeconomic status. These findings indicate that intergenerational transmission of risk for AUD and ND is driven primarily by direct genetic effects, with modest indirect genetic effects on smoking quantity. Larger samples and cross-trait analyses are needed to further elucidate these mechanisms.

Regular cannabis use has been associated with alterations in reward-related neural processes, yet findings remain inconsistent and the relationship between neural activity and behavioural performance is not fully understood. The present study aimed to characterise neural and behavioural correlates of reward processing in regular cannabis users (CU) compared with matched non-users (NU) using the Monetary Incentive Delay Task (MIDT). Firstly, we assessed behavioural performance through reaction times, accuracy and monetary earnings to determine whether potential neural alterations were reflected in task performance. Secondly, focusing on reward-related brain regions, we examined group differences in BOLD functional MRI activity during anticipation and outcome phases separately for monetary win and loss conditions. Finally, we explored the association between behavioural performance and neural activation. Our findings indicate that regular cannabis use is associated with altered engagement of key nodes within the mesocorticolimbic circuit during both anticipatory and outcome phases of reward processing, accompanied by impaired behavioural performance. Particularly, compared with NU, CU showed (I) lower striatal activity during anticipation of monetary win and higher ventral striatum and frontal pole activity during anticipation of monetary loss; (II) greater VTA activation during outcome of successful monetary win and loss avoidance and lower frontal pole activity during outcome of unsuccessful loss avoidance; (III) impaired behavioural performance, reflected in lower monetary rewards and a trend towards slower reaction times and reduced accuracy; (IV) disrupted brain-behaviour coupling. Results from this study may help inform future research on the neurobiological mechanisms underlying changes in reward function and the resultant behavioural consequences of cannabis use.

BackgroundPsilocybin is a classic psychedelic that acutely alters brain functional connectivity. These changes are linked to therapeutic doses and subjective effects, with some evidence that changes persist beyond acute drug administration. However, the effects of lower doses on sustained connectivity changes remain unclear. MethodsTen healthy volunteers received three psilocybin doses (between 5 and 20 mg) in a randomized and blinded order, with at least one week between doses. Resting-state functional magnetic resonance imaging was completed at baseline and one week after a single dose. Functional connectivity changes were analyzed in relation to dose and altered conscious states at both the level of individual brain region connections (edges) and resting-state networks. ResultsDose-dependent changes in 77 edges (76 increases, 1 decrease, of 1275 possible) were observed, but none survived multiple-comparison correction. At the network level, we observed one dose-dependent between-network increase (of 21 possible), and one dose-dependent within-network increase (of seven possible); the latter surviving correction. Alterations in conscious state were positively associated with widespread connectivity changes (dose-adjusted), with many network-level associations surviving correction. These directional patterns showed that lower doses and smaller conscious state alterations were linked to decreased connectivity, whereas higher doses and greater conscious state alterations were linked to increased connectivity. ConclusionsDose level and acute subjective effects were positively associated with multiple functional connectivity changes one week after a low-to-moderate psilocybin dose. Further research is warranted to characterize these sustained effects and their therapeutic relevance to inform studies adopting similar dosing regimens in clinical cohorts. Trial RegistrationAustralian New Zealand Clinical Trials Registry: ACTRN12621000560897 Date registered: 12 May 2021 URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381526&isReview=true

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.

Catatonia is a severe psychomotor syndrome that occurs across psychiatric diagnoses and is increasingly conceptualized as reflecting neurodevelopmental vulnerability. The anterior cingulate cortex (ACC) plays a central role in motor initiation and cognitive-affective integration and displays substantial interindividual variability in its sulcal morphology, which is established prenatally and remains stable across life. In this MRI study, we examined whether ACC sulcal patterns represent a structural trait marker of catatonia. We analyzed high-resolution T1-weighted images from a hospital-based cohort comprising patients with catatonia (N = 109), psychiatric patients without catatonia (N = 323), and healthy controls (N = 91). The presence of the paracingulate sulcus (PCS) in each hemisphere was determined through blinded visual inspection, and regression analyses tested associations with diagnostic group, adjusting for age, sex, scanner type, intracranial volume, and benzodiazepine and antipsychotic exposure. Patients with catatonia exhibited a significantly reduced prevalence of the left PCS and diminished hemispheric asymmetry compared with both non-catatonic patients and healthy controls. These effects were independent of whether catatonia occurred within psychotic or mood disorders. PCS size did not differ across groups, and sulcal pattern did not correlate with catatonia severity among affected individuals. The findings demonstrate that ACC sulcal deviations are specifically associated with catatonia across diagnostic categories, supporting a neurodevelopmental etiology and reinforcing ACC involvement in its pathophysiology. Early-determined sulcal morphology may represent a trait-level marker contributing to vulnerability for catatonia, with implications for early identification, risk stratification, and targeted intervention strategies.

ImportanceBlood-based biomarkers hold promise for psychiatric diagnosis and prognosis, yet clinical translation is constrained by poor reproducibility. Psychiatric biomarker studies are typically small, and demographic, behavioral, and temporal covariates often go undetected or cannot be adequately modeled. This may lead to residual confounding and unstable associations. ObservationsLeveraging UK Biobank data (N=~500,000), we systematically quantified how technical, demographic, behavioral, and temporal covariates influence 29 blood biomarkers commonly measured in research studies in psychiatry. Variance analyses showed substantial differences across biomarkers. Technical factors explained 1-6% and demographic factors explained 5-15% of the variance, with pronounced age-by-sex interactions for lipids and sex hormones. Behavioral covariates, particularly body mass index (BMI) and smoking, strongly influenced inflammatory markers. Temporal factors introduced systematic confounding. Chronotype was associated with blood collection time, multiple biomarkers exhibited marked diurnal rhythms (including testosterone, triglycerides, and immune markers), and inflammatory markers showed seasonal peaks in winter. In association analysis of biomarkers with major depression, bipolar disorder and schizophrenia, covariate adjustments attenuated or eliminated a substantial proportion of the biomarker-disorder associations, with BMI emerging as the dominant confounder. These findings demonstrate that such confounding structures exist and can be characterized in large cohorts, though specific biomarker-disorder relationships require validation in clinical samples. Conclusions and RelevancePoor reproducibility of biomarkers may not only stem from insufficient biological signal but also from inconsistent handling of confounders. We propose a systematic framework distinguishing technical factors (to be removed), demographic factors (addressed through adjustment or stratification), temporal factors (ideally controlled at design stages), and behavioral factors (requiring explicit causal reasoning). Associations robust to multiple adjustment strategies should be prioritized for clinical biomarker development. Standardized collection protocols, comprehensive covariate measurement, and transparent reporting across models are essential to improve reproducibility and identify biomarkers that reflect genuine illness-related pathophysiology.

GLP-1 agonists are an emerging treatment for disorders of consumption. They are most prominent as treatments for obesity, but recent literature suggests that they are effective at reducing the consumption of all types of hedonic substances. This clearly suggests a central, cognitive, mechanism rather than a peripheral mechanism or an interaction with a single signalling pathway, but the specific site or sites for this mechanism remain to be discovered. Candidate brain regions for this reward-modulating activity have a relative paucity of GLP-1 receptors, with the exception of lateral septum, which expresses an abundance of them. In these experiments we recorded local field potential from lateral septum while animals received either saline control or the GLP-1R agonist liraglutide. We find that liraglutide significantly reduced the power of both high-frequency oscillations and theta rhythm in the lateral septum, suggesting that GLP-1R agonism changes how lateral septum communicates with its network. In addition, we show that liraglutide causes animals to wait longer to respond for reward in a differential reinforcement of low rates paradigm. Together, these results suggest that a primary region in the control of the anticonsumptive action of GLP-1 agonists is the lateral septum, and that the coding of reward by this region is a central node in the network responsible for cognition about and behaviour with respect to reward.

Lithium is the gold standard mood stabiliser used to treat cycling mania and depression in bipolar disorder. Despite seven decades of clinical use, the mechanisms of its mood stabilisation are incompletely understood, fundamentally limiting development of improved alternatives. Two established lithium targets, glycogen synthase kinase 3{beta} (GSK3{beta}) and inositol monophosphatase, both modulate phosphorylation, suggesting lithium may exert broad effects on neuronal phosphorylation networks. We performed a discovery-phase in vitro screen of 140 kinases at 10mM LiCl and demonstrated that lithium inhibits 17 kinases beyond GSK3{beta}. We therefore used untargeted quantitative phosphoproteomics to create a comprehensive map of lithiums neural phosphorylation signature in lithium-treated mouse synaptoneurosomes. Samples were collected at dawn and dusk to match the peaks in phosphorylation that are induced by the sleep/wake cycle. Pathway analysis revealed convergence on synaptic plasticity, neurotransmitter release, and chemical transmission. Critically, lithium-sensitive phosphoproteins are significantly enriched in bipolar disorder genome-wide association study (GWAS) loci, providing independent genomic evidence that the phosphorylation networks we identified are relevant to bipolar pathophysiology. We identified novel kinase targets and phosphorylation sites not previously associated with lithiums mechanism of action and tied them to bipolar pathology. We further refined existing models of lithiums action by showing that GSK3{beta} inhibition is temporally restricted to dawn, indicating cross talk with sleep/wake cycles of phosphorylation. Overall, our data demonstrate that lithiums pleiotropic effects result from coordinated multi-kinase network reorganisation rather than single-target inhibition -- a principle with direct implications for rational polypharmacology in mood stabiliser development.

Subcallosal cingulate cortex (SCC) deep brain stimulation (DBS) can provide relief for individuals with Treatment Resistant Depression (TRD), but ongoing clinical management remains challenging due to nonspecific symptom fluctuations that can obscure core depression recovery on standard rating scales. Objective, stable biomarkers that selectively track the therapeutic effects of SCC DBS are therefore essential for developing principled decision support systems to guide stimulation adjustments. Recent bidirectional DBS systems enable chronic recording of local field potentials (LFPs) and prior work using the Activa PC+S device identified an electrophysiological signature of stable clinical recovery. However, translation to practical clinical deployment requires demonstrating that this biomarker is robustly generalizable, specific to the impact of the DBS therapy, and deployable in real-world recording contexts. To address this need, we developed an at-home SCC LFP data collection platform (built on the Medtronic Summit RC+S system) enabling at home data collection for a new cohort of ten SCC DBS participants with TRD (ClinicalTrials.gov identifier NCT04106466). Using longitudinal LFP recordings collected from this system, we report findings demonstrating that the previously reported biomarker of stable recovery generalizes across subject cohorts and devices, is robust to common potential confounds (including time of day and stimulation status), and shows symptom specificity, sensitivity and stability necessary to support clinical decision making. Across both cohorts, biomarker changes show relationships to pre-DBS white matter structure and network function measured using diffusion MRI and resting-state functional MRI (rsFMRI). These findings replicating and extending previous findings support the biomarkers utility as a foundation for scalable, electrophysiology-informed decision support in SCC DBS.

Schizophrenia frequently follows a chronic relapsing-remitting course, comprising alternating episodes with and without psychotic symptoms (hereafter: psychosis and psychotic remission). One potential neurobiological correlate of this course is aberrant dopamine synthesis and storage (DSS) in the striatum, which can be estimated by 18F-DOPA positron emission tomography (PET). We hypothesised that striatal DSS in patients with schizophrenia decreases from psychosis to psychotic remission, with lower striatal DSS in patients during psychotic remission compared to healthy subjects. Additionally, we explored whether striatal DSS is associated with psychotic relapse after remission. 18F-DOPA PET scans and clinical assessments were conducted in 28 patients with schizophrenia at two timepoints, first during psychosis and second during early psychotic remission 6 weeks to 12 months after the first timepoint, as well as in 21 healthy controls, assessed twice in a comparable time interval. The averaged influx constant kicer as proxy for DSS was calculated for striatal subregions (i.e., nucleus accumbens, caudate, and putamen) using voxel-wise Patlak modelling with a cerebellar reference region. Mixed-effects models and post hoc analyses were used to test for longitudinal changes in kicer and cross-sectional group differences. An exploratory clinical follow-up 12 months after the second scan was conducted to assess psychotic relapse, and post hoc ANCOVAs were used to test for differences in kicer at each session between relapsing and non-relapsing patients. Kicer in both caudate and nucleus accumbens significantly changed from psychosis to psychotic remission compared to healthy controls, with a significant longitudinal decrease of caudate kicer in patients. Furthermore, kicer in both caudate and accumbens was significantly lower in patients during early psychotic remission compared to controls. At the exploratory clinical follow-up, 32% of patients had experienced a psychotic relapse; they showed higher caudate kicer compared to non-relapsing patients during psychosis, with no difference during psychotic remission. These findings provide evidence for the link between striatal, particularly caudate, DSS and the relapsing-remitting course of psychotic symptoms in schizophrenia, with lower caudate DSS during early psychotic remission. Data suggest altered striatal dopamine synthesis together with impaired DSS dynamics along the course of psychotic symptoms in schizophrenia.

Background: Substance use disorders (SUDs), including alcohol and drug dependence, and smoking, pose a public health threat with their high prevalence and comorbidity with other diseases, and contribution to mortality. SUDs are highly correlated, and their genetic background is shared to some degree. Objectives: We aimed to investigate the genetic associations of previously reported loci for a wide range of SUDs in an unstudied Ukrainian population. Methods: We collected data from 595 individuals (339 women, 253 men), including 321 participants from two rehab centres. Based on clinical review and questionnaire data we defined drug dependence, alcohol dependence, alcohol abuse, binge drinking, smoking, opiate, amphetamine, cannabis, and hallucinogen use, along with several intermediary alcohol use and smoking variables considering the amount of use and the level of dependence. We genotyped COMT-rs4680, ADH1B-ADH1C-rs1789891, and HTR2A-rs6313, and applied logistic and ordered logistic regression assuming an additive inheritance model, controlling for the recruitment group, other substance uses, age, and sex, in the association analyses. Results: We replicate (P<0.05) the associations at COMT-rs4680 with smoking status (OR[95% CI]=1.56[1.01-2.41], P=0.047) and heaviness (1.37[1.04-1.80], P=0.026), and at ADH1B-ADH1C-rs1789891 and HTR2A-rs6313 with alcohol dependence (1.69[1.03-2.76], P=0.038 and 0.66[0.47-0.92, P=0.016], respectively). Furthermore, we provide evidence for an association at HTR2A-rs6313 with hallucinogen use (0.58[0.35-0.98], P=0.040). Conclusion: In this study on multiple SUDs we shed light on the genetic background of SUDs in Ukrainians and provide further evidence that variation at COMT is mainly associated with smoking, at ADH1B-ADH1C with alcohol-related variables, whereas HTR2A is a more general SUD-associated locus.

BackgroundThe severity of positive psychotic symptoms largely defines emerging psychosis syndromes. However, depressive and negative symptoms are strongly psychologically and biologically interlinked. A transdiagnostic exploration of symptom severity across early illness syndromes could enhance the understanding of shared common factors and future trajectories of mental illness. We aimed to identify subgroups based on the severity of positive, negative, and depressive symptoms and assess relationships with: 1) premorbid functioning, 2) longitudinal illness course, 3) genetic risk, and 4) brain volume differences. MethodsWe analysed 749 participants from a multisite, naturalistic, longitudinal (18 months) cohort study of: clinical high risk for psychosis (n=147), recent onset psychosis (n=161), and healthy controls (n=286), and recent onset depression (n=155). Participants were stratified into subgroups based on severity of baseline positive, negative, and depression symptoms. Baseline and longitudinal differences between groups for clinical, functioning, and polygenic risk scores (schizophrenia, depression, cross-disorder) were assessed with ANOVAs and linear mixed models. Voxel-based morphometry was used to examine whole-brain grey matter volume differences. Discovery findings were replicated in a held-out sample (n=610). ResultsParticipants were stratified into no (n=241), mild (n=50), moderate (n=182), and severe symptom (n=254) subgroups. The mean (SD) age was 25.3 (6.0) and 344 (47.3%) were male. Symptom severity was associated with poorer premorbid functioning and illness trajectory, greater genetic risk, and lower brain volume. Findings were not confounded by the original study groups or symptoms and were largely replicated. Conclusions and relevanceTransdiagnostic symptom severity is linked to shared aetiologies, prognoses, and biological markers across diagnoses and illness stages. Such commonalities could guide therapeutic selection and future research aiming to detect unique contributions to specific psychopathologies.

Obsessive compulsive disorder (OCD) is significantly heritable, but only a fraction of the contributory genetic variation has been identified, and the molecular etiology involved remains obscure. Identifying rare contributory variants of large effect would be an important milestone in helping to elucidate the mechanisms involved. Analysis of densely affected pedigrees is a potentially useful strategy to bypass the sample size challenges of standard case-control approaches. Here we performed whole genome sequencing (WGS) of 25 individuals across two multiplex OCD pedigrees. We prioritised rare variants using a Bayesian inference approach which incorporates variant pathogenicity and co-segregation with OCD. In the first pedigree, we identified a highly deleterious missense variant in NPY5R, carried by the majority of affected individuals. This gene is brain-expressed and has previously been implicated in panic disorder and internet addiction GWAS studies. In the second pedigree, we identified a large deletion of DLGAP1 and a missense variant in MAPK8IP3, that perfectly co-segregated in a specific branch of the family: both genes have previously been implicated in OCD and autism. Both genes contribute to a protein interaction network including ERBB4 and RAPGEF1 which we had previously identified in a large Tourette Syndrome pedigree. Our analysis suggests that both energy homeostasis and downstream signalling from the post-synaptic density may both be important avenues for future research.

Background: The etiology and nosological status of seasonal affective disorder (SAD) as a specifier of depressive episodes versus a transdiagnostic disorder are the subject of debate. In this study, we investigated the underlying etiology of SAD and dimensional seasonality by examining their association with latitude and genetic risk for a range of traits, and investigated gene-environment interactions. Methods: This study included 12,460 adults aged 18-90 with a history of depression from the Australian Genetics of Depression Study. Regression models included predictors for latitude (distance from equator) and polygenic scores for eight traits; major depressive disorder, bipolar disorder, anxiety disorders, chronotype, sleep duration, body mass index, vitamin D levels, and educational attainment. Outcomes were SAD status and general seasonality score. Results: SAD was positively associated with latitude (OR[95%CI] = 1.05[1.03-1.06], padjusted<0.001), and there was nominal evidence of additive and multiplicative interactions between chronotype genetic risk and latitude (OR = 0.99[0.99-0.99], padjusted=0.381; OR=0.98[0.97-0.99], padjusted=0.489). General seasonality score was associated with latitude (IRR=1.01[1.01-1.01], padjusted 0.001) and genetic risk for major depressive disorder (IRR =1.02[1.01-1.03], padjusted<0.001), bipolar disorder (IRR=1.02[1.01-1.03], padjusted=0.001), anxiety disorders (IRR=1.03[1.01-1.04], padjusted<0.001), vitamin D levels (OR=0.89[0.80-0.95], padjusted=0.048), and educational attainment (IRR=0.97[0.96-0.99], padjusted<0.001). Conclusions: These findings enhance understanding of SAD etiology, highlighting contributions of psychiatric genetic risk and geographic measures on seasonal behavior, and support examining seasonality as a continuous dimension.

Adaptive behavior under threat requires balancing reward pursuit against the risk of harm. During approach-avoidance conflict, animals often pause at decision points, but whether these pauses reflect a unified process or distinct decision states remains unclear. Here, we replicate and extend findings from Calvin et al.1 by analyzing hippocampal activity in rats performing a predator-based foraging task across two cohorts. We compared three behaviors: mid-track aborts (MTAs), mid-track continues (MTCs), and attack-triggered retreats. Behaviorally, MTAs and MTCs emerged from a shared pause state but led to different outcomes, whereas retreats reflected rapid, reactive escape following attack. Despite similar behavioral endpoints (return to safety), retreats and MTAs differed markedly in movement dynamics and neural activity. During retreats, hippocampal representations remained biased toward the attack location, consistent with ongoing encoding of immediate threat. In contrast, MTAs showed a shift in representation toward safe locations following the decision to abort. During pauses, hippocampal activity differentiated future behavioral outcomes before movement diverged: pauses preceding MTAs showed stronger representation of threat-related locations, whereas pauses preceding MTCs emphasized goal-related locations. These representational biases were already present during the outbound approach, indicating that decision-related processes emerged at the beginning of the outbound journey. Across experience, representations of threat and goal locations became increasingly differentiated when encountering an attacking robot, diminished during extinction, and re-emerged when the attack was introduced again. Together, these findings extend prior work by dissociating hippocampal representations associated with reactive escape from those underlying anticipatory, anxiety-like decision-making, suggesting that the hippocampus dynamically tracks behaviorally relevant features to guide decisions under threat.

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.