Based on post-mortem studies, a long-standing hypothesis on the biological bases of specific reading disabilities (RD) has been that alterations in neuronal migration alter language neural circuits. However, there are questions concerning the original studies (small sample size, comorbidities). Further, this idea has not been strongly supported by current genetic studies. In this study, we test altered neural cell phenotypes using cells derived from two pairs of siblings strongly discordant for reading-probands with severe RD and their strong-reader siblings. We observed significant differences in neurosphere outgrowth between the neural precursor cells (NPCs) from the probands compared to their strong-reader siblings. Transcriptome analyses of adherent NPCs and neurons derived from the NPCs identified genes differentially expressed between the probands and siblings, including genes previously identified in neurodevelopmental disorders. Of note was the overexpression of the hormone IGF1 and the transcription factor OTX2, responsible for the opening and closing of critical windows in development and predicted to be involved in critical windows for language acquisition. Our results support altered transcriptome and cellular phenotypes in RD neural cells and suggest possible molecular mechanisms underlying the changes.

The Reln gene encodes the extracellular glycoprotein Reelin that regulates synaptic plasticity and activity-dependent gene expression with implication in several neuropsychiatric disorders, including substance use disorder. Although reduction of Reln expression has been associated with altered responses to psychostimulants and cannabinoids, its role in opioid-evoked behaviors has not been investigated. Here, we tested whether Reln haploinsufficiency alters behavioral and molecular responses to the synthetic opioid fentanyl. Heterozygous Reeler (Reln+/-) mice and wild-type littermates were assessed using complementary contingent and non-contingent models of fentanyl exposure, including multi-phase fentanyl intravenous self-administration paradigm, conditioned place preference paradigm, locomotor assays, and dorsal striatal immediate early gene expression. Reln haploinsufficiency did not alter acquisition, extinction, or cue-induced fentanyl seeking during self-administration, indicating stable opioid reinforcement and relapse-like behavior. Following acute, passive fentanyl exposure, Reln+/- mice exhibited enhanced fentanyl-induced locomotion and Fos immunoreactivity in the dorsal striatum, while fentanyl conditioned place preference remained unchanged. Together, these findings demonstrate that Reln haploinsufficiency does not modify opioid reinforcement or cue-driven drug seeking but enhances acute drug-evoked neuronal activation in the dorsal striatum. These results identify Reln as a modulatory factor in opioid-responsive neural circuits rather than in the associative learning processes underlying opioid reinforcement.

Alzheimer's disease (AD), a neurodegenerative condition marked by amyloid-beta plaques and tau protein neurofibrillary tangles, progresses against a backdrop of essential biological processes. Manganese, an indispensable trace element for vital functions including energy metabolism and antioxidant defense, is integral to neurological health. Its precise metabolic role throughout the course of AD pathogenesis is not fully elucidated. Four essential manganese metabolism-related genes were identified as diagnostic markers through a multi-omic framework. This approach integrated Weighted Gene Co-Expression Network Analysis with machine learning ensembles (Least Absolute Shrinkage and Selection Operator/Random Forest/Extreme Gradient Boosting), followed by rigorous testing in an independent dataset. Beyond identification, we utilized CIBERSORT and ssGSEA to characterize immune infiltration and leveraged GSEA/GO/KEGG for pathway elucidation. Finally, AD patients were stratified into molecular subgroups based on these hub genes, and their underlying regulatory networks involving miRNAs and transcription factors were reconstructed. An integrated bioinformatics framework identified 12 differentially expressed genes related to manganese metabolism in AD. Machine-learning-based feature selection further pinpointed four key diagnostic biomarkers (TSPO, PTBP1, GLO1, and ACACB) with high discriminative power (AUC: 0.831-0.905). Immune infiltration analysis revealed substantial immune remodeling in AD, including an elevation of naïve B cells. Moreover, AD samples were classified into two molecular subtypes displaying distinct immune and metabolic characteristics, and regulatory miRNA/TF interaction networks were constructed for the core genes. Our results shed new light on the molecular mechanisms underlying AD and support future efforts toward early diagnosis and personalized therapeutic interventions based on molecular subtypes.

Glucocorticoid signalling plays a central role in the processing of traumatic memories and contributes to adaptive and pathological responses to stress, with dysregulation frequently reported in trauma-related conditions such as post-traumatic stress disorder (PTSD). A key stage in trauma memory formation is the early consolidation window, during which aversive experiences are stabilised into long-term memory through protein synthesis and activity-dependent gene expression. To investigate how glucocorticoid levels during trauma exposure shape this process, we examined the behavioural and molecular consequences of acute and chronic corticosterone elevation, the rodent analogue of cortisol. Adult male mice received either repeated corticosterone injections for 5 days prior to fear conditioning (FC) or vehicle injections for 5 days followed by a single corticosterone injection immediately before FC. Two hours after FC, we quantified expression of genes encoding mineralocorticoid receptors (Nr3c2, MR), glucocorticoid receptors (Nr3c1, GR), and FK506-binding protein 5 (Fkbp5) in the amygdala, hippocampus, and anterior cingulate cortex (ACC). Trauma memory was assessed 24 h later by measuring freezing and exploratory behaviour to conditioned cues in separate experimental cohorts. Chronic corticosterone exposure was associated with attenuated conditioning-related behavioural responses, whereas acute corticosterone did not alter these responses. These effects were accompanied by region-specific alterations in glucocorticoid-signalling gene expression, most notably coordinated regulation of hippocampal and ACC Nr3c2 following FC. We propose that this regional Nr3c2 transcriptional signature represents an early molecular adaptation to prolonged glucocorticoid exposure that may alter hippocampal-prefrontal communication during trauma-memory formation.

GPR158 is a G protein coupled receptor (GPCR) that is abundantly expressed in the brain and has been shown to organize synaptic architecture and regulate synaptic function. Previous studies have demonstrated a role for GPR158 in hippocampal-dependent learning and stress-related affective behaviors yet its contribution to cognitive function under naturalistic, low-stress conditions remains unclear. Here, we investigated the role of GPR158 in spatial learning, cognitive flexibility, and working memory using both traditional and automated home-cage paradigms. The use of automated, socially enriched testing paradigms minimizes stress-related confounds and allows us to discover the naturalistic roles of GPR158 in cognition and behavior. Using the IntelliCage to test spatial learning and working memory in a social enriched environment, we found that female GPR158 knockout mice exhibited deficits in spatial learning but showed intact working memory. Consistent with these findings, spatial impairments were also observed in the Barnes Maze, where female GPR158 KO mice showed pronounced deficits in spatial strategy acquisition, increased latency, reduced time spent in the reward area, and impaired performance during the probe trial. Male GPR158 knockout mice showed no significant difference in either spatial learning or working memory compared to their wild-type littermates in the IntelliCage, whereas in the Barnes Maze knockout mice showed mild impairment in spatial strategy acquisition. These findings reveal a profound impairment with female GPR158 knockout mice in hippocampal-dependent cognition and highlight the importance of low-stress, ethologically testing environments.

A major subpopulation of 5-hydroxytryptamine (5-HT) neurons expresses the vesicular glutamate transporter 3 (VGLUT3) allowing the co-release of glutamate. Previous evidence has implicated VGLUT3 in 5-HT neurons in mechanisms of anxiety and reward. Here we examined mice with a genetic loss of VGLUT3 targeted to 5-HT neurons (VGLUT3 cKO[5-HT]) and littermate controls in a battery of behavioural tests, including paradigms assessing levels of anxiety and learning with appetitive rewards. Compared to littermate controls, VGLUT3 cKO[5-HT] mice displayed no evidence of altered anxiety-like behaviour in the elevated plus maze, light/dark box, marble burying and social interaction tests. However, VGLUT3 cKO[5-HT] mice showed reduced preference for low (but not high) sucrose-containing solution and reduced correct responses in an appetitively motivated spatial reference memory task. Similarly, in an appetitively motivated operant task, VGLUT3 cKO[5-HT] mice displayed evidence of reduced responding to cues associated with reward. These effects appeared specific in that VGLUT3 cKO[5-HT] mice did not differ from controls in terms of home cage food consumption, performance in a spatial novelty preference test, as well as contextual and cued fear memory tests. These findings support a role for VGLUT3 in 5-HT neurons in some aspects of learning, here in association with learning for reward, although not anxiety-like behaviour.

Steroid sulfatase (STS) cleaves sulphate groups from steroid hormones. In humans, STS deficiency is associated with X-linked ichthyosis, an increased predisposition to neurodevelopmental and mood conditions (including Attention Deficit Hyperactivity Disorder, autism, depression and anxiety), and cardiac arrhythmia risk. Until recently, no single-gene 'knockout' mammalian model existed; previous work in such a model is limited to skin phenotypes. We generated a novel C57BL/6J mouse model with a deletion in exon 2 of Sts. We examined gene expression and enzyme activity in liver and brain samples of homozygous mice, and assessed the breeding performance and health of male and female deletion-carriers. Subsequently, we compared performance across a range of behavioural paradigms in wildtype and homozygous male and female mice: elevated plus maze, open field, rotarod, spontaneous alternation, and acoustic startle/prepulse inhibition. We also investigated serum steroid hormone levels by liquid chromatography-mass spectrometry and measured heart weights and two morphological indices (bodyweight/tibia length) post mortem. Homozygous mice almost completely lacked STS expression/activity. Genetically-altered mice exhibited grossly-normal breeding performance, health, and endocrinology. Homozygous mice were more active and had higher normalised heart weights than wildtype mice. We also found significant genotype × sex interactions on bodyweight and on two behavioural measures (potentially reflecting lower anxiety in homozygous males and heightened anxiety in homozygous females). The 'Sts-deletion' mouse represents an experimentally-tractable model in which to identify and characterise phenotypes associated with STS deficiency. The mechanistic basis of the associations described here requires further investigation, and whether these translate to humans remains to be tested.

Schizophrenia (SCZ) is a highly heritable psychiatric disorder, yet its genetic links with chronic pulmonary diseases remain poorly defined. Such links may reflect shared biological pathways and could create opportunities for cross-disorder risk prediction and therapeutic repurposing. Here we applied a multiancestry, multitrait GWAS framework to SCZ and chronic pulmonary disease datasets. The analysis included 322,321 participants of European and East Asian ancestry from the Psychiatric Genomics Consortium, FinnGen, and 23andMe. We identified 16 previously unreported genetic variants associated with schizophrenia across ancestries. Transcriptome-wide association analysis and machine learning prioritization highlighted candidate genes, including WBP1L and CNNM2, that may contribute to schizophrenia biology. Gene-expression-based drug repurposing further nominated potential therapeutic opportunities shared across psychiatric and pulmonary traits. These findings indicate that schizophrenia and chronic pulmonary diseases share part of their inherited architecture, supporting integrated genetic models for comorbidity, risk stratification, and therapeutic discovery.

The rewarding effects of psychostimulants are strongly influenced by social context, yet the underlying neurochemical and neuropeptidergic mechanisms remain unclear. This study examined the role of oxytocin (OT) and vasopressin (AVP) in context-dependent reward induced by subchronic mephedrone treatment in rats. Using classic- and social-conditioned place preference (CPP) we assessed reward and later-monoamine levels in the prefrontal cortex (PFC) and hippocampus, plasma OT and AVP levels, and mRNA expression of oxytocin (OTRs) and vasopressin V1A (AVPV1ARs) receptors in the nucleus accumbens (NAc) and hippocampus. Pharmacological manipulations of OTRs and AVPV1ARs were used to evaluate their role in social-CPP. We confirmed that mephedrone (5 mg/kg) induced social- but not classic-CPP. In classic-CPP, mephedrone elevated PFC dopamine, an effect abolished under social conditioning, which instead reduced hippocampal serotonin and noradrenaline. Social context alone lowered baseline monoamines, suggesting dampened neurochemical signaling. Social conditioning increased plasma OT and AVP, whereas mephedrone selectively reversed the OT rise. At the receptor level, mephedrone up-regulated AVPV1AR mRNA in the hippocampus and OTR mRNA in the NAc, indicating central adaptations distinct from peripheral peptide changes. Behaviorally, social-CPP was abolished by OTR agonism (carbetocin) or AVPV1AR antagonism (SR49059), while OTR antagonism (L-368,899) or peripheral AVP had no effect. These findings show that mephedrone-induced social reward is shaped by OT and AVP systems. Social context modulates peripheral neuropeptides and engages central receptor adaptations in the hippocampus and NAc, influencing behavioral outcomes. This study provides insights into the neurobiological mechanisms through which the social environment alters drug reward.

Mouse models are an essential tool for understanding behavior and disease states in neuroscience research. While genetic and sex-specific effects have been reported in many neurodegenerative and psychiatric illnesses, these factors may also alter baseline neuroanatomical features of mice. This raises the question of whether the observed changes are related to the disease being studied (i.e., pathological differences) or if there are baseline strain or sex differences that may predispose animals to different responses. Over the past decade, tremendous effort has been made to map neural architecture at various scales; however, the complex relationships, including identifying genetic and sex-specific differences in brain structure and function, remain understudied. To bridge this gap, we used C57BL/6J and DBA/2J mice, two of the most widely used inbred mouse strains in neuroscience research, to investigate strain and sex-specific features of the brain connectome in awake animals using magnetic resonance imaging (MRI). By combining resting-state functional MRI and diffusion MRI, we found that the motor, sensory, limbic, and salience networks exhibit significant differences in both functional and structural domains between C57BL/6J and DBA/2J mice. Further, functional and structural properties of the brain were significantly correlated in both strains. Our results underscore the importance of considering these baseline differences when interpreting brain-behavior interactions in mouse models of human disorders.

Major depression, bipolar disorder, and schizophrenia are common mental illnesses, and their potential association with arrhythmias has long been a focus of clinical and research interest. To explore the possible causal relationship between these mental disorders and arrhythmias, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis using publicly available GWAS summary statistics. The primary analysis employed the inverse-variance weighted (IVW) method, with sensitivity analyses including MR-Egger regression and the weighted median estimator to assess robustness and address potential pleiotropy. Results indicated that genetic predisposition to major depression was associated with increased risks of atrial fibrillation/flutter (IVW: OR = 1.214, 95% CI: 1.092-1.349, p < 0.001), paroxysmal tachycardia (IVW: OR = 1.493, 95% CI: 1.261-1.769, p < 0.001), and atrioventricular block (IVW: OR = 1.257, 95% CI: 1.147-1.377, p < 0.001). Reverse MR also suggested a modest effect of atrioventricular block on depression risk (IVW: OR = 1.045, 95% CI: 1.011-1.079, p = 0.008). In conclusion, from the perspective of genetic liability and using the MR framework, our analysis supports a causal role of major depression in increasing the risk of several arrhythmias and suggests potential bidirectional causal effects between depression and atrioventricular block.

Studies have shown that substance use liability is associated with novelty seeking, anxiety-like behavior, and pain sensitivity. We examined whether common genetic variation in outbred Sprague-Dawley rats explained variation in behavioral measures from three assays with established links to substance use: locomotor response to a novel environment, elevated plus maze, and tail flick. We estimated single-nucleotide polymorphism heritability and performed genome-wide association analyses using permutation-derived significance thresholds (N = 534-654 rats across traits). Heritability estimates ranged from 0.14 to 0.38 across 11 traits. Three independent loci were identified: chromosome 1 for elevated plus maze open-arm behavior (α = 0.05), chromosome 14 for elevated plus maze immobility (α = 0.10), and chromosome 17 for tail flick latency (α = 0.05). Candidate genes included Slc18a2, Gfra1, and Pdzd8 (chromosome 1); Rel and Bcl11a (chromosome 14); and Eci2 and Eci3 (chromosome 17). We compared these loci with our genome-wide association study of a F2 intercross of selectively bred high- and low-responder rats, originally derived from Sprague-Dawleys, that model individual differences in externalizing and internalizing behavior. The current loci are distinct from the ones identified in the bred lines. This difference likely reflects selection history in the high- and low-responder F2s, which focused on facets of exploratory locomotion, while loci for anxiety and pain sensitivity traits were identified in the outbreds. This highlights the benefit of using both outbred and selectively bred rats to probe causal variants contributing to individual differences in substance use liability. The current outbred findings implicate monoaminergic signaling, transcriptional control, and lipid metabolism as testable mechanisms for addiction-relevant behaviors.

During pregnancy, estrogen levels rise dramatically, but quickly drop to prepartum levels following birth and remain suppressed until ovulation resumes. This "postpartum estrogen withdrawal" state has been linked to changes in the brain and behavior in humans and rodents. Previous research has demonstrated that following a hormone-simulated pseudopregnancy (HSP), an experimental model of postpartum estrogen withdrawal, female mice show increased anxiety-like behaviors and decreased social motivation. Further, these behavioral changes occur concurrently with an increase in ∆FOSB, a transcription factor associated with stable long-term plasticity, in the nucleus accumbens core. To test whether this increase in ∆FOSB is required for these behavioral changes, we used a viral-mediated gene transfer approach to prevent ∆FOSB-mediated transcription in the NAcC during HSP and found that it reduced the high-anxiety behavioral phenotype in estrogen-withdrawn females. However, preventing ∆FOSB-mediated transcription had little effect on social motivation. Together, these results suggest that postpartum estrogen withdrawal increases ∆FOSB in the NAc core to impact anxiety-like behaviors but not social motivation following estrogen withdrawal.

Dietary stereotypes driven by health anxiety weaken the assumption that higher taste preference of a food necessarily implies higher intake, potentially mismatching ancestrally imprinted nutrient-handling tendencies with modern diets. We tested whether inherited nutrient predispositions exist and mediate the associations between taste preferences and disease susceptibility. A total of 137 taste-preferences and more than 850 nutrient biomarkers were included for analysis, with seven common gastroduodenal diseases specified as outcomes. Mediation by nutrient predispositions was quantified using a causal-chain model; genetic collinearity along preference-disease links was assessed using Bayesian tests. Maximum-likelihood estimation was applied as a validation analysis for the primary results. External East Asian cohorts were further used to compare and replicate effects observed in the European cohorts. We identified 36 significant causal chains across four gastroduodenal diseases. Mediation involved 14 nutrient or metabolic predispositions. The maximum-likelihood method provided additional confirmation of the initial effect estimates. Cross-ancestry analyses using external cohorts showed directionally consistent effects in East Asian and European cohorts. In comparisons for five foods, only white bread showed concordant associations for both intake and preference with gastric adenocarcinoma risk. Individuals with different taste preferences show marked differences in susceptibility to the same disease, because taste preferences which are inherited across generations shape inter-individual nutrient predispositions. This implicates behavior-gene coevolution as a key driver of divergent disease susceptibility among individuals consuming the same diet. When using intake as the exposure in diet-disease studies, stratifying by taste preference is advisable to mitigate genetic confounding.

Reeler mice have a mutation in the reelin gene. As a result, Reeler mice lack cortical layers, yet their brains are still largely functional. However, Reeler mice display strong motor phenotypes, including ataxic gait and tics, and we posit that their whisking behaviour might also be disrupted. We used high-speed video to film and track whisker movements in 9 adult Reeler mice and 9 age-matched controls in three whisker movement assessment tasks, including our established novel object exploration and open field tasks, as well as a new open field habituation task. Overall, whisker movements in Reeler mice were highly conserved during the novel object exploration and open field tasks, and they demonstrated all behaviourally relevant whisking features during exploratory contact with an object, including contact-induced asymmetry, spread reduction, and decreasing whisker speeds following object contact. In the habituation task, whisker angular position and whisker spread decreased between the first consecutive sessions in all mice, suggesting that the animals were less focused on sampling the area as they got more familiar with the environment. However, only Reeler mice were affected by more extensive habituation. We suggest that whisker-dependent sensory function is surprisingly intact in Reeler mice. However, our observed habituation-related changes in Reeler mice whisker movements suggest some behavioural differences in these mice, which is a likely result of their disorganised cortex due to reelin deficiency.