Neurodevelopmental Trajectories Research Articles

Multiplexing cortical brain organoids for the longitudinal dissection of developmental traits at single-cell resolution.

Dissecting human neurobiology at high resolution and with mechanistic precision requires a major leap in scalability, given the need for experimental designs that include multiple individuals and, prospectively, population cohorts. To lay the foundation for this, we have developed and benchmarked complementary strategies to multiplex brain organoids by pooling cells from different pluripotent stem cell (PSC) lines either during organoid generation (mosaic models) or before single-cell RNA sequencing (scRNA-seq) library preparation (downstream multiplexing). We have also developed a new computational method, SCanSNP, and a consensus call to deconvolve cell identities, overcoming current criticalities in doublets and low-quality cell identification. We validated both multiplexing methods for charting neurodevelopmental trajectories at high resolution, thus linking specific individuals' trajectories to genetic variation. Finally, we modeled their scalability across different multiplexing combinations and showed that mosaic organoids represent an enabling method for high-throughput settings. Together, this multiplexing suite of experimental and computational methods provides a highly scalable resource for brain disease and neurodiversity modeling.

Persistence of the developmental language disorder diagnosis, neurodevelopmental trajectories and attendance at offered interventions.

To study the diagnostic stability of developmental language disorders, other neurodevelopmental disorders and interventions received until age 6 years in children who screened positive for language delay, but not for autism, at age 2.5 years. In 2016, in Gothenburg, Sweden, 100 monolingual or multilingual children underwent language assessment at a mean age of 2.9 years. At age 6 years, 85 of these children underwent language assessment. A review of paediatric records was performed after the clinical assessment to obtain information about other neurodevelopmental disorders and interventions received. At age 6 years, 74/85 (87%) of the children had persistent language disorders, and 20/85 (24%) had been diagnosed with at least one additional neurodevelopmental disorder. Five of them had autism. In general, families only attended half of the offered intervention sessions irrespective of intervention type and no difference between monolingual and multilingual families was found. The persistence of language disorder and the presence of later additional neurodevelopmental disorders highlight the importance of longitudinal and multidisciplinary monitoring of children with delayed language development. Further studies and analyses are warranted to investigate the reasons behind the poor attendance rate for interventions offered.

Neurocognitive correlates of polygenic risk for bipolar disorder among youth with and without bipolar disorder

IntroductionThere is well-established evidence of reduced neurocognitive performance in adults and youth with bipolar disorder (BD). However, little is known about the polygenic underpinnings of neurocognition in individuals with BD, particularly in youth. The current study aimed to examine the association between polygenic risk score for BD (BD-PRS) and neurocognition among youth with BD and healthy controls (HC). Methods129 youth of European ancestry (72 BD, 57 HC), ages 13–20 years, were included. Six neurocognitive tasks within the Cambridge Neuropsychological Test Automated Battery were assessed. General linear models were used to examine the association between BD-PRS and neurocognitive composite scores, controlling for age, sex, IQ, and two genetic principal components. ResultsIn the overall sample, higher BD-PRS was associated with significantly poorer affective processing (β = −0.25, p = 0.01), decision-making (β = −0.23, p = 0.02), and sustained attention (β = −0.28, p = 0.002). Secondary analyses revealed that higher BD-PRS was associated with significantly poorer sustained attention within the BD group (β = −0.27, p = 0.04), and with significantly poorer affective processing within the HC group (β = −0.29, p = 0.04). LimitationsCross-sectional design. Modest sample size may have reduced power to detect smaller effect sizes. ConclusionThe current study found that higher BD-PRS generated based on adult GWAS was associated with poorer neurocognitive performance in youth with BD and HC. Future longitudinal studies incorporating repeated neurocognitive assessments would further inform whether the associations of BD-PRS with neurocognition vary from youth to adulthood, and whether BD-PRS is associated with differential neurodevelopmental trajectories in individuals with and without BD.

Prenatal exposure to hypoxic risk conditions in autistic and neurotypical youth: Associated ventricular differences, sleep disturbance, and sensory processing.

There is a growing body of research that suggests conditions during the period of pregnancy and birth can affect how autism spectrum disorder (ASD) presents itself. This study aimed to investigate the incidence of oxygen deprivation during this period known as prenatal and perinatal hypoxic risk (HR) conditions in ASD compared with neurotypical control (NTC) youth. We also examined ventricular morphology variations associated with HR exposure, and to evaluate associations with clinical symptoms. Results from a cohort of 104 youth revealed a higher incidence of exposure to prenatal hypoxic conditions in the ASD group. Additionally, ASD individuals with prenatal hypoxic exposure (ASD + HR) demonstrated larger third ventricle volumes compared with both ASD and NTC individuals without such exposure (ASD-HR and NTC-HR, respectively). Furthermore, associations were identified between prenatal hypoxic exposure, third ventricle volume, sensory dysfunction, and severity of sleep disturbances. These findings suggest exposure to prenatal hypoxic risk conditions may exacerbate or modify the neurodevelopmental trajectory and symptom severity in ASD, emphasizing the need for better prenatal care and specific interventions to reduce these risks.

Longitudinal multi-omics reveals pathogenic TSC2 variants disrupt developmental trajectories of human cortical organoids derived from Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC), an autosomal dominant condition, is caused by heterozygous mutations in either the TSC1 or TSC2 genes, manifesting in systemic growth of benign tumors. In addition to brain lesions, neurologic sequelae represent the greatest morbidity in TSC patients. Investigations utilizing TSC1/2 -knockout animal or human stem cell models suggest that TSC deficiency-causing hyper-activation of mTOR signaling might precipitate anomalous neurodevelopmental processes. However, how the pathogenic variants of TSC1/2 genes affect the longitudinal trajectory of human brain development remains largely unexplored. Here, we employed 3-dimensional cortical organoids derived from induced pluripotent stem cells (iPSCs) from TSC patients harboring TSC2 variants, alongside organoids from age- and sex-matched healthy individuals as controls. Through comprehensively longitudinal molecular and cellular analyses of TSC organoids, we found that TSC2 pathogenic variants dysregulate neurogenesis, synaptogenesis, and gliogenesis, particularly for reactive astrogliosis. The altered developmental trajectory of TSC organoids significantly resembles the molecular signatures of neuropsychiatric disorders, including autism spectrum disorders, epilepsy, and intellectual disability. Intriguingly, single cell transcriptomic analyses on TSC organoids revealed that TSC2 pathogenic variants disrupt the neuron/reactive astrocyte crosstalk within the NLGN-NRXN signaling network. Furthermore, cellular and electrophysiological assessments of TSC cortical organoids, along with proteomic analyses of synaptosomes, demonstrated that the TSC2 variants precipitate perturbations in synaptic transmission, neuronal network activity, mitochondrial translational integrity, and neurofilament formation. Notably, similar perturbations were observed in surgically resected cortical specimens from TSC patients. Collectively, our study illustrates that disease-associated TSC2 variants disrupt the neurodevelopmental trajectories through perturbations of gene regulatory networks during early cortical development, leading to mitochondrial dysfunction, aberrant neurofilament formation, impaired synaptic formation and neuronal network activity.

The genetics of spatiotemporal variation in cortical thickness in youth

Prior studies have shown strong genetic effects on cortical thickness (CT), structural covariance, and neurodevelopmental trajectories in childhood and adolescence. However, the importance of genetic factors on the induction of spatiotemporal variation during neurodevelopment remains poorly understood. Here, we explore the genetics of maturational coupling by examining 308 MRI-derived regional CT measures in a longitudinal sample of 677 twins and family members. We find dynamic inter-regional genetic covariation in youth, with the emergence of regional subnetworks in late childhood and early adolescence. Three critical neurodevelopmental epochs in genetically-mediated maturational coupling were identified, with dramatic network strengthening near eleven years of age. These changes are associated with statistically-significant (empirical p-value <0.0001) increases in network strength as measured by average clustering coefficient and assortativity. We then identify genes from the Allen Human Brain Atlas with similar co-expression patterns to genetically-mediated structural covariation in children. This set was enriched for genes involved in potassium transport and dendrite formation. Genetically-mediated CT-CT covariance was also strongly correlated with expression patterns for genes located in cells of neuronal origin.

Maternal depressed mood and serotonergic antidepressant treatment during pregnancy differentially shape the continuity between fetal–newborn neurobehaviour

BackgroundPrenatal serotonin reuptake inhibitor (SRI) antidepressant exposure is associated with newborn neurobehavioural disturbances, but it remains unclear whether this reflects a transient pharmacologic condition or an altered neurodevelopmental trajectory emerging in utero from sustained gestational SRI exposure. AimThis study explored longitudinal relationships between third-trimester fetal physiology and newborn neurobehaviour, and determined whether early neurobehavioural continuity is shaped by prenatal SRI or depression exposure. MethodsParticipants were 127 pregnant mothers and their fetal-newborn offspring. Four groups were defined based on antenatal depressive symptoms and SRI treatment: Control (n = 51), Depressed (unmedicated; n = 35), SRI-Depressed (n = 26) and SRI-Non-Depressed (n = 15). Doppler measures of fetal heart rate (fHR), motor activity and vascular hemodynamics were obtained at 36-weeks' gestation, then newborn neurobehavioural maturity was evaluated at postnatal day-7. Partial least squares analysis was used to identify latent correlations between fetal-newborn measures; associations were further studied with hierarchical regression testing group moderation. ResultsTwo dimensions described 74% of the covariance between fetal physiologic and newborn neurobehavioural measures (permuted p < 0.05). Three latent fetal-newborn relationships were significantly moderated by group: (1) lower fHR variability, and (2) greater fHR decelerations, predicted lower alertness/orientation scores but only in SRI-Depressed-group newborns; and (3) lower fetal cerebrovascular resistance predicted lower motor scores in Depressed-group newborns. SRI treatment to euthymia was not associated with fetal-newborn neurobehavioural disturbances. ConclusionsMaternal depression, both unmedicated and SRI-treated with persistent/poorly-managed mood symptoms, differentially shaped fetal-newborn neurobehavioural continuity. These findings suggest that neurobehavioural disturbances may predate birth, and underscore the importance of effective mental health management during pregnancy.

The ABCD and HBCD Studies: Longitudinal Studies to Inform Prevention Science.

Increasing rates of overdose among U.S. adolescents and young adults, along with rising rates of emotional distress in these groups, are renewing the urgency for developmentally targeted and personalized substance use and other mental health prevention interventions. Most prevention programs recognize the unique vulnerability of childhood and adolescence and target parents and youths, addressing modifiable environmental risk and protective factors that affect behavior during periods when the brain is most susceptible to change. Until recently, a scarcity of comprehensive studies has limited a full understanding of the complexity of factors that may affect neurodevelopment, including substance exposure in pregnancy and/or subsequent substance use in adolescence, alongside their dynamic interactions with environmental factors and genetics. Two large longitudinal cohort studies funded by National Institutes of Health-the Adolescent Brain Cognitive Development (ABCD) Study and the HEALthy Brain and Child Development (HBCD) Study-are collecting data on neurodevelopment and a wide range of environmental and biological factors across the first two decades of life to build databases that will allow researchers to study how individual neurodevelopmental trajectories are influenced by drugs, adverse childhood experiences, and genetics, among other factors. These studies are already deepening the understanding of risk and resilience factors that prevention programs could target and will identify critical windows where interventions can have the most impact on an individual's neurodevelopmental trajectory. This article describes what is being learned from ABCD and expected from HBCD and how these studies might inform prevention as these children grow and more data are gathered.

Fail to plan, plan to fail: Tools for data-driven neurodevelopmental service planning

Over recent years, Scotland has seen a substantial increase in children, young people, and adults presenting to Primary and Secondary Care services seeking information, assessments, and support for neurodevelopmental conditions. In NHS Ayrshire &amp; Arran, much work has been done to address this growing demand, including the creation of support pathways and a Neurodevelopmental Empowerment and Strategy Team (NEST), in addition to work to review and re-design assessment services. To estimate the demand on services and the human and financial resources required to cover this demand in a data-driven fashion, two tools have been used: a locally developed Neurodevelopmental Assessment Service Demand and Capacity Calculator (NAS-DCC) and Public Health Scotland’s Neurodevelopmental Trajectory Modelling Tool (NTMT). This paper aims to provide a local background to the complexities of planning assessment and support services for neurodevelopmental conditions and introduce readers to the tools that have facilitated this. It is hoped that this will increase awareness of how data-driven service planning can improve the experience of individuals seeking neurodevelopmental assessments and support and ensure that resources are allocated appropriately to these services.

Development, External Validation, and Biomolecular Corroboration of Interoperable Models for Identifying Critically Ill Children at Risk of Neurologic Morbidity.

Declining mortality in the field of pediatric critical care medicine has shifted practicing clinicians' attention to preserving patients' neurodevelopmental potential as a main objective. Earlier identification of critically ill children at risk for incurring neurologic morbidity would facilitate heightened surveillance that could lead to timelier clinical detection, earlier interventions, and preserved neurodevelopmental trajectory. Develop machine-learning models for identifying acquired neurologic morbidity while hospitalized with critical illness and assess correlation with contemporary serum-based, brain injury-derived biomarkers. Retrospective cohort study. Two large, quaternary children's hospitals. Critical illness. The outcome was neurologic morbidity, defined according to a computable, composite definition at the development site or an order for neurocritical care consultation at the validation site. Models were developed using varying time windows for temporal feature engineering and varying censored time horizons prior to identified neurologic morbidity. Optimal models were selected based on F1 scores, cohort sizes, calibration, and data availability for eventual deployment. A generalizable created at the development site was assessed at an external validation site and optimized with spline recalibration. Correlation was assessed between development site model predictions and measurements of brain biomarkers from a convenience cohort. After exclusions there were 14,222-25,171 encounters from 2010-2022 in the development site cohorts and 6,280-6,373 from 2018-2021 in the validation site cohort. At the development site, an extreme gradient boosted model (XGBoost) with a 12-hour time horizon and 48-hour feature engineering window had an F1-score of 0.54, area under the receiver operating characteristics curve (AUROC) of 0.82, and a number needed to alert (NNA) of 2. A generalizable XGBoost model with a 24-hour time horizon and 48-hour feature engineering window demonstrated an F1-score of 0.37, AUROC of 0.81, AUPRC of 0.51, and NNA of 4 at the validation site. After recalibration at the validation site, the Brier score was 0.04. Serum levels of the brain injury biomarker glial fibrillary acidic protein measurements significantly correlated with model output (r s =0.34; P =0.007). We demonstrate a well-performing ensemble of models for predicting neurologic morbidity in children with biomolecular corroboration. Prospective assessment and refinement of biomarker-coupled risk models in pediatric critical illness is warranted. Question Can interoperable models for predicting neurological deterioration in critically ill children be developed, correlated with serum-based brain-derived biomarkers, and validated at an external site? Findings A development site model demonstrated an area under the receiver operating characteristics curve (AUROC) of 0.82 and a number needed to alert (NNA) of 2. Predictions correlated with levels of glial fibrillary acidic protein in a subset of children. A generalizable model demonstrated an AUROC of 0.81 and NNA of 4 at the validation site. Meaning Well performing prediction models coupled with brain biomarkers may help to identify critically ill children at risk for acquired neurological morbidity.

High Diagnostic Yield and Clinical Utility of Next-Generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays: A Retrospective Study.

Advances in genetics led to the identification of hundreds of epilepsy-related genes, some of which are treatable with etiology-specific interventions. However, the diagnostic yield of next-generation sequencing (NGS) in unexplained epilepsy is highly variable (10-50%). We sought to determine the diagnostic yield and clinical utility of NGS in children with unexplained epilepsy that is accompanied by neurodevelopmental delays and/or is medically intractable. A 5-year retrospective review was conducted at the American University of Beirut Medical Center to identify children who underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Data on patient demographics, neurodevelopment, seizures, and treatments were collected. Forty-nine children underwent NGS with an overall diagnostic rate of 68.9% (27/38 for WES, and 4/7 for WGS). Most children (42) had neurodevelopmental delays with (18) or without (24) refractory epilepsy, and only three had refractory epilepsy without delays. The diagnostic yield was 77.8% in consanguineous families (18), and 61.5% in non-consanguineous families (26); consanguinity information was not available for one family. Genetic test results led to anti-seizure medication optimization or dietary therapies in six children, with subsequent improvements in seizure control and neurodevelopmental trajectories. Not only is the diagnostic rate of NGS high in children with unexplained epilepsy and neurodevelopmental delays, but also genetic testing in this population may often lead to potentially life-altering interventions.

Functional connectivity of the pediatric brain.

This review highlights the importance of functional connectivity in pediatric neuroscience, focusing on its role in understanding neurodevelopment and potential applications in clinical practice. It discusses various techniques for analyzing brain connectivity and their implications for clinical interventions in neurodevelopmental disorders. The principles and applications of independent component analysis and seed-based connectivity analysis in pediatric brain studies are outlined. Additionally, the use of graph analysis to enhance understanding of network organization and topology is reviewed, providing a comprehensive overview of connectivity methods across developmental stages, from fetuses to adolescents. Findings from the reviewed studies reveal that functional connectivity research has uncovered significant insights into the early formation of brain circuits in fetuses and neonates, particularly the prenatal origins of cognitive and sensory systems. Longitudinal research across childhood and adolescence demonstrates dynamic changes in brain connectivity, identifying critical periods of development and maturation that are essential for understanding neurodevelopmental trajectories and disorders. Functional connectivity methods are crucial for advancing pediatric neuroscience. Techniques such as independent component analysis, seed-based connectivity analysis, and graph analysis offer valuable perspectives on brain development, creating new opportunities for early diagnosis and targeted interventions in neurodevelopmental disorders, thereby paving the way for personalized therapeutic strategies.

Effect of per- and polyfluoroalkyl substances on neurodevelopment: Evidence-based risk assessment in the TRAEC strategy context

Although emerging evidence on the association between per- and polyfluoroalkyl substances (PFASs) and neurodevelopment have been investigated, there is no consensus on the effect of maternal PFASs on neurodevelopment in offspring. Here, we assessed the risk of maternal PFASs exposure on the neurodevelopment of offspring using a novel Targeted Risk Assessment of Environmental Chemicals (TRAEC) strategy based on multiple evidence. The evidence from five online databases were analyzed the effect of PFASs on neurodevelopment. The potential neurodevelopment risk of PFASs was evaluated by the TRAEC strategy, which was conducted on a comprehensive scoring system with reliability, correlation, outcome fitness and integrity. The studies from five databases and additional researchers’ experiments were included the present study to proceed following risk assessment. Based on the framework with TRAEC strategy, the comprehensive evaluation of health risks was classified as low (absolute value 0–4), medium (absolute value 4–8), high (absolute value 8–10). In the present study, the effect of PFASs exposure on neurodevelopment was a medium-risk level with 5.61 overall risk-score. The population-attributable risk (PAR) was 8.26 % for maternal PFASs exposure. The study identified a low-risk effect of prenatal PFASs exposure on ASD and behavioral disabilities. The chain length, type of PFASs and neurodevelopmental trajectories contributed to the risk of maternal PFASs on the neurodevelopment of offspring. Consistent with results of four criteria-based tools (ToxRTool, SciRAP, OHAT and IRIS), health risk assessment based on the TRAEC strategy demonstrated robustness and reliability in the present study. These results illustrated a medium-risk effect of maternal PFASs exposure on neurodevelopmental disorders of offspring. In addition, the TRAEC strategy provided a scientific and structured method for effect evaluation between prenatal PFASs and neurodevelopmental disorders, promoting the consistency and validation in risk assessment.

Multispecies probiotic intake during pregnancy modulates neurodevelopmental trajectories of offspring: Aiming towards precision microbial intervention

Recent research highlights the pivotal role of the maternal gut microbiome during pregnancy in shaping offspring neurodevelopment. In this study, we investigated the impact of maternal intake of a multispecies probiotic formulation during a critical prenatal window (from gestational day 6 until birth) on neurodevelopmental trajectories in mice. Our findings demonstrate significant and persistent benefits in emotional behavior, gut microbiota composition, and expression of tight junction-related genes, particularly in male offspring, who exhibited heightened sensitivity to the probiotic intervention compared to females. Additionally, we observed elevated gene expression levels of the anti-inflammatory cytokine IL-10 and the oxytocin receptor (Oxtr) in the prefrontal cortex (PFC) of exposed juvenile offspring; however, these changes persisted only in the adult male offspring. Furthermore, the sustained increase in the expression of the proton-coupled oligopeptide transporter 1 (PepT1), which is involved in the transport of bacterial peptidoglycan motifs, in the PFC of exposed male offspring suggests a potential mechanistic pathway underlying the observed sex-dependent effects on behavior and gene expression. These results underscore the potential of prenatal multispecies probiotic interventions to promote long-term neurodevelopmental outcomes, with implications for precision microbial reconstitution aimed at promoting healthy neurodevelopment and behavior.

Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2

Autosomal-recessive cutis laxa type 2 (ARCL2) is a rare genetic disorder caused by pyrroline-5-carboxylate reductase 1 (PYCR1) mutations and characterized by loose and sagging skin, typical facial features, intrauterine growth retardation, and developmental delay. To study the effect of PYCR1 mutations on protein function and clinical features, we identified a homozygous missense mutation c.559G > A (p.Ala187Thr) in PYCR1 in a Chinese child with typical clinical features, especially severe developmental delays. The three-dimensional (3D) model showed the modification of the hydrogen bonds produce a misfolding in the mutant PYCR1 protein. Mutagenesis and enzyme assay study revealed decreased activity of the mutant protein in vitro, indicating that this mutation impairs PYCR1 function. Our findings confirmed abnormal enzymatic activity and neurodevelopmental trajectory of this PYCR1 mutation.

The PRECISE-DYAD Neurodevelopmental substudy protocol: neurodevelopmental risk in children of mothers with pregnancy complications.

Over 250 million children are not reaching their developmental potential globally. The impact of prenatal factors and their interplay with postnatal environmental factors on child neurodevelopment, is still unclear-particularly in low- and middle-income settings. This study aims to understand the impact of pregnancy complications as well as environmental, psychosocial, and biological predictors on neurodevelopmental trajectories. This is an observational cohort study of female and male children (≈3,950) born to women (≈4,200) with and without pregnancy complications (pregnancy-induced hypertension, foetal growth restriction, and premature birth) previously recruited into PREgnancy Care Integrating Translational Science, Everywhere study with detailed biological data collected in intrapartum and post-partum periods. Children will be assessed at six weeks to 6 months, 11-13 months, 23-25 months and 35-37 months in rural and semi-urban Gambia (Farafenni, Illiasa, and Ngayen Sanjal) and Kenya (Mariakani and Rabai). We will assess children's neurodevelopment using Prechtls General Movement Assessment, the Malawi Development Assessment Tool (primary outcome), Observation of Maternal-Child Interaction, the Neurodevelopmental Disorder Screening Tool, and the Epilepsy Screening tool. Children screening positive will be assessed with Cardiff cards (vision), Modified Checklist for Autism in Toddlers Revised, and Pediatric Quality of Life Inventory Family Impact. We will use multivariate logistic regression analysis to investigate the impact of pregnancy complications on neurodevelopment and conduct structural equation modelling using latent class growth to study trajectories and relationships between biological, environmental, and psychosocial factors on child development. We aim to provide information regarding the neurodevelopment of infants and children born to women with and without pregnancy complications at multiple time points during the first three years of life in two low-resource African communities. A detailed evaluation of developmental trajectories and their predictors will provide information on the most strategic points of intervention to prevent and reduce the incidence of neurodevelopmental impairments.

Maternal immune response during pregnancy and neurodevelopmental outcomes: A longitudinal approach

Background and objectivesThe neurodevelopment of the offspring is suggested to be influenced by the maternal immune system's responses throughout pregnancy, which in turn is also vulnerable to maternal psychosocial stress conditions. Therefore, our main goal was to investigate whether maternal peripheral immunological biomarkers (IB) during two stages of gestation are associated with distinct neurodevelopmental trajectories in the first two years of life. As a second goal, we also explored the association between maternal distal (childhood) and proximal (gestation) stressful experiences and the immunological markers assessed during pregnancy. MethodsMaternal childhood trauma, depressive and anxiety symptoms, and peripheral IB (IFNγ, IL-10, IL1β, IL6, IL8, TNFα, EGF, IL13, IL17, IL1Ra and IL4) were measured at baseline (8–16 weeks of pregnancy) and at 30 weeks of pregnancy in 160 women. The participants had the blood samples collected from two randomized clinical trials conducted by the same team and methods in the same community. A Principal Component Analysis (PCA) was implemented to create meaningful composite variables that describe the cytokines joint variation. Finally, linear mixed-effects modeling was used to investigate the influence of inflammatory biomarkers, maternal childhood trauma, anxiety, and depressive symptoms on Bayley's III scores trajectories. ResultsThe IB profile during the 3rd trimester of pregnancy predicted the offspring's neurodevelopmental trajectories in the first two years of life. The components derived from PCA were important predictors and captured different immune responses, reflecting both pro- and anti-inflammatory states. Maternal stressful experiences did not correlate with the immunological markers. Although not a reliable predictor alone, maternal psychosocial stress at the 1st trimester of pregnancy interacted with the mother's immune response while predicting the neurodevelopmental scores during the first two years of life. ConclusionsOur results underscore the importance of the maternal immune response during pregnancy in shaping the neurodevelopmental trajectory of the offspring. Additionally, we observed that the maternal distress at the early stages of pregnancy has an incremental effect on the neurodevelopmental outcome but depends upon the immune response.

Correlations of brain structure with the social behavior of 15q11-13 duplication mice, an animal model of autism

Duplication of chromosome 15q11–13 has been reported to be one of the most frequent cytogenetic copy number variations in autism spectrum disorder (ASD), and a mouse model of paternal 15q11–13 duplication was generated, termed 15q dup mice. While previous studies have replicated some of the behavioral and brain structural phenotypes of ASD separately, the relationship between brain structure and behavior has rarely been examined. In this study, we performed behavioral experiments related to anxiety and social behaviors and magnetic resonance imaging (MRI) using the same set of 15q dup and wild-type mice. 15q dup mice showed increased anxiety and a tendency toward alterations in social behaviors, as reported previously, as well as variability in terms of sociability. MRI analysis revealed that a lower sociability index was correlated with a smaller gray matter volume in the right medial entorhinal cortex. These results may help to understand how variability in behavioral phenotypes of ASD arises even in individuals with the same genetic background and to determine the individual differences in neurodevelopmental trajectory correlated with specific brain structures that underlie these phenotypes.

Dynamic stress- and inflammatory-based regulation of psychiatric risk loci in human neurons.

The prenatal environment can alter neurodevelopmental and clinical trajectories, markedly increasing risk for psychiatric disorders in childhood and adolescence. To understand if and how fetal exposures to stress and inflammation exacerbate manifestation of genetic risk for complex brain disorders, we report a large-scale context-dependent massively parallel reporter assay (MPRA) in human neurons designed to catalogue genotype x environment (GxE) interactions. Across 240 genome-wide association study (GWAS) loci linked to ten brain traits/disorders, the impact of hydrocortisone, interleukin 6, and interferon alpha on transcriptional activity is empirically evaluated in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons. Of ~3,500 candidate regulatory risk elements (CREs), 11% of variants are active at baseline, whereas cue-specific CRE regulatory activity range from a high of 23% (hydrocortisone) to a low of 6% (IL-6). Cue-specific regulatory activity is driven, at least in part, by differences in transcription factor binding activity, the gene targets of which show unique enrichments for brain disorders as well as co-morbid metabolic and immune syndromes. The dynamic nature of genetic regulation informs the influence of environmental factors, reveals a mechanism underlying pleiotropy and variable penetrance, and identifies specific risk variants that confer greater disorder susceptibility after exposure to stress or inflammation. Understanding neurodevelopmental GxE interactions will inform mental health trajectories and uncover novel targets for therapeutic intervention.

Brain region-specific alterations in gene expression trajectories in the offspring born from influenza A virus infected mice

Influenza A virus (IAV) infection during pregnancy can increase the risk for neurodevelopmental disorders in the offspring, however, the underlying neurobiological mechanisms are largely unknown. To recapitulate viral infection, preclinical studies have traditionally focused on using synthetic viral mimetics, rather than live IAV, to examine consequences of maternal immune activation (MIA)-dependent processes on offspring. In contrast, few studies have used live IAV to assess effects on global gene expression, and none to date have addressed whether moderate IAV, mimicking seasonal influenza disease, alters normal gene expression trajectories in different brain regions across different stages of development. Herein, we show that moderate IAV infection during pregnancy, which causes mild maternal disease and no overt foetal complications in utero, induces lasting effects on the offspring into adulthood. We observed behavioural changes in adult offspring, including disrupted prepulse inhibition, dopaminergic hyper-responsiveness, and spatial recognition memory deficits. Gene profiling in the offspring brain from neonate to adolescence revealed persistent alterations to normal gene expression trajectories in the prefronal cortex, hippocampus, hypothalamus and cerebellum. Alterations were found in genes involved in inflammation and neurogenesis, which were predominately dysregulated in neonatal and early adolescent offspring. Notably, late adolescent offspring born from IAV infected mice displayed altered microglial morphology in the hippocampus. In conclusion, we show that moderate IAV during pregnancy perturbs neurodevelopmental trajectories in the offspring, including alterations in the neuroinflammatory gene expression profile and microglial number and morphology in the hippocampus, resulting in behavioural changes in adult offspring. Such early perturbations may underlie the vulnerability in human offspring for the later development of neurodevelopmental disorders, including schizophrenia. Our work highlights the importance of using live IAV in developing novel preclinical models that better recapitulate the real-world impact of inflammatory insults during pregnancy on offspring neurodevelopmental trajectories and disease susceptibility later in life.