Sensitive Window Research Articles

AI-powered simulation-based inference of a genuinely spatial-stochastic gene regulation model of early mouse embryogenesis.

Understanding how multicellular organisms reliably orchestrate cell-fate decisions is a central challenge in developmental biology, particularly in early mammalian development, where tissue-level differentiation arises from seemingly cell-autonomous mechanisms. In this study, we present a multi-scale, spatial-stochastic simulation framework for mouse embryogenesis, focusing on inner cell mass (ICM) differentiation into epiblast (EPI) and primitive endoderm (PRE) at the blastocyst stage. Our framework models key regulatory and tissue-scale interactions in a biophysically realistic fashion, capturing the inherent stochasticity of intracellular gene expression and intercellular signaling, while efficiently simulating these processes by advancing event-driven simulation techniques. Leveraging the power of Simulation-Based Inference (SBI) through the AI-driven Sequential Neural Posterior Estimation (SNPE) algorithm, we conduct a large-scale Bayesian inferential analysis to identify parameter sets that faithfully reproduce experimentally observed features of ICM specification. Our results reveal mechanistic insights into how the combined action of autocrine and paracrine FGF4 signaling coordinates stochastic gene expression at the cellular scale to achieve robust and reproducible ICM patterning at the tissue scale. We further demonstrate that the ICM exhibits a specific time window of sensitivity to exogenous FGF4, enabling lineage proportions to be adjusted based on timing and dosage, thereby extending current experimental findings and providing quantitative predictions for both mutant and wild-type ICM systems. Notably, FGF4 signaling not only ensures correct EPI-PRE lineage proportions but also enhances ICM resilience to perturbations, reducing fate-proportioning errors by 10-20% compared to a purely cell-autonomous system. Additionally, we uncover a surprising role for variability in intracellular initial conditions, showing that high gene-expression heterogeneity can improve both the accuracy and precision of cell-fate proportioning, which remains robust when fewer than 25% of the ICM population experiences perturbed initial conditions. Our work offers a comprehensive, spatial-stochastic description of the biochemical processes driving ICM differentiation and identifies the necessary conditions for its robust unfolding. It also provides a framework for future exploration of similar spatial-stochastic systems in developmental biology.

The effect of tris (1,3-dichloro-2-propyl) phosphate on the early embryonic heart development of Oryzias melastigma

The flame retardant tri (1, 3-dichloro-2-propyl) phosphate (TDCIPP) is widely present in environmental media and organisms. People have paid much attention to the growth and developmental toxicity of TDCIPP, but there is little information about its cardiotoxicity and potential mechanisms. In this study, marine medaka (Oryzias melastigma) embryos were exposed to TDCIPP solutions (0, 0.05, 0.5, 5, and 50 μg/L) for 21 days to investigate the adverse effects of TDCIPP on cardiac development. The results showed that TDCIPP exposure altered the heart rate at different stages of embryonic development. In addition, 50 μg/L TDCIPP resulted in increased sinus venosus (SV)–bulbus arteriosus (BA) distance, pericardial cysts, and cardiac linearization in newly hatched fish. During embryonic development, the expression level of key genes regulating cardiac development is disturbed. The early stage of cardiac development is the sensitive window period for the toxic effects of TDCIPP. Oxidative stress was observed in newly hatched juveniles, but no significant lipid peroxidation damage was observed. In addition, vitellogenin (VTG) levels in juvenile fish were significantly reduced. Our results show that TDCIPP exposure induces cardiotoxicity in marine medaka embryos, which is induced in the early stages and promotes heart defects by amplifying inflammatory responses at a later stage.

Impulsive adolescents exhibit inefficient processing and a low decision threshold when decoding facial expressions of emotions.

Borderline personality disorder (BPD) is a debilitating psychiatric illness whose symptoms frequently emerge during adolescence. Initial studies in adults suggest that the interpersonal difficulties common in BPD may emerge from disrupted processing of social and emotional stimuli. Less is known about these processes in adolescents with BPD symptoms, despite substantial changes in socioemotional processing during this developmental period. 86 adolescents and young adults with and without BPD symptoms completed an emotional interference task involving the identification of a facial emotion expression in the presence of a conflicting or congruent emotion word. We used hierarchical drift diffusion modeling to index speed of processing and decision boundary. Using Bayesian multilevel regression, we characterized age-related differences in facial emotion processing. We then examined whether BPD symptom dimensions were associated with facial emotion processing on this task. To determine the specificity of our effects, we analyzed behavioral data from a corresponding nonemotional interference task. Impulsivity, but not negative affectivity or interpersonal dysfunction, predicted inefficient processing when presented with conflicting negative emotional stimuli. Across both tasks, impulsivity in adolescents was further associated with a lower decision boundary. Impulsive adolescents were especially likely to make fast, but inaccurate decisions about another person's emotional state. Impulsive adolescents with BPD symptoms are prone to making errors when appraising facial expressions of emotions, which may potentiate or worsen interpersonal conflicts. Our findings highlight the role of lower-level social cognitive processes in interpersonal difficulties among vulnerable youth during a sensitive developmental window.

Temporal dynamics of negative emotional memory reprocessing during sleep

Memory reprocessing during sleep is a well-established phenomenon in numerous studies. However, it is unclear whether the intensity of memory reprocessing is consistently maintained throughout the night or exhibits dynamic changes. This study investigates the temporal dynamics of negative emotional memory reprocessing during sleep, with a specific focus on slow oscillation (SO)-spindle coupling and its role in memory reprocessing. In the first experiment (N = 40, mean age = 22.5 years), we detected the negative emotional memory reprocessing strength in each sleep cycle, we found that the 2nd sleep cycle after negative emotional memory learning constitute the most sensitive window for memory reprocessing, furthermore, SO-spindle coupling signals in this window plays a role in stabilizing negative emotional memory. To verify the role of SO-spindle coupling in negative emotional memory reprocessing, we utilized transcranial alternating current stimulation (tACS) to disrupt SO-spindle coupling during the 2nd sleep cycle (N = 21, mean age = 19.3 years). Notably, the outcomes of the tACS intervention demonstrated a significant reduction in the recognition of negative emotional memories. These findings offer new insights into the mechanisms that regulate emotional memory consolidation during sleep and may have implications for addressing psychiatric disorders associated with pathological emotional memory.

Anti-inflammatory diet mitigate cardiovascular risks due to particulate matter exposure in women during pregnancy: A perspective cohort study from China

BackgroundParticulate matter (PM) exposure during pregnancy may increase cardiovascular risk (CVR). However, the specific time windows of exposure contributing to this association and the potential biological mechanisms underlying it remain unclear. ObjectiveTo determine the sensitive time window for CVR related to PM exposure. We investigated whether levels of inflammatory biomarkers mediate the relationship between PM exposure and CVR, and examined the potential impact of an anti-inflammatory diet on this association. MethodsFrom 2015 to 2021, 9294 pregnant women from three Hefei hospitals were included. We used a 1 × 1 km satellite dataset to assess PM1, PM2.5, and PM10 exposure. High-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were measured as inflammatory biomarkers. The empirical dietary inflammatory pattern (EDIP) score, based on a validated food frequency questionnaire. The CVR score was calculated using five clinical metrics based on American Heart Association criteria. ResultsWe found a significant association between PM exposure and increased CVR score, especially during the 2nd to 8th weeks of the first trimester. For every increase of 10-μg/m3 of PM1, PM2.5, and PM10, there was an associated increase in CVR of 0.51 (95%CI: 0.21, 082), 0.25 (95% CI: 0.11 to 0.39), and 0.29 (95% CI: 0.09 to 0.37), respectively. Mediation analysis revealed that the proportion of the association between PM1, PM2.5, and PM10 exposure and CVR mediated by inflammatory biomarkers was 24.3%, 22.4%, and 20.1%, respectively. Stratified analyses showed no positive correlation between PM exposure and CVR in the anti-inflammatory diet (low EDIP) group. The β coefficients were 0.52 for PM1 (95% CI: -0.06 to 1.11), 0.31 for PM2.5 (95% CI: -0.04 to 0.79), and 0.25 for PM10 (95% CI: -0.03 to 0.54). ConclusionsPM exposure, particularly during weeks 2–8 of pregnancy, correlates with CVR, partly mediated by levels of inflammatory biomarkers. An anti-inflammatory diet mitigates CVR associated with PM exposure.

Vulnerable periods for the mouse mammary gland: Comparison of the effects of ethinyl estradiol exposures during two early stages of development

The mammary gland is responsive to endogenous hormones and environmental chemicals that are estrogen receptor (ER) agonists. The mouse mammary gland offers the opportunity to dissect the most sensitive windows of exposure. 17α-ethinyl estradiol (EE2) is a pharmaceutical ER agonist that often serves as a positive control for estrogen-active chemicals. Here, adult female mice were exposed to EE2 starting either at pregnancy day 7, or on lactational day 1, and exposures continued until the litters were weaned. The pups were therefore exposed during gestation + the juvenile period, or during the juvenile period alone. The morphology of the mammary gland was evaluated in both male and female offspring at two life stages: weaning (postnatal day [PND]21) and at puberty (PND32). Other hormone-sensitive outcomes evaluated included body weight, anogenital index, frequency of open vagina, and weight of the uterus. We found age- and sex-dependent effects of EE2 on these estrogen-responsive endpoints including the morphology of the mammary gland. Importantly, EE2 altered mammary gland morphology even when exposures were limited to the juvenile period. However, the number of endpoints that were affected in animals from the EE2-Juvenile-Only period were fewer, and typically of a lower magnitude, compared to those observed in the EE2-Gest-Juvenile group. Understanding the effects of environmental estrogen exposures during the juvenile period is critical because humans are exposed to estrogenic pollutants throughout life, including in early childhood.

Inhibition of striatal indirect pathway during second postnatal week leads to long-lasting deficits in motivated behavior.

Schizophrenia is a neuropsychiatric disorder with postulated neurodevelopmental etiology. Genetic and imaging studies have shown enhanced dopamine and D2 receptor occupancy in the striatum of patients with schizophrenia. However, whether alterations in postnatal striatal dopamine can lead to long-lasting changes in brain function and behavior is still unclear. Here, we approximated striatal D2R hyperfunction in mice via designer receptor-mediated activation of inhibitory Gi-protein signaling during a defined postnatal time window. We found that Gi-mediated inhibition of the indirect pathway (IP) during postnatal days 8-15 led to long-lasting decreases in locomotor activity and motivated behavior measured in the adult animal. In vivo photometry further showed that the motivational deficit was associated with an attenuated adaptation of outcome-evoked dopamine levels to changes in effort requirements. These data establish a sensitive time window of D2R-regulated striatal development with long-lasting impacts on neuronal function and behavior.

Developmental transcriptomics in Pristionchus reveals the logic of a plasticity gene regulatory network.

Developmental plasticity enables the production of alternative phenotypes in response to different environmental conditions. While significant advances in understanding the ecological and evolutionary implications of plasticity have been made, understanding its genetic basis has lagged. However, a decade of genetic screens in the model nematode Pristionchus pacificus has culminated in 30 genes which affect mouth-form plasticity. We also recently reported the critical window of environmental sensitivity, and therefore have clear expectations for when differential gene expression should matter. Here, we collated previous data into a gene-regulatory network (GRN), and performed developmental transcriptomics across different environmental conditions, genetic backgrounds, and mouth-form mutants to assess the regulatory logic of plasticity. We found that only two genes in the GRN (eud-1 and seud-1/sult-1) are sensitive to the environment during the critical window. Interestingly, the time points of their sensitivity differ, suggesting that they act as sequential checkpoints. We also observed temporal constraint upon the transcriptional effects of mutating the GRN and revealed unexpected feedback between mouth-form genes. Surprisingly, expression of seud-1/sult-1, but not eud-1, correlated with mouth form biases across different strains and species. Finally, a comprehensive analysis of all samples identified metabolism as a shared pathway for regulating mouth-form plasticity. These data are presented in a Shiny app to facilitate gene-expression comparisons across development in up to 14 different conditions. Collectively, our results suggest that mouth-form plasticity evolved a constrained, two-tiered logic to integrate environmental information leading up to the final developmental decision.

Development and child health in a world of synthetic chemicals.

Chemical pollution is one of today's most significant threats to the developmental potential of children worldwide. Maternal exposure to toxicants can perturb sensitive windows of fetal development, indirectly through promoting antenatal disorders, abnormal placental adaptation, or directly through maternal-fetal transport. Current evidence clearly shows that persistent organic chemicals promote hypertensive disorders of pregnancy, placental abnormalities, and fetal growth restriction, whereas findings are less consistent for phthalates and bisphenols. Prospective birth cohorts strongly support a link between adverse neurodevelopmental outcomes and prenatal exposure to flame retardants and organophosphate pesticides. Emerging evidence reveals a potential association between in utero exposure to bisphenols and childhood behavioral disorders, while childhood metabolic health is more consistently associated with postnatal exposure to phthalates and bisphenols. IMPACT: Synthesizes emerging evidence linking modern forms of chemical pollution to antenatal disorders, fetal growth restriction and childhood disorders. Highlights potential developmental impacts of emerging pollutants of concern now ubiquitous in our environment but without regulatory restrictions.

Prenatal exposure to ambient air pollution and persistent postpartum depression

BackgroundAmbient air pollution during pregnancy has been linked with postpartum depression up to 12 months, but few studies have investigated its impact on persistent depression beyond 12 months postpartum. This study aimed to evaluate prenatal ambient air pollution exposure and the risk of persistent depression over 3 years after childbirth and to identify windows of susceptibility. MethodsThis study included 361 predominantly low-income Hispanic/Latina participants with full-term pregnancies in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) cohort. We estimated daily residential PM2.5, PM10, NO2, and O3 concentrations throughout 37 gestational weeks using inverse-distance squared spatial interpolation from monitoring data and calculated weekly averaged levels. Depression was assessed by the 20-item Center for Epidemiologic Studies-Depression (CES-D) scale at 12, 24, and 36 months postpartum, with persistent postpartum depression defined as a CES-D score ≥16 at any of these timepoints. We performed robust Poisson log-linear distributed lag models (DLM) via generalized estimating equations (GEE) to estimate the adjusted risk ratio (RR). ResultsDepression was observed in 17.8 %, 17.5 %, and 13.4 % of participants at 12, 24, and 36 months, respectively. We found one IQR increase (3.9 ppb) in prenatal exposure to NO2 during the identified sensitive window of gestational weeks 13–29 was associated with a cumulative risk ratio of 3.86 (95 % CI: 3.24, 4.59) for persistent depression 1–3 years postpartum. We also found one IQR increase (7.4 μg/m3) in prenatal exposure to PM10 during gestation weeks 12–28 was associated a cumulative risk ratio of 3.88 (95 % CI: 3.04, 4.96) for persistent depression. No clear sensitive windows were identified for PM2.5 or O3. ConclusionsMid-pregnancy PM10 and NO2 exposures were associated with nearly 4-fold increased risks of persistent depression after pregnancy, which has critical implications for prevention of perinatal mental health outcomes.

Prenatal exposure to PM2.5 and its composition on child growth trajectories in the first two years: A prospective birth cohort study

The findings on the relationship between prenatal exposure to particulate matter with aerodynamic diameter ≤2.5 μm (PM2.5) and its constituent and children's growth trajectories are inconsistent. This association's sensitive exposure time window and possible gender differences remain unclear. Our aim was to determine the association between prenatal exposure to PM2.5 and its component and children's growth trajectories by the age of two. From 2015 to 2021, 6407 mother-infant pairs were enrolled in the study. The PM2.5 include sulfate (SO42−), nitrate (NO3−), ammonium (NH4+), organic matter (OM), and black carbon (BC), from the ChinaHighAirPollutants (CHAP) datasets. Children were followed at birth, 1, 3, 6, 9, 12, 18, and 24 months. Population-based and individual-based methods were used to simulate child growth trajectories: slow growth, normal growth, and rapid growth. The distributed lags modeling was used to identify sensitive time windows for the effects of prenatal exposure to PM2.5 and its components on child growth. Sex-stratified analyses estimated sex differences. Median concentrations [interquartile ranges (IQRs)] were 57.46(17.3), 10.59(3.8), 14.26(4.4), 8.69(2.8), 13.05(3.4), and 2.53(0.7) μg/m3 for PM2.5, SO42−, NO3−, NH4+, OM, and BC, respectively. Compared with the normal growth trajectory group, exposure to PM2.5 was significantly associated with a higher risk of rapid growth trajectory in boys (ORs with 95% CI for the entire, first trimester, and second trimester of pregnancy, respectively: 1.016[1.006,1.025], 1.007[1.002,1.011], 1.007[1.002,1.011]). Exposure to PM2.5 was significantly associated with a higher risk of slow growth trajectory in girls (ORs with 95% CI for the entire, second trimester, and third trimester of pregnancy, respectively: 1.010 [1.001,1.018], 1.006 [1.001,1.011], 1.007 [1.002,1.012]). Prenatal PM2.5 and its composition exposure was positively associated with BMI peak in boys (βs with 95% CI for PM2.5, SO42−, NO3−, NH4+, OM, BC: 0.004[0.000,0.007], 0.025[0.006,0.044], 0.012[0.002,0.023], 0.022[0.004,0.039], 0.016[0.001,0.031], 0.082[0.005,0.159]), and not statistically significant in girls. We observed a more pronounced BC effect in our cohort. Prenatal exposure to PM2.5 and its component, especially at 10–22 weeks of gestation, is associated with a higher risk of rapid growth in boys and a risk of slow growth in girls.

Early social isolation disrupts adult personality expression in group-living mites.

Animal personalities are characterized by intra-individual consistency and consistent inter-individual variability in behaviour across time and contexts. Personalities abound in animals, ranging from sea anemones to insects, arachnids, birds, fish and primates, yet the pathways mediating personality formation and expression remain elusive. Social conditions during the early postnatal period are known determinants of mean behavioural trait expressions later in life, but their relevance in shaping personality trajectories is unknown. Here, we investigated the consequences of early social isolation on adult personality expression in plant-inhabiting predatory mites Phytoseiulus persimilis. These mites are adapted to live in groups. We hypothesized that transient experience of social isolation early in life, that is, deprivation of any social contact during a sensitive window in the post-hatching phase, has enduring adverse effects on adult personality expression. Newly hatched mites were transiently reared in isolation or in groups and tested as adults for repeatability of various within-group behaviours, such as movement patterns and mutual interactions including sociability, defined as the propensity to associate and interact benignly with conspecifics, and activity patterns when alone. Groups composed of individuals with the same or different early-life experiences were repeatedly videotaped and individual behaviours were automatically analysed using AnimalTA. Social experiences early in life had persistent effects on mean behavioural traits as well as adult personality expression, as measured by intraclass correlation coefficients (indicating repeatability). On average, isolation-reared females moved at higher speeds, meandered less, kept greater distances from others and had fewer immediate neighbours than group-reared females. Group-reared females were highly repeatable in inter-individual distance, moving speed, meandering and area explored, whereas isolation-reared females were repeatable only in the number of immediate neighbours. Activity, quantified as the proportion of time spent moving within groups, was only repeatable in group-reared females, whereas activity, quantified as the proportion of time spent moving when alone, was only repeatable in females reared in isolation. Strikingly, also the early-life experiences of male mates influenced personality expression of mated females, with isolation-reared males boosting the repeatability of behavioural traits of group-reared females. Overall, our study provides evidence that a transient phase of social isolation during a critical period early in life has lasting effects that extend into adulthood, impairing adult personality expression. These effects should cascade upward, changing the phenotypic composition and diversity within populations.

The Camp fire and perinatal health: An example of the generalized synthetic control method to identify susceptible windows of exposure.

The November 2018 Camp fire was the most destructive wildfire in California history, but its effects on reproductive health are not known. We linked California birth records from 2017-2019 to daily smoke levels using U.S. EPA Air Quality System (AQS) PM2.5 data and NOAA Hazard Mapping System smoke plume polygons during the Camp fire. In the main analysis, pregnancies were considered exposed if they had median AQS PM2.5 levels above 50 μg/m3 for at least 7 days during November 8-22, 2018. We calculated rates of preterm birth and the infant sex ratio based on week of conception and used the generalized synthetic control method to estimate the average treatment effect on the treated and to propose a novel approach to identify potential critical weeks of exposure during pregnancy. We found associations between Camp fire-related smoke exposure and rates of preterm birth, with a risk difference (RD) = 0.005, 95% CI 0.001, 0.010. Exposure during week 10 of pregnancy was consistently associated with increased preterm birth (RD = 0.030, 95% CI 0.004, 0.056). We did not observe differences in the infant sex ratio. Camp fire smoke exposure was associated with increased rates of preterm birth, with sensitive windows in the first trimester.

Measuring neuroplasticity in human development: the potential to inform the type and timing of mental health interventions.

Neuroplasticity during sensitive periods, the molecular and cellular process of enduring neural change in response to external stimuli during windows of high environmental sensitivity, is crucial for adaptation to expected environments and has implications for psychiatry. Animal research has characterized the developmental sequence and neurobiological mechanisms that govern neuroplasticity, yet gaps in our ability to measure neuroplasticity in humans limit the clinical translation of these principles. Here, we present a roadmap for the development and validation of neuroimaging and electrophysiology measures that index neuroplasticity to begin to address these gaps. We argue that validation of measures to track neuroplasticity in humans will elucidate the etiology of mental illness and inform the type and timing of mental health interventions to optimize effectiveness. We outline criteria for evaluating putative neuroimaging measures of plasticity in humans including links to neurobiological mechanisms shown to govern plasticity in animal models, developmental change that reflects heightened early life plasticity, and prediction of neural and/or behavior change. These criteria are applied to three putative measures of neuroplasticity using electroencephalography (gamma oscillations, aperiodic exponent of power/frequency) or functional magnetic resonance imaging (amplitude of low frequency fluctuations). We discuss the use of these markers in psychiatry, envision future uses for clinical and developmental translation, and suggest steps to address the limitations of the current putative neuroimaging measures of plasticity. With additional work, we expect these markers will significantly impact mental health and be used to characterize mechanisms, devise new interventions, and optimize developmental trajectories to reduce psychopathology risk.

Ill-defined constructs in SLA research using event-related potentials

An emerging trend in Second Language Acquisition (SLA) research is that proficiency is more important than the age of acquisition (AoA) to account for L2 ultimate attainment. An increasing number of researchers play down the role – or in some cases even deny the very existence – of a critical period (or ‘window of sensitivity’) and state that learners’ proficiency – and its various determinants – may trump age. There is a serious methodological issue with such a stance though. While AoA is easily factorised consistently across most experimental studies, participants’ proficiency is not. Authors of Event-Related Potentials (ERP) studies in particular are extremely vague and discordant as to how they rate participants’ proficiency. This makes the construct ‘proficiency’ unreliable, the results of ERP studies hard to compare, and the claims based on the primacy of proficiency in respect to AoA much weaker. This paper suggests more caution in general and in particular the need for collaboration between neurolinguists and SLA experts in the field of foreign language teaching and testing.

Adolescent high fat diet alters the transcriptional response of microglia in the prefrontal cortex in response to stressors in both male and female mice

Both obesity and high fat diets (HFD) have been associated with an increase in inflammatory gene expression within the brain. Microglia play an important role in early cortical development and may be responsive to HFD, particularly during sensitive windows, such as adolescence. We hypothesized that HFD during adolescence would increase proinflammatory gene expression in microglia at baseline and potentiate the microglial stress response. Two stressors were examined, a physiological stressor [lipopolysaccharide (LPS), IP] and a psychological stressor [15 min restraint (RST)]. From 3 to 7 weeks of age, male and female mice were fed standard control diet (SC, 20% energy from fat) or HFD (60% energy from fat). On P49, 1 h before sacrifice, mice were randomly assigned to either stressor exposure or control conditions. Microglia from the frontal cortex were enriched using a Percoll density gradient and isolated via fluorescence-activated cell sorting (FACS), followed by RNA expression analysis of 30 genes (27 target genes, three housekeeping genes) using Fluidigm, a medium throughput qPCR platform. We found that adolescent HFD induced sex-specific transcriptional response in cortical microglia, both at baseline and in response to a stressor. Contrary to our hypothesis, adolescent HFD did not potentiate the transcriptional response to stressors in males, but rather in some cases, resulted in a blunted or absent response to the stressor. This was most apparent in males treated with LPS. However, in females, potentiation of the LPS response was observed for select proinflammatory genes, including Tnfa and Socs3. Further, HFD increased the expression of Itgam, Ikbkb, and Apoe in cortical microglia of both sexes, while adrenergic receptor expression (Adrb1 and Adra2a) was changed in response to stressor exposure with no effect of diet. These data identify classes of genes that are uniquely affected by adolescent exposure to HFD and different stressor modalities in males and females.

Serine racemase deletion alters adolescent social behavior and whole-brain cFos activation.

Neurodevelopmental disorders (NDDs) can cause debilitating impairments in social cognition and aberrant functional connectivity in large-scale brain networks, leading to social isolation and diminished everyday functioning. To facilitate the treatment of social impairments, animal models of NDDs that link N- methyl-D-aspartate receptor (NMDAR) hypofunction to social deficits in adulthood have been used. However, understanding the etiology of social impairments in NDDs requires investigating social changes during sensitive windows during development. We examine social behavior during adolescence using a translational mouse model of NMDAR hypofunction (SR-/-) caused by knocking out serine racemase (SR), the enzyme needed to make D-serine, a key NMDAR coagonist. Species-typical social interactions are maintained through brain-wide neural activation patterns; therefore, we employed whole-brain cFos activity mapping to examine network-level connectivity changes caused by SR deletion. In adolescent SR-/- mice, we observed disinhibited social behavior toward a novel conspecific and rapid social habituation toward familiar social partners. SR-/- mice also spent more time in the open arm of the elevated plus maze which classically points to an anxiolytic behavioral phenotype. These behavioral findings point to a generalized reduction in anxiety-like behavior in both social and non-social contexts in SR-/- mice; importantly, these findings were not associated with diminished working memory. Inter-regional patterns of cFos activation revealed greater connectivity and network density in SR-/- mice compared to controls. These results suggest that NMDAR hypofunction - a potential biomarker for NDDs - can lead to generalized behavioral disinhibition in adolescence, potentially arising from disrupted communication between and within salience and default mode networks.

Sex-specific effects of maternal blood pressure on newborn telomere length: A prospective study.

To investigate the relationship between maternal blood pressure (BP) and neonatal cord blood telomere length (TL) during pregnancy, and to clarify the sensitive period. We conducted a prospective cohort study with 621 mother-newborn pairs from the Guangxi Zhuang Birth Cohort (GZBC) in China. Multiple informant models, restricted cubic spline regression (RCS) models, and quantile regression models were conducted to analyze the correlation between maternal BP and neonatal TL. Maternal diastolic blood pressure (DBP) was inversely related to neonatal cord blood TL in the second trimester (P = 0.015) and the third trimester (P = 0.011). There was a male-specific relationship between maternal BP and neonatal TL. A 1 mmHg increment in maternal systolic blood pressure (SBP) and DBP during the second trimester was related with 0.42% (95% CI: -0.80%, -0.04%) and 0.61% (95% CI: -1.13%, -0.09%) shorter TL in male newborns, respectively. Per unit increase of maternal DBP during the third trimester was related with 0.54% (95% CI: -1.03%, -0.05%) shorter TL in male newborns. Pregnant women with hypertensive disease of pregnancy (HDP) had male offspring with shorter TL (P = 0.003). However, no significant relationships were found in female newborns (P = 0.570). Maternal BP during pregnancy is inversely correlated with male neonatal TL and the second and third trimesters are sensitive windows.

Trait‐specific sensitive developmental windows: Wing growth best integrates weather conditions encountered throughout the development of nestling Alpine swifts

AbstractThe size and growth patterns of nestling birds are key determinants of their survival up to fledging and long‐term fitness. However, because traits such as feathers, skeleton and body mass can follow different developmental trajectories, our understanding of the impact of adverse weather on development requires insights into trait‐specific sensitive developmental windows. We analysed data from nestling Alpine swifts in Switzerland measured throughout growth up to the age of 50 days (i.e. fledging between 50 and 70 days), for wing length and body mass (2693 nestlings in 25 years) and sternum length (2447 nestlings in 22 years). We show that the sensitive developmental windows for wing and sternum length corresponded to the periods of trait‐specific peak growth, which span almost the whole developmental period for wings and the first half for the sternum. Adverse weather conditions during these periods slowed down growth and reduced size. Although nestling body mass at 50 days showed the greatest inter‐individual variation, this was explained by weather in the two days before measurement rather than during peak growth. Interestingly, the relationship between temperature and body mass was not linear, and the initial sharp increase in body mass associated with the increase in temperature was followed by a moderate drop on hot days, likely linked to heat stress. Nestlings experiencing adverse weather conditions during wing growth had lower survival rates up to fledging and fledged at later ages, presumably to compensate for slower wing growth. Overall, our results suggest that measures of feather growth and, to some extent, skeletal growth best capture the consequences of adverse weather conditions throughout the whole development of offspring, while body mass better reflects the short, instantaneous effects of weather conditions on their body reserves (i.e. energy depletion vs. storage in unfavourable vs. favourable conditions).

Episodic ozone exposure in Long-Evans rats has limited effects on cauda sperm motility and non-coding RNA populations

Epidemiological evidence suggests the potential for air pollutants to induce male reproductive toxicity. In experimental studies, exposure to ozone during sensitive windows in the sperm lifecycle has been associated with impaired sperm motility. Subsequently, we sought to investigate the effects of episodic exposure to ozone during sperm maturation in the rat. Long-Evans rats were exposed to either filtered air or ozone (0.4 or 0.8 ppm) for five non-consecutive days over two weeks. Ozone exposure did not impact male reproductive organ weights or sperm motility ∼24 hours following the final exposure. Furthermore, circulating sex hormones remained unchanged despite increased T3 and T4 in the 0.8 ppm group. While there was indication of altered adrenergic signaling attributable to ozone exposure in the testis, there were minimal impacts on small non-coding RNAs detected in cauda sperm. Only two piwi-interacting RNAs (piRNAs) were altered in the mature sperm of ozone-exposed rats (piR-rno-346434 and piR-rno-227431). Data across all rats were next analyzed to identify any non-coding RNAs that may be correlated with reduced sperm motility. A total of 7 microRNAs (miRNAs), 8 RNA fragments, and 1682 piRNAs correlated well with sperm motility. Utilizing our exposure paradigm herein, we were unable to substantiate the relationship between ozone exposure during maturation with sperm motility. However, these approaches served to identify a suite of non-coding RNAs that were associated with sperm motility in rats. With additional investigation, these RNAs may prove to have functional roles in the acquisition of motility or be unique biomarkers for male reproductive toxicity.