The effects of physical activity on sleep architecture and mood in naturalistic environments.

Physical activity has been found to alter sleep architecture, but these effects have been studied predominantly in the laboratory and the generalizability of these findings to naturalistic environments and longer time intervals, as well as their psychological effects, have not been evaluated. Recent technological advancements in wearable devices have made it possible to capture detailed measures of sleep outside the lab, including timing of specific sleep stages. In the current study, we utilized photoplethysmography coupled with accelerometers and smartphone ambulatory assessment to collect daily measurements of sleep, physical activity and mood in a sample of N = 82 over multi-month data collection intervals. We found a robust inverse relationship between sedentary behavior and physical activity and sleep architecture: both low-intensity and moderate-to-vigorous physical activity were associated with increased NREM sleep and decreased REM sleep, as well as a longer REM latency, while higher levels of sedentary behavior showed the opposite pattern. A decreased REM/NREM ratio and increased REM latency were in turn associated with improved wellbeing, including increased energy, reduced stress and enhanced perceived restfulness of sleep. Our results suggest that physical activity and sleep account for unique variance in a person's mood, suggesting that these effects are at least partially independent.

Postnatal maternal care moderates the effects of prenatal bisphenol exposure on offspring neurodevelopmental, behavioral, and transcriptomic outcomes.

Bisphenols (BPs), including BPA and "BPA-free" structural analogs, are commonly used plasticizers that are present in many plastics and are known endocrine disrupting chemicals. Prenatal exposure to BPA has been associated with negative neurodevelopmental and behavioral outcomes in children and rodent models. Prenatal BPA exposure has also been shown to impair postnatal maternal care provisioning, which can also affect offspring neurodevelopment and behavior. However, there is limited knowledge regarding the biological effects of prenatal exposure to bisphenols other than BPA and the interplay between prenatal BP exposure and postnatal maternal care on adult behavior. The purpose of the current study was to determine the interactive impact of prenatal BP exposure and postnatal maternal care on neurodevelopment and behavior. Our findings suggest that the effects of prenatal BP exposure on eye-opening, adult attentional set shifting and anxiety-like behavior in the open field are dependent on maternal care in the first five days of life. Interestingly, maternal care might also attenuate the effects of prenatal BP exposure on eye opening and adult attentional set shifting. Finally, transcriptomic profiles in male and female medial prefrontal cortex and amygdala suggest that the interactive effects of prenatal BP exposure and postnatal maternal care converge on estrogen receptor signaling and are involved in biological processes related to gene expression and protein translation and synthesis. Overall, these findings indicate that postnatal maternal care plays a critical role in the expression of the effects of prenatal BP exposure on neurodevelopment and adult behavior. Understanding the underlying biological mechanisms involved might allow us to identify potential avenues to mitigate the adverse effects of prenatal BP exposure and improve health and well-being in human populations.

Shaping the development of complex social behavior.

Early life experiences can have an enduring impact on the brain and behavior, with implications for stress reactivity, cognition, and social behavior. In particular, the neural systems that contribute to the expression of social behavior are altered by early life social environments. However, paradigms that have been used to alter the social environment during development have typically focused on exposure to stress, adversity, and deprivation of species-typical social stimulation. Here, we explore whether complex social environments can shape the development of complex social behavior. We describe lab-based paradigms for studying early life social complexity in rodents that are generally focused on enriching the social and sensory experiences of the neonatal and juvenile periods of development. The impact of these experiences on social behavior and neuroplasticity is highlighted. Finally, we discuss the degree to which our current approaches for studying social behavior outcomes give insight into "complex" social behavior and how social complexity can be better integrated into lab-based methodologies.

Automated maternal behavior during early life in rodents (AMBER) pipeline.

Mother-infant interactions during the early postnatal period are critical for infant survival and the scaffolding of infant development. Rodent models are used extensively to understand how these early social experiences influence neurobiology across the lifespan. However, methods for measuring postnatal dam-pup interactions typically involve time-consuming manual scoring, vary widely between research groups, and produce low density data that limits downstream analytical applications. To address these methodological issues, we developed the Automated Maternal Behavior during Early life in Rodents (AMBER) pipeline for quantifying home-cage maternal and mother-pup interactions using open-source machine learning tools. DeepLabCut was used to track key points on rat dams (32 points) and individual pups (9 points per pup) in postnatal day 1-10 video recordings. Pose estimation models reached key point test errors of approximately 4.1-10 mm (14.39 pixels) and 3.44-7.87 mm (11.81 pixels) depending on depth of animal in the frame averaged across all key points for dam and pups respectively. Pose estimation data and human-annotated behavior labels from 38 videos were used with Simple Behavioral Analysis (SimBA) to generate behavior classifiers for dam active nursing, passive nursing, nest attendance, licking and grooming, self-directed grooming, eating, and drinking using random forest algorithms. All classifiers had excellent performance on test frames, with F1 scores above 0.886. Performance on hold-out videos remained high for nest attendance (F1 = 0.990), active nursing (F1 = 0.828), and licking and grooming (F1 = 0.766) but was lower for eating, drinking, and self-directed grooming (F1 = 0.534-0.554). A set of 242 videos was used with AMBER and produced behavior measures in the expected range from postnatal 1-10 home-cage videos. This pipeline is a major advancement in assessing home-cage dam-pup interactions in a way that reduces experimenter burden while increasing reproducibility, reliability, and detail of data for use in developmental studies without the need for special housing systems or proprietary software.

The contributions of parental lactation on offspring development: It's not udder nonsense!

The Developmental Origins of Health and Disease (DOHaD) hypothesis describes how maternal stress exposures experienced during critical periods of perinatal life are linked to altered developmental trajectories in offspring. Perinatal stress also induces changes in lactogenesis, milk volume, maternal care, and the nutritive and non-nutritive components of milk, affecting short and long-term developmental outcomes in offspring. For instance, selective early life stressors shape the contents of milk, including macro/micronutrients, immune components, microbiota, enzymes, hormones, milk-derived extracellular vesicles, and milk microRNAs. In this review, we highlight the contributions of parental lactation to offspring development by examining changes in the composition of breast milk in response to three well-characterized maternal stressors: nutritive stress, immune stress, and psychological stress. We discuss recent findings in human, animal, and in vitro models, their clinical relevance, study limitations, and potential therapeutic significance to improving human health and infant survival. We also discuss the benefits of enrichment methods and support tools that can be used to improve milk quality and volume as well as related developmental outcomes in offspring. Lastly, we use evidence-based primary literature to convey that even though select maternal stressors may modulate lactation biology (by influencing milk composition) depending on the severity and length of exposure, exclusive and/or prolonged milk feeding may attenuate the negative in utero effects of early life stressors and promote healthy developmental trajectories. Overall, scientific evidence supports lactation to be protective against nutritive and immune stressors, but the benefits of lactation in response to psychological stressors need further investigation.

Sex-specific effects of chronic paternal stress on offspring development are partially mediated via mothers.

Paternal stress exposure is known to impact the development of stress-related behaviors in offspring. Previous work has highlighted the importance of sperm mediated factors, such as RNAs, in transmitting the effects of parental stress. However, a key unanswered question is whether mothers behavior could drive or modulate the transmission of paternal stress effects on offspring development. Here we investigate how chronic variable stress in Balb/C mice influences the sex-specific development of anxiety- and depression-like neural and behavioral development in offspring. Moreover, we examined how stressed fathers influenced mate maternal investment towards their offspring and how this may modulate the transmission of paternal stress effects on offspring. We show that paternal stress leads to sex-specific effects on offspring behavior. Males that are chronically stressed sire female offspring that show increased anxiety and depression-like behaviors. However, male offspring of stressed fathers show reductions in anxiety- and depression-behaviors and are generally more exploratory. Moreover, we show that females mated with stressed males gain less weight during pregnancy and provide less care towards their offspring which additionally influenced offspring development. These data indicate that paternal stress can influence offspring development both directly and indirectly via changes in mothers, with implications for sex-specific offspring development.

Hypertensive disorders during pregnancy and polycystic ovary syndrome are associated with child communication and social skills in a sex-specific and androgen-dependent manner.

Prenatal exposure to testosterone is implicated in the etiology of autism spectrum disorder (ASD). Hypertensive disorders of pregnancy and polycystic ovary syndrome are associated with both hyperandrogenism and increased risk for ASD. We examined whether increased maternal testosterone mediates the relationship between these hyperandrogenic disorders (HDs) during pregnancy and child communication and social skills. Maternal plasma was collected during the second trimester and parent-report measures of child communication and social skills were obtained at 4.5-6.5 years of age from 270 participants enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). Our retrospective frequency-matched cohort study design identified 58 mothers with one or both of the HDs and 58 matched controls. Women diagnosed with an HD who carried a female had higher testosterone levels compared to those carrying a male (t(56) = -2.70, p = 0.01). Compared to females controls, females born to women with an HD had significantly higher scores on the Social Communication Questionnaire (t(114) = -2.82, p =0.01). Maternal testosterone partially mediated the relationship between a diagnosis of an HD and SCQ scores among females. These findings point to sex-specific associations of two HDs - hypertensive disorders of pregnancy and polycystic ovary syndrome - on child communication and social skills and a mediating effect of maternal testosterone during pregnancy. Further research is needed to understand placental-mediated effects of maternal testosterone on child brain development and neurodevelopmental outcomes.

Distinct immune and transcriptomic profiles in dominant versus subordinate males in mouse social hierarchies.

Social status is a critical factor determining health outcomes in human and nonhuman social species. In social hierarchies with reproductive skew, individuals compete to monopolize resources and increase mating opportunities. This can come at a significant energetic cost leading to trade-offs between different physiological systems. In particular, changes in energetic investment in the immune system can have significant short and long-term effects on fitness and health. We have previously found that dominant alpha male mice living in social hierarchies have increased metabolic demands related to territorial defense. In this study, we tested the hypothesis that high-ranking male mice favor adaptive immunity, while subordinate mice show higher investment in innate immunity. We housed 12 groups of 10 outbred CD-1 male mice in a social housing system. All formed linear social hierarchies and subordinate mice had higher concentrations of plasma corticosterone (CORT) than alpha males. This difference was heightened in highly despotic hierarchies. Using flow cytometry, we found that dominant status was associated with a significant shift in immunophenotypes towards favoring adaptive versus innate immunity. Using Tag-Seq to profile hepatic and splenic transcriptomes of alpha and subordinate males, we identified genes that regulate metabolic and immune defense pathways that are associated with status and/or CORT concentration. In the liver, dominant animals showed a relatively higher expression of specific genes involved in major urinary production and catabolic processes, whereas subordinate animals showed relatively higher expression of genes promoting biosynthetic processes, wound healing, and proinflammatory responses. In spleen, subordinate mice showed relatively higher expression of genes facilitating oxidative phosphorylation and DNA repair and CORT was negatively associated with genes involved in lymphocyte proliferation and activation. Together, our findings suggest that dominant and subordinate animals adaptively shift immune profiles and peripheral gene expression to match their contextual needs.

Convergent neural correlates of prenatal exposure to air pollution and behavioral phenotypes of risk for internalizing and externalizing problems: Potential biological and cognitive pathways.

Humans are ubiquitously exposed to neurotoxicants in air pollution, causing increased risk for psychiatric outcomes. Effects of prenatal exposure to air pollution on early emerging behavioral phenotypes that increase risk of psychopathology remain understudied. We review animal models that represent analogues of human behavioral phenotypes that are risk markers for internalizing and externalizing problems (behavioral inhibition, behavioral exuberance, irritability), and identify commonalities among the neural mechanisms underlying these behavioral phenotypes and the neural targets of three types of air pollutants (polycyclic aromatic hydrocarbons, traffic-related air pollutants, fine particulate matter < 2.5 µm). We conclude that prenatal exposure to air pollutants increases risk for behavioral inhibition and irritability through distinct mechanisms, including altered dopaminergic signaling and hippocampal morphology, neuroinflammation, and decreased brain-derived neurotrophic factor expression. Future studies should investigate these effects in human longitudinal studies incorporating complex exposure measurement methods, neuroimaging, and behavioral characterization of temperament phenotypes and neurocognitive processing to facilitate efforts aimed at improving long-lasting developmental benefits for children, particularly those living in areas with high levels of exposure.

Experience-Regulated Neuronal Signaling in Maternal Behavior.

Maternal behavior is shaped and challenged by the changing developmental needs of offspring and a broad range of environmental factors, with evidence indicating that the maternal brain exhibits a high degree of plasticity. This plasticity is displayed within cellular and molecular systems, including both intra- and intercellular signaling processes as well as transcriptional profiles. This experience-associated plasticity may have significant overlap with the mechanisms controlling memory processes, in particular those that are activity-dependent. While a significant body of work has identified various molecules and intracellular processes regulating maternal care, the role of activity- and experience-dependent processes remains unclear. We discuss recent progress in studying activity-dependent changes occurring at the synapse, in the nucleus, and during the transport between these two structures in relation to maternal behavior. Several pre- and postsynaptic molecules as well as transcription factors have been found to be critical in these processes. This role reflects the principal importance of the molecular and cellular mechanisms of memory formation to maternal and other behavioral adaptations.

Elevated prenatal maternal sex hormones, but not placental aromatase, are associated with child neurodevelopment.

Fetal exposure to testosterone may contribute to vulnerability for autism spectrum disorder (ASD). It is hypothesized that placental aromatase prevents fetal exposure to maternal testosterone, however, this pathway and the implications for child neurodevelopment have not been fully explored. We examined the relationships between prenatal maternal testosterone and estradiol at 19.2 ± 1.3 weeks, cord blood testosterone and estradiol at birth, placental aromatase mRNA expression, and neurodevelopment using the Social Communication Questionnaire (SCQ), the Behavioral Assessment System for Children, 3rd Edition (BASC-3), and the Empathizing Quotient for Children (EQ-C) at 4.5-6.5 years of age in a sample of 270 Nulliparous-Mothers-to-be (nuMoM2b) study participants. Maternal testosterone levels were positively associated with SCQ scores, but the association was not significant after adjusting for maternal age at delivery, nor was there a significant interaction with sex. Maternal estradiol levels were negatively associated with BASC-3 Clinical Probability scores among males (n = 139). We report a significant interaction effect of cord blood testosterone and fetal sex on both total SCQ scores and t-scores on the Developmental Social Disorders subscale. Placental aromatase was not associated with any neurodevelopmental or hormone measure, but under conditions of low placental aromatase expression, high maternal testosterone was positively associated with SCQ scores in males (n = 46). No other associations between hormone levels and neurodevelopment were significant. Our findings provide a foundation for further investigation of the mechanisms through which maternal sex hormones and placental steroidogenesis may affect fetal hormone production and neurobehavior.

Added sugar intake during pregnancy: Fetal behavior, birth outcomes, and placental DNA methylation.

Pregnancy is a critical time for the effects of environmental factors on children's development. The effect of added sugar intake on fetal development and pregnancy outcomes remains understudied despite increasing dietary intake in the United States. This study investigated the effect of added sugar on fetal programming by examining the association between maternal added sugar consumption, fetal movement, birth outcomes, and placental DNA methylation. Further, primary human fibroblasts were cultured under normal or high glucose conditions to assess the effect of high glucose exposure on cells' DNA methylation. We found that higher added sugar intake across pregnancy was associated with reduced 3rd-trimester fetal movement (p < .05) and shorter gestation (p < .01). Our sample size was not powered to detect the alteration of individual placental CpG with genome-wide significance. However, a secondary analysis suggested that added sugar consumption was associated with differential methylation of functionally related gene families across pregnancy. Consistent with this, high glucose exposure in primary cultured human fibroblasts altered the methylation of 17% of all CpGs, providing converging evidence for an effect of sugar on DNA methylation. Our results suggest that diets high in added sugar during pregnancy may have implications for offspring health via prenatal programming effects measurable before birth.

Defining the relationship between maternal care behavior and sensory development in Wistar rats: Auditory periphery development, eye opening and brain gene expression.

Defining the relationship between maternal care, sensory development and brain gene expression in neonates is important to understand the impact of environmental challenges during sensitive periods in early life. In this study, we used a selection approach to test the hypothesis that variation in maternal licking and grooming (LG) during the first week of life influences sensory development in Wistar rat pups. We tracked the onset of the auditory brainstem response (ABR), the timing of eye opening (EO), middle ear development with micro-CT X-ray tomography, and used qRT-PCR to monitor changes in gene expression of the hypoxia-sensitive pathway and neurotrophin signaling in pups reared by low-LG or high-LG dams. The results show the first evidence that the transcription of genes involved in the hypoxia-sensitive pathway and neurotrophin signaling is regulated during separate sensitive periods that occur before and after hearing onset, respectively. Although the timing of ABR onset, EO, and the relative mRNA levels of genes involved in the hypoxia-sensitive pathway did not differ between pups from different LG groups, we found statistically significant increases in the relative mRNA levels of four genes involved in neurotrophin signaling in auditory brain regions from pups of different LG backgrounds. These results suggest that sensitivity to hypoxic challenge might be widespread in the auditory system of neonate rats before hearing onset, and that maternal LG may affect the transcription of genes involved in experience-dependent neuroplasticity.

Potential frameworks to support evaluation of mechanistic data for developmental neurotoxicity outcomes: A symposium report.

A key challenge in systematically incorporating mechanistic data into human health assessments is that, compared to studies of apical health endpoints, these data are both more abundant (mechanistic studies routinely outnumber other studies by several orders of magnitude) and more heterogeneous (e.g. different species, test system, tissue, cell type, exposure paradigm, or specific assays performed). A structured decision-making process for organizing, integrating, and weighing mechanistic DNT data for use in human health risk assessments will improve the consistency and efficiency of such evaluations. At the Developmental Neurotoxicology Society (DNTS) 2016 annual meeting, a symposium was held to address the application of existing organizing principles and frameworks for evaluation of mechanistic data relevant to interpreting neurotoxicology data. Speakers identified considerations with potential to advance the use of mechanistic DNT data in risk assessment, including considering the context of each exposure, since epigenetics, tissue type, sex, stress, nutrition and other factors can modify toxicity responses in organisms. It was also suggested that, because behavior is a manifestation of complex nervous system function, the presence and absence of behavioral change itself could be used to organize the interpretation of multiple complex simultaneous mechanistic changes. Several challenges were identified with frameworks and their implementation, and ongoing research to develop these approaches represents an early step toward full evaluation of mechanistic DNT data for assessments.

DNA methylation patterns in T lymphocytes are generally stable in human pregnancies but CD3 methylation is associated with perinatal psychiatric symptoms.

OBJECTIVES: To determine whether DNA methylation patterns in genes coding for selected T-lymphocyte proteins are associated with perinatal psychiatric distress or with complications of pregnancy. METHODS: T lymphocyte DNA was obtained from pregnant women across three time points in pregnancy and the postpartum period and epigenetic patterns were assessed using Illumina 450 â€‹K Methylation Beadchips. Seven selected genes critical for T cell function were analyzed for methylation changes during pregnancy and for associations of methylation patterns with psychiatric distress or with pregnancy complications, with particular attention paid to spatial aggregations of methyl groups, termed 'hotspots,' within the selected genes. RESULTS: In the candidate gene approach, DNA methylation density within a single cluster of 9 contiguous CpG loci within the CD3 gene was found to be strongly associated with anxiety and depression in mid- and late pregnancy, and weakly associated with the presence of complications of pregnancy. Average DNA methylation density across each of the seven genes examined, and assay-wide, was found to be relatively stable across pregnancy and postpartum, but methylation within the CD3 hotspot was more malleable and changes over time were coordinated across the nine cytosines in the hotspot. CD3 CpGs did not pass array-wide tests for significance, but CpG clusters in two other genes, DTNBP1 and OXSR1, showed array-wide significant associations with anxiety. CONCLUSIONS: Despite the need for tolerating the fetal hemi-allograft, overall DNA methylation patterns in T lymphocytes are generally stable over the mid to late course of human pregnancies and postpartum. However, site-specific changes in DNA methylation density in CD3 appear linked to both symptoms of depression and anxiety in pregnancy and, less strongly, to adverse pregnancy outcomes.

Maternal prenatal stress phenotypes associate with fetal neurodevelopment and birth outcomes.

Maternal prenatal stress influences offspring neurodevelopment and birth outcomes including the ratio of males to females born; however, there is limited understanding of what types of stress matter, and for whom. Using a data-driven approach with 27 variables from questionnaires, ambulatory diaries, and physical assessments collected early in the singleton pregnancies of 187 women, 3 latent profiles of maternal prenatal stress emerged that were differentially associated with sex at birth, birth outcomes, and fetal neurodevelopment. Most women (66.8%) were in the healthy group (HG); 17.1% were in the psychologically stressed group (PSYG), evidencing clinically meaningful elevations in perceived stress, depression, and anxiety; and 16% were in the physically stressed group (PHSG) with relatively higher ambulatory blood pressure and increased caloric intake. The population normative male:female secondary sex ratio (105:100) was lower in the PSYG (2:3) and PHSG (4:9), and higher in the HG (23:18), consistent with research showing diminished male births in maternal stress contexts. PHSG versus HG infants were born 1.5 wk earlier (P < 0.05) with 22% compared to 5% born preterm. PHSG versus HG fetuses had decreased fetal heart rate-movement coupling (P < 0.05), which may indicate slower central nervous system development, and PSYG versus PHSG fetuses had more birth complications, consistent with previous findings among offspring of women with psychiatric illness. Social support most strongly differentiated the HG, PSYG, and PHSG groups, and higher social support was associated with increased odds of male versus female births. Stress phenotypes in pregnant women are associated with male vulnerability and poor fetal outcomes.

The neural mechanisms and consequences of paternal caregiving.

In recent decades, human sociocultural changes have increased the numbers of fathers that are involved in direct caregiving in Western societies. This trend has led to a resurgence of interest in understanding the mechanisms and effects of paternal care. Across the animal kingdom, paternal caregiving has been found to be a highly malleable phenomenon, presenting with great variability among and within species. The emergence of paternal behaviour in a male animal has been shown to be accompanied by substantial neural plasticity and to be shaped by previous and current caregiving experiences, maternal and infant stimuli and ecological conditions. Recent research has allowed us to gain a better understanding of the neural basis of mammalian paternal care, the genomic and circuit-level mechanisms underlying paternal behaviour and the ways in which the subcortical structures that support maternal caregiving have evolved into a global network of parental care. In addition, the behavioural, neural and molecular consequences of paternal caregiving for offspring are becoming increasingly apparent. Future cross-species research on the effects of absence of the father and the transmission of paternal influences across generations may allow research on the neuroscience of fatherhood to impact society at large in a number of important ways.

Maternal modulation of paternal effects on offspring development.

The paternal transmission of environmentally induced phenotypes across generations has been reported to occur following a number of qualitatively different exposures and appear to be driven, at least in part, by epigenetic factors that are inherited via the sperm. However, previous studies of paternal germline transmission have not addressed the role of mothers in the propagation of paternal effects to offspring. We hypothesized that paternal exposure to nutritional restriction would impact male mate quality and subsequent maternal reproductive investment with consequences for the transmission of paternal germline effects. In the current report, using embryo transfer in mice, we demonstrate that sperm factors in adult food restricted males can influence growth rate, hypothalamic gene expression and behaviour in female offspring. However, under natural mating conditions females mated with food restricted males show increased pre- and postnatal care, and phenotypic outcomes observed during embryo transfer conditions are absent or reversed. We demonstrate that these compensatory changes in maternal investment are associated with a reduced mate preference for food restricted males and elevated gene expression within the maternal hypothalamus. Therefore, paternal experience can influence offspring development via germline inheritance, but mothers can serve as a modulating factor in determining the impact of paternal influences on offspring development.