The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities.

This review discusses the long-term effects of early-life environment on epileptogenesis, epilepsy, and neuropsychiatric comorbidities with an emphasis on the absence epilepsy. The WAG/Rij rat strain is a well-validated genetic model of absence epilepsy with mild depression-like (dysthymia) comorbidity. Although pathologic phenotype in WAG/Rij rats is genetically determined, convincing evidence presented in this review suggests that the absence epilepsy and depression-like comorbidity in WAG/Rij rats may be governed by early-life events, such as prenatal drug exposure, early-life stress, neonatal maternal separation, neonatal handling, maternal care, environmental enrichment, neonatal sensory impairments, neonatal tactile stimulation, and maternal diet. The data, as presented here, indicate that some early environmental events can promote and accelerate the development of absence seizures and their neuropsychiatric comorbidities, while others may exert anti-epileptogenic and disease-modifying effects. The early environment can lead to phenotypic alterations in offspring due to epigenetic modifications of gene expression, which may have maladaptive consequences or represent a therapeutic value. Targeting DNA methylation with a maternal methyl-enriched diet during the perinatal period appears to be a new preventive epigenetic anti-absence therapy. A number of caveats related to the maternal methyl-enriched diet and prospects for future research are discussed.

Environmental influences on early language and literacy development: Social policy and educational implications.

A growing body of literature suggests strong associations between environmental factors and young children's early language and literacy development. In the United States, large socio-economic differences are evident in children's skills when they enter Kindergarten, differences that persist through schooling and can be explained by children's early communicative environments. Here, I highlight three themes that characterize the features of children's communicative environments that are found to promote language learning: (1) Talking with children helps more than talking to children, (2) Linguistic input should increase in diversity and complexity during early childhood, and (3) A gradual transition from contextualized to decontextualized conversations is helpful. There are many reasons for the large variability in early communicative environments within and across social class groups. Two primary reasons include parents' knowledge of child development and parenting stress. Social policies that reduce parenting stress and increase parental knowledge have the potential to improve early language environments and lead to better educational outcomes for all children.

Mouse model of panic disorder: Vulnerability to early environmental instability is strain-dependent.

Early life experiences and genetic background shape phenotypic variation. Several mouse models based on early treatments have evaluated short- and long-term phenotypic alterations and explored their molecular mechanisms. The instability of maternal cues was used to model human separation anxiety in outbred mice, one of the etiopathogenetic factors that predict panic disorder (PD). Application of the repeated cross-fostering (RCF) protocol to inbred strains (C57 and DBA) allowed us to measure differential responses to the same experimental manipulation. Ultrasounds emitted during isolation indicated that after RCF, pups from both strains lose their ability to be comforted by nest cues, but the frequency modulation of separation calls increased in RCF-C57 and decreased in RCF-DBA mice. No strain-specific difference in olfactory ability explained these responses in RCF-exposed mice. Rather, disruption of the infant-mother bond may differentially affect separation calls in the two strains. Moreover, the RCF-associated increased respiratory response to hypercapnia-an endophenotype of human PD documented among mice outbred strains-was replicated in the C57 strain only. We suggest that RCF-induced instability of the early environment affects emotionality and respiratory physiology differentially, depending on pups' genetic background. These strain-specific responses provide a lead to understand differential vulnerability to emotional disorders.

Contrasting associations between nestling telomere length and pre and postnatal helpers' presence in a cooperatively breeding bird.

Studies on cooperative breeders have addressed the effects of non-breeding 'helpers' on reproduction and parental care, but the consequences for offspring physiology and long-term survival are less understood. Helpers are expected to benefit offspring, but their presence can also lead to decreased pre- or post-natal parental reproductive effort. To examine whether prenatal and postnatal helpers influence offspring condition, we conducted a whole-clutch cross-fostering experiment in sociable weavers (Philetairus socius) that altered the nestlings' social environment (presence/absence of helpers). We tested whether relative telomere length (rTL), an indicator of somatic maintenance, was influenced by prenatal and/or postnatal presence of helpers 9 and 17 days after hatching, and whether rTL predicted long-term survival. Nine days after hatching, we found an overall positive effect of postnatal helpers on rTL: for nestlings with prenatal helpers, a reduction in the number of helpers post-hatch was associated with shorter telomeres, while nestlings swapped from nests without helpers to nests with helpers had a larger rTL. However, when prenatal helpers were present, an increased number of helpers after hatching led to shorter telomeres. Nine-day old chicks with longer rTL tended to be more likely to survive over the 5 years following hatching. However, close to fledging, there was no detectable effect of the experiment on rTL and no link between rTL and survival. This experimental study of a wild cooperative breeder, therefore, presents partial support for the importance of the presence of helpers for offspring rTL and the link between early-life telomere length and long-term survival.

Amygdala 5-HTT Gene Network Moderates the Effects of Postnatal Adversity on Attention Problems: Anatomo-Functional Correlation and Epigenetic Changes.

Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children.

Transcriptomic signatures of social experience during early development in a highly social cichlid fish.

The social environment encountered early during development can temporarily or permanently influence life history decisions and behaviour of individuals and correspondingly shape molecular pathways. In the highly social cichlid fish Neolamprologus pulcher, deprivation of brood care permanently affects social behaviour and alters the expression of stress axis genes in juveniles and adults. It is unclear when gene expression patterns change during early life depending on social experience, and which genes are involved. We compared brain gene expression of N. pulcher at two time points during the social experience phase when juveniles were reared either with or without brood care, and one time point shortly afterwards. We compared (a) whole transcriptomes and (b) expression of 79 genes related to stress regulation, in order to define a neurogenomic state of stress for each fish. At developmental day 75, that is, after the social experience phase, 43 genes were down-regulated in fish having experienced social deprivation, while two genes involved in learning and memory and in post-translational modifications of proteins (PTM), respectively, were up-regulated. Down-regulated genes were mainly associated with immunity, PTM and brain function. In contrast, during the experience phase no genes were differentially expressed when assessing the whole transcriptome. When focusing on the neurogenomic state associated with the stress response, we found that individuals from the two social treatments differed in how their brain gene expression profiles changed over developmental stages. Our results indicate that the early social environment influences the transcriptional activation in fish brains, both during and after an early social experience, possibly affecting plasticity, immune system function and stress axis regulation.

Sex-specific effects of the in ovo environment on early-life phenotypes in eiders.

Maternal effects affect offspring phenotype and fitness. However, the roles of offspring sex-specific sensitivity to maternal glucocorticoids and sex-biased maternal investment remain unclear. It is also uncertain whether telomere length (a marker associated with lifespan) depends on early growth in a sex-specific manner. We assessed whether maternal traits including corticosterone (CORT; the main avian glucocorticoid) and in ovo growth rate are sex-specifically related to offspring CORT exposure, relative telomere length (RTL) and body condition in eiders (Somateria mollissima). We measured feather CORT (fCORT), RTL and body condition of newly hatched ducklings, and growth rate in ovo was expressed as tarsus length at hatching per incubation duration. Maternal traits included baseline plasma CORT, RTL, body condition and breeding experience. We found that fCORT was negatively associated with growth rate in daughters, while it showed a positive association in sons. Lower offspring fCORT was associated with higher maternal baseline plasma CORT, and fCORT was higher in larger clutches and in those hatching later. The RTL of daughters was negatively associated with maternal RTL, whereas that of males was nearly independent of maternal RTL. Higher fCORT in ovo was associated with longer RTL at hatching in both sexes. Duckling body condition was mainly explained by egg weight, and sons had a slightly lower body condition. Our correlational results suggest that maternal effects may have heterogeneous and even diametrically opposed effects between the sexes during early development. Our findings also challenge the view that prenatal CORT exposure is invariably associated with shorter telomeres.

Early-life social environment alters juvenile behavior and neuroendocrine function in a highly social cichlid fish.

Early-life experiences can shape adult behavior, with consequences for fitness and health, yet fundamental questions remain unanswered about how early-life social experiences are translated into variation in brain and behavior. The African cichlid fish Astatotilapia burtoni, a model system in social neuroscience, is well known for its highly plastic social phenotypes in adulthood. Here, we rear juveniles in either social groups or pairs to investigate the effects of early-life social environments on behavior and neuroendocrine gene expression. We find that both juvenile behavior and neuroendocrine function are sensitive to early-life effects. Behavior robustly co-varies across multiple contexts (open field, social cue investigation, and dominance behavior assays) to form a behavioral syndrome, with pair-reared juveniles towards the end of syndrome that is less active and socially interactive. Pair-reared juveniles also submit more readily as subordinates. In a separate cohort, we measured whole brain expression of stress and sex hormone genes. Expression of glucocorticoid receptor 1a was elevated in group-reared juveniles, supporting a highly-conserved role for the stress axis mediating early-life effects. The effect of rearing environment on androgen receptor α and estrogen receptor α expression was mediated by treatment duration (1 vs. 5 weeks). Finally, expression of corticotropin-releasing factor and glucocorticoid receptor 2 decreased significantly over time. Rearing environment also caused striking differences in gene co-expression, such that expression was tightly integrated in pair-reared juveniles but not group-reared or isolates. Together, this research demonstrates the important developmental origins of behavioral phenotypes and identifies potential behavioral and neuroendocrine mechanisms.

Sex-dependent effects of early unstable post-natal environment on response to positive and negative stimuli in adult mice.

Alterations in early environmental conditions that interfere with the creation of a stable mother-pup bond have been suggested to be a risk factor for the development of stress-related psychopathologies later in life. The long-lasting effects of early experiences are mediated by changes in various cerebral circuits, such as the corticolimbic system, which processes aversive and rewarding stimuli. However, it is evident that the early environment is not sufficient per se to induce psychiatric disorders; interindividual (eg, sex-based) differences in the response to environmental challenges exist. To examine the sex-related effects that are induced by an early experience on later events in adulthood, we determine the enduring effects of repeated cross-fostering (RCF) in female and male C57BL/6J mice. To this end, we assessed the behavioral phenotype of RCF and control (male and female) mice in the saccharine preference test and cocaine-induced conditioned place preference to evaluate the response to natural and pharmacological stimuli and in the elevated plus maze test and forced swimming test to measure their anxiety- and depression-like behavior. We also evaluated FST-induced c-Fos immunoreactivity in various brain regions that are engaged in the response to acute stress exposure (FST). Notably, RCF has opposing effects on the adult response to these tests between sexes, directing male mice toward an "anhedonia-like" phenotype and increasing the sensitivity for rewarding stimuli in female mice.

Early-life social environment predicts social network position in wild zebra finches.

Early-life experience can fundamentally shape individual life-history trajectories. Previous research has suggested that exposure to stress during development causes differences in social behaviour later in life. In captivity, juvenile zebra finches exposed to elevated corticosterone levels were less socially choosy and more central in their social networks when compared to untreated siblings. These differences extended to other aspects of social life, with 'stress-exposed' juveniles switching social learning strategies and juvenile males less faithfully learning their father's song. However, while this body of research suggests that the impacts of early-life stress could be profound, it remains unknown whether such effects are strong enough to be expressed under natural conditions. Here, we collected data on social associations of zebra finches in the Australian desert after experimentally manipulating brood sizes. Juveniles from enlarged broods experienced heightened sibling competition, and we predicted that they would express similar patterns of social associations to stress-treated birds in the captive study by having more, but less differentiated, relationships. We show striking support for the suggested consequences of developmental stress on social network positions, with our data from the wild replicating the same results in 9 out of 10 predictions previously tested in captivity. Chicks raised in enlarged broods foraged with greater numbers of conspecifics but were less 'choosy' and more central in the social network. Our results confirm that the natural range of variation in early-life experience can be sufficient to predict individuals' social trajectories and support theory highlighting the potential importance of developmental conditions on behaviour.

Digit ratio predicts the number of lifetime recruits in female collared flycatchers.

The early environment in which an organism grows can have long-lasting impacts on both its phenotype and fitness. However, assessing this environment comprehensively is a formidable task. The relative length of the second to the fourth digit (2D : 4D) is a broadly studied skeletal trait that is fixed for life during ontogeny. 2D : 4D has been shown to indicate various early effects including the perinatal steroid milieu in both humans and non-human animals. However, the fitness relevance of the early effects indicated by 2D : 4D remains unknown. Here, we investigated hindlimb 2D : 4D and measures of lifetime performance in wild collared flycatcher ( Ficedula albicollis) females. We found that females with higher 2D : 4D had a greater number of recruiting offspring to the breeding population. This was the case despite the fact that such females did not lay more eggs or breed more frequently during their reproductive life. Our results support the suggestion that 2D : 4D, known to be a retrospective marker of perinatal development, positively associates with female quality in the collared flycatcher.

Socioeconomic Status in Infancy and the Developing Brain: Functional Connectivity of the Hippocampus and Amygdala.

The development of the hippocampus and amygdala is particularly sensitive to environmental factors, including socioeconomic status (SES). Studies that have investigated associations between SES and brain development markers have rarely focused on connectivity. Accordingly, this longitudinal study examined whether SES in infancy (parental education and income-to-needs ratio) predicts the functional connectivity of the hippocampus and amygdala in late childhood, and in turn whether functional connectivity is associated with child socioemotional adjustment in a middle-class sample. SES indices were measured when children (n = 28) were 7 months old. When children were 10 years of age, they underwent a resting-state functional magnetic resonance imaging exam, and their school teachers completed a questionnaire assessing child socioemotional adjustment. Whole-brain regression analyses, including left and right hippocampi and amygdalae as seeds and SES indices as predictors, revealed that higher parental education predicted stronger functional connectivity between the left and right hippocampi and the right amygdala with the dorsal anterior cingulate cortex, and between the left amygdala and bilateral angular gyrus, after accounting for child age and sex. In turn, the connectivity of these regions was associated with higher child prosocial behavior. These findings contribute to the emerging literature suggesting that SES is associated with variability in the neural substrates of social abilities in children.

Genetic and Environmental Influences on the Affective Regulation Network: A Prospective Experience Sampling Analysis.

Background: The study of networks of affective mental states that play a role in psychopathology may help model the influence of genetic and environmental risks. The aim of the present paper was to examine networks of affective mental states (AMS: "cheerful," "insecure," "relaxed," "anxious," "irritated," and "down") over time, stratified by genetic liability for psychopathology and exposure to environmental risk, using momentary assessment technology. Methods: Momentary AMS, collected using the experience sampling method (ESM) as well as childhood trauma and genetic liability (based on the level of shared genes and psychopathology in the co-twin) were collected in a population-based sample of female-female twin pairs and sisters (585 individuals). Networks were generated using multilevel time-lagged regression analysis, and regression coefficients were compared across three strata of childhood trauma severity and three strata of genetic liability using permutation testing. Regression coefficients were presented as network connections. Results: Visual inspection of network graphs revealed some suggestive changes in the networks with more exposure to either childhood trauma or genetic liability (i.e., stronger reinforcing loops between the three negative AMS anxious, insecure, and down both under higher early environmental, and under higher genetic liability exposure, stronger negative association between AMS of different valences: i.e., between "anxious" at t-1 and "relaxed" at t, "relaxed" at t-1 and "down" at t, under intermediate genetic liability exposure when compared to both networks under low and high genetic liability). Yet, statistical evaluation of differences across exposure strata was inconclusive. Conclusions: Although suggestive of a difference in the emotional dynamic, there was no conclusive evidence that genetic and environmental factors may impact ESM network models of individual AMS.

Effects of an early-life paraquat exposure on adult resistance to oxidative stress, plumage colour and sperm performance in a wild bird.

Early-life stressful conditions can shape individual phenotypes and ultimately influence fitness. Oxidative stress is a pervasive threat that affects many fitness-related traits and can modulate life-history trade-offs. Yet, the extent to which exposure to oxidative stress during early life can have long-lasting effects on key fitness-related traits remains to be elucidated, particularly in natural populations of vertebrates. Using a wild population of great tits Parus major, we experimentally dosed 11-day-old birds with paraquat, a pro-oxidant molecule, aiming at increasing oxidative stress. One year later, we recaptured 39 of them as adult recruiting breeders and quantified effects of the paraquat exposure on their resistance to oxidative stress, carotenoid-based plumage coloration and male sperm performance. Despite the absence of a short-term effect of paraquat on oxidative stress measured two days later, the pre-fledging exposure to paraquat induced a reduction in individual oxidative damage measured at adulthood. Paraquat-dosed individuals also had brighter plumage, but no effect was observed on male sperm performance. For the first time in a natural population of vertebrates, we experimentally show that an early-life acute exposure to a pro-oxidant has long-lasting effects on individual resistance to oxidative stress at adulthood. Our results are in line with the environmental matching and the hormesis hypotheses but may also reflect selective disappearance of individuals with lower resistance to oxidative stress.

Evolutionary conserved neural signature of early life stress affects animal social competence.

In vertebrates, the early social environment can persistently influence behaviour and social competence later in life. However, the molecular mechanisms underlying variation in animal social competence are largely unknown. In rats, high-quality maternal care causes an upregulation of hippocampal glucocorticoid receptors (gr) and reduces offspring stress responsiveness. This identifies gr regulation as a candidate mechanism for maintaining variation in animal social competence. We tested this hypothesis in a highly social cichlid fish, Neolamprologus pulcher, reared with or without caring parents. We find that the molecular pathway translating early social experience into later-life alterations of the stress axis is homologous across vertebrates: fish reared with parents expressed the glucocorticoid receptor gr1 more in the telencephalon. Furthermore, expression levels of the transcription factor egr-1 (early growth response 1) were associated with gr1 expression in the telencephalon and hypothalamus. When blocking glucocorticoid receptors (GR) with an antagonist, mifepristone (RU486), parent-reared individuals showed more socially appropriate, submissive behaviour when intruding on a larger conspecific's territory. Remarkably, mifepristone-treated fish were less attacked by territory owners and had a higher likelihood of territory takeover. Our results indicate that early social-environment effects on stress axis programming are mediated by an evolutionary conserved molecular pathway, which is causally involved in environmentally induced variation of animal social competence.

Prenatal Stress as a Risk-and an Opportunity-Factor.

Two separate lines of research indicate (a) that prenatal stress is associated with heightened behavioral and physiological reactivity and (b) that these postnatal phenotypes are associated with increased susceptibility to both positive and negative developmental experiences. Therefore, prenatal stress may increase sensitivity to the rearing environment. We tested this hypothesis by manipulating prenatal stress and rearing-environment quality, using a cross-fostering paradigm, in prairie voles. Results showed that prenatally stressed voles, as adults, displayed the highest behavioral and physiological reactivity when cross-fostered to low-contact (i.e., low-quality) rearing but the lowest behavioral and physiological reactivity when cross-fostered to high-contact (i.e., high-quality) rearing; non-prenatally stressed voles showed no effect of rearing condition. Additionally, while neither prenatal stress nor rearing condition affected oxytocin receptor binding, prenatally stressed voles cross-fostered to high-contact rearing showed the highest vasopressin-1a receptor binding in the amygdala. Results indicate that prenatal stress induces greater environmental sensitivity, making it both a risk and an opportunity factor.

Developmental Contributors to Trauma Response: The Importance of Sensitive Periods, Early Environment, and Sex Differences.

This review considers early factors that interact with development to contribute to later trauma responses, including developmental sensitive periods, the effects of early environment, and the emergence of sex differences. We also describe development of neural substrates that have been associated with posttraumatic stress disorder and specifically focus on fear behavior and circuitry. Emerging evidence suggests that there may be developmental shifts around age 10 in these underlying circuits that may contribute to vulnerability. We also discuss age-related changes in the importance of caregiver availability as positive buffering factors. Hormonal changes later in development with onset during puberty appear to further shape development trajectories toward risk or resilience. We highlight these recent findings as well as the great need for further longitudinal research from middle childhood through early adulthood.

Long-term effects of early environment on the brain: Lesson from rodent models.

The postnatal period is characterized by extensive neuronal plasticity, synaptic organization, and remodeling. High neuroplasticity renders the brain sensitive to the remodeling effects induced by environmental factors, such as exposure to adversity, which can imprint neurochemical, neuroendocrine, morphological, and behavioral changes. Early experiences that influence developmental trajectories during maturation of the brain can have a wide range of long-lasting effects, modulating stress-coping strategies in adult life and inducing vulnerability or resilience to psychopathologies, depending on the gene×later experience interplay. Future studies will clarify how manipulation of the early environment induces these effects acting on genetic and epigenetic factors.

Social makes smart: rearing conditions affect learning and social behaviour in jumping spiders.

There is a long-standing debate as to whether social or physical environmental aspects drive the evolution and development of cognitive abilities. Surprisingly few studies make use of developmental plasticity to compare the effects of these two domains during development on behaviour later in life. Here, we present rearing effects on the development of learning abilities and social behaviour in the jumping spider Marpissa muscosa. These spiders are ideally suited for this purpose because they possess the ability to learn and can be reared in groups but also in isolation without added stress. This is a critical but rarely met requirement for experimentally varying the social environment to test its impact on cognition. We split broods of spiders and reared them either in a physically or in a socially enriched environment. A third group kept under completely deprived conditions served as a 'no-enrichment' control. We tested the spiders' learning abilities by using a modified T-maze. Social behaviour was investigated by confronting spiders with their own mirror image. Results show that spiders reared in groups outperform their conspecifics from the control, i.e. 'no-enrichment', group in both tasks. Physical enrichment did not lead to such an increased performance. We therefore tentatively suggest that growing up in contact with conspecifics induces the development of cognitive abilities in this species.