•Both male and female adult offspring were responsive to the acute activational effects of cocaine.•Both male and female adult offspring exhibited a strong cocaine-conditioned locomotor response ...after repeated cocaine.•Maternal diet did not interact in these effects of cocaine.•Maternal high fat diet (HFD) enhanced the expression of behavioural anxiety in female adult offspring.•Cocaine reversed the effect of maternal HFD on the expression of behavioural anxiety in female offspring.
Building on previous work in the field, we examined the effect of maternal high fat diet (HFD) during gestation and lactation on the sensitivity of male and female adult offspring to acute and repeated cocaine exposures, and to the expression of cocaine-induced anxiety in the elevated plus maze (EPM). In both male and female offspring, acute injections of cocaine induced a strong locomotor-activating effect; repeated injections produced a robust conditioned locomotor response to the context in which they were given cocaine, and heightened activity in response to a subsequent acute challenge of cocaine. Although female offspring of HFD relative to control house chow diet (CHD) dams exhibited a generally elevated level of locomotor activity, this effect was not further enhanced by cocaine administration/s and there were no significant interactions between maternal diet and cocaine in either male or female offspring. Finally, female offspring of HFD relative to CHD dams exhibited enhanced behavioral anxiety in the EPM, an effect that was reversed when the offspring were exposed to cocaine 48 h prior. Although, in contradiction to our hypotheses, the present study failed to demonstrate an effect of maternal diet on the locomotor-activating effects of cocaine, it did replicate all of the established findings upon which its rationale and predictions were based. Thus, we believe that our results provide important context for future studies.
The mother is the major interface between the offspring and its prenatal environment. Prenatal toxins and stress-inducing physical agents are important factors programming the developmental ...trajectory of mammals that likely involve epigenetic modifications. However, prenatal stressors commonly-used in the laboratory (e.g. prenatal restraint stress and prenatal chronic variable stress) are typically administered at high intensities. These exposures typically lead to pathological phenotypes supporting the development origin of health and disease hypothesis. In this review, we compare the phenotypic outcomes of these commonly-used prenatal stressors to an ecologically-relevant, psychogenic stressor that has been present over evolutionary times, predator or predator cues presence. Prenatal stress by predator threat results in behavioral, physiological, endocrine, transcript abundance and epigenetic (DNA methylation) modifications. These phenotypic modifications are consistent with developmental forecasting according to the Predictive Adaptive Response hypothesis, yielding adaptive responses in environments where such predation stress is present. The evidence described in this review suggests that the type of prenatal stress agent and its intensity modifies the phenotype expressed, which can range from adaptive to pathological. Prenatal Bisphenol A exposure studies are presented as an example where graded intensities (concentrations) of prenatal toxin exposure can be compared directly. Finally, we emphasize the importance of studying both sexes in these studies, as sex differences appear to be a common feature of the response to prenatal stress.
•Predator presence or cues are ecologically-relevant stressors eliciting evolutionary-conserved phenotypic responses•High intensity maternal stressors commonly used eliciting phenotypic changes include physical restraint and variable stress•Commonly-used maternal stress paradigms elicit phenotypic changes consistent with the DOHaD hypothesis•Maternal mild predator presence or cue exposure elicits adaptations consistent with the predictive adaptive response hypothesis•Maternal stress studies should consider the stressor intensity and the ecological relevance of the resulting phenotype
This article highlights the defining principles, progress, and future directions in epigenetics research in relation to this Special Issue. Exciting studies in the fields of neuroscience, psychology, ...and psychiatry have provided new insights into the epigenetic factors (e.g., DNA methylation) that are responsive to environmental input and serve as biological pathways in behavioral development. Here we highlight the experimental evidence, mainly from animal models, that factors such as psychosocial stress and environmental adversity can become encoded within epigenetic factors with functional consequences for brain plasticity and behavior. We also highlight evidence that epigenetic marking of genes in one generation can have consequences for future generations (i.e., inherited), and work with humans linking epigenetics, cognitive dysfunction, and psychiatric disorder. Though epigenetics has offered more of a beginning than an answer to the centuries-old nature-nurture debate, continued research is certain to yield substantial information regarding biological determinants of central nervous system changes and behavior with relevance for the study of developmental psychopathology.
Early life maternal care received has a profound effect on later-life behaviour in adult offspring, and previous studies have suggested epigenetic mechanisms are involved. Changes in thyroid hormone ...receptor signalling may be related to differences in maternal care received and DNA methylation modifications. We investigated the effects of variations in temperature exposure (a proxy of maternal contact) and licking-like tactile stimulation on these processes in week-old female rat pups. We assessed thyroid hormone receptor signalling by measuring circulating triiodothyronine and transcript abundance of thyroid hormone receptors and the thyroid hormone-responsive genes DNA methyltransferase 3a and oxytocin in the paraventricular nucleus of the hypothalamus. DNA methylation of the oxytocin promoter was assessed in relation to changes in thyroid hormone receptor binding. Repeated room temperature exposure was associated with a decrease in thyroid hormone receptor signalling measures relative to nest temperature exposure, while acute room temperature exposure was associated with an increase. Repeated room temperature exposure also increased thyroid hormone receptor binding and DNA methylation at the oxytocin promoter. These findings suggest that repeated room temperature exposure may affect DNA methylation levels as a consequence of alterations in thyroid hormone receptor signalling.
•Maternal care has a profound effect on later-life behavior in offspring.•Extra-maternal factors have also been shown to influence later-life behavior.•We discuss variations in ambient temperature ...exposure and gene x environment interactions.•Other examples include milk composition, sibling interactions, and paternal care.•Future work on extra-maternal influences is important to understand the development of behavior.
The early-life maternal environment has a profound and persistent effect on offspring neuroendocrine function, neurotransmitter systems, and behavior. Studies using rodent models suggest that early-life maternal care can influence the ‘developmental programming’ of offspring in part through altered epigenetic regulation of specific genes. The exploration of epigenetic regulation of these genes as a biological mechanism has been important to our understanding of how animals adapt to their environments and how these developmental trajectories may be altered. However, other non-maternal factors have been shown to act directly, or to interact with maternal care, to influence later-life phenotype. Based on accumulating evidence, including our research, we discuss other important influences on the developmental programming of offspring. We highlight early-life variations in temperature exposure and offspring genotype x environment interactions as prominent examples. We conclude with recommendations for future investigations on how early-life maternal care and extra-maternal influences lead to persistent changes in the brain and behavior of the offspring throughout development.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease of unknown etiology. Multiple studies point to disruptions in immune functioning in ME/CFS patients as well as ...specific genetic polymorphisms and alterations of the DNA methylome in lymphocytes. However, potential interactions between DNA methylation and genetic background in relation to ME/CFS have not been examined. In this study we explored this association by characterizing the epigenetic (~480 thousand CpG loci) and genetic (~4.3 million SNPs) variation between cohorts of ME/CFS patients and healthy controls. We found significant associations of DNA methylation states in T-lymphocytes at several CpG loci and regions with ME/CFS phenotype. These methylation anomalies are in close proximity to genes involved with immune function and cellular metabolism. Finally, we found significant correlations of genotypes with methylation modifications associated with ME/CFS. The findings from this study highlight the role of epigenetic and genetic interactions in complex diseases, and suggest several genetic and epigenetic elements potentially involved in the mechanisms of disease in ME/CFS.
•Maternal obesity and neonatal infection are linked to offspring psychopathology.•We examined their effects on anxiety, spatial memory, and related neural transcripts.•Maternal high-fat ...diet + neonatal LPS exposure altered stress-related mRNA levels.•Independent exposures did not affect anxiety phenotypes but impaired spatial memory.•Combined exposures normalized spatial memory-related gene expression and behavior.
Both neonatal infections and exposure to maternal obesity are inflammatory stressors in early life linked to increased rates of psychopathologies related to mood and cognition. Epidemiological studies indicate that neonates born to mothers with obesity have a higher likelihood of developing neonatal infections, however effects on offspring physiology and behavior resulting from the combination of these stressors have yet to be investigated. The aim of this study was to explore immediate and persistent phenotypes resulting from neonatal lipopolysaccharide (nLPS) administration in rat offspring born to dams consuming a high-fat diet (HFD). Neural transcript abundance of genes involved with stress regulation and spatial memory were examined alongside related behaviors. At the juvenile age point, unlike offspring exposed to maternal HFD (mHFD) or nLPS alone, offspring with combined exposure to mHFD + nLPS displayed altered transcript abundances of stress-related genes in the ventral hippocampus (HPC) in a manner conducive to potentiating stress responses. For memory-related phenotypes, juveniles exposed to mHFD + nLPS exhibited normalized spatial memory and levels of memory-related gene expression in the dorsal HPC similar to control diet offspring, while control diet + nLPS, and mHFD offspring exhibited reduced levels of memory-related gene expression and impaired spatial memory. These findings suggest that dual exposure to unique inflammatory stressors in early life can disrupt neural stress regulation but normalize spatial memory processes.
Maternal obesity as a result of high levels of saturated fat (HFD) consumption leads to significant negative health outcomes in both mother and exposed offspring. Offspring exposed to maternal HFD ...show sex-specific alterations in metabolic, behavioral, and endocrine function, as well as increased levels of basal neuroinflammation that persists into adulthood. There is evidence that psychosocial stress or exogenous administration of corticosterone (CORT) potentiate inflammatory gene expression; however, the response to acute CORT or immune challenge in adult offspring exposed to maternal HFD during perinatal life is unknown. We hypothesize that adult rat offspring exposed to maternal HFD would show enhanced pro-inflammatory gene expression in response to acute administration of CORT and lipopolysaccharide (LPS) compared to control animals, as a result of elevated basal pro-inflammatory gene expression. To test this, we examined the effects of acute CORT and/or LPS exposure on pro and anti-inflammatory neural gene expression in adult offspring (male and female) with perinatal exposure to a HFD or a control house-chow diet (CHD).
Rat dams consumed HFD or CHD for four weeks prior to mating, during gestation, and throughout lactation. All male and female offspring were weaned on to CHD. In adulthood, offspring were 'challenged' with administration of exogenous CORT and/or LPS, and quantitative PCR was used to measure transcript abundance of glucocorticoid receptors and downstream inflammatory markers in the amygdala, hippocampus, and prefrontal cortex.
In response to CORT alone, male HFD offspring showed increased levels of anti-inflammatory transcripts, whereas in response to LPS alone, female HFD offspring showed increased levels of pro-inflammatory transcripts. In addition, male HFD offspring showed greater pro-inflammatory gene expression and female HFD offspring exhibited increased anti-inflammatory gene expression in response to simultaneous CORT and LPS administration.
These findings suggest that exposure to maternal HFD leads to sex-specific changes that may alter inflammatory responses in the brain, possibly as an adaptive response to basal neuroinflammation.
•Humans, rodents, and wild mammals share biological generalities in maternal programming.•Maternal androgens, photoperiod, microbiome and immunity influence offspring phenotype.•Milk is a rich source ...of maternal hormones, microbiota, immune factors and exosomes.•Milk exosomes transfer microRNA into offspring cells and may induce biological changes.•The extent of maternal programming cannot be fully understood by examining a single cue.
The perinatal period is a sensitive time in mammalian development that can have long-lasting consequences on offspring phenotype via maternal effects. Maternal effects have been most intensively studied with respect to two major conditions: maternal diet and maternal stress. In this review, we shift the focus by discussing five major additional maternal cues and their influence on offspring phenotype: maternal androgen levels, photoperiod (melatonin), microbiome, immune regulation, and milk composition. We present the key findings for each of these topics in mammals, their mechanisms of action, and how they interact with each other and with the maternal influences of diet and stress. We explore their impacts in the contexts of both predictive adaptive responses and the developmental origins of disease, identify knowledge gaps and research opportunities in the field, and place a particular emphasis on the application and consideration of these effects in non-model species and natural ecological systems.
Predation is a key organizing force in ecosystems. The threat of predation may act to programme the endocrine hypothalamic-pituitary-adrenal axis during development to prepare offspring for the ...environment they are likely to encounter. Such effects are typically investigated through the measurement of corticosteroids (Cort). Corticosteroid-binding globulin (CBG) plays a key role in regulating the bioavailability of Cort, with only free unbound Cort being biologically active. We investigated the effects of prenatal predator odour exposure (POE) in mice on offspring CBG and its impact on Cort dynamics before, during and after restraint stress in adulthood. POE males, but not females, had significantly higher serum CBG at baseline and during restraint and lower circulating levels of Free Cort. Restraint stress was associated with reduced liver transcript abundance of
(CBG-encoding gene) only in control males. POE did not affect
promoter DNA methylation. Our results indicate that prenatal exposure to a natural stressor led to increased CBG levels, decreased per cent of Free Cort relative to total and inhibited restraint stress-induced downregulation of CBG transcription. These changes suggest an adaptive response to a high predator risk environment in males but not females that could buffer male offspring from chronic Cort exposure.
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