James P. Curley

Epigenetic mechanisms mediating the long-term effects of maternal care on development

The long-term consequences of early environmental experiences for development have been explored extensively in animal models to better understand the mechanisms mediating risk of psychopathology in individuals exposed to childhood adversity. One common feature of these models is disruption of the mother-infant relationship which is associated with impairments in stress responsivity and maternal behavior in adult offspring. These behavioral and physiological characteristics are associated with stable changes in gene expression which emerge in infancy and are sustained into adulthood. Recent evidence suggests that these long-term effects may be mediated by epigenetic modification to the promoter regions of steroid receptor genes. In particular, DNA methylation may be critical to maternal effects on gene expression and thus generate phenotypic differentiation of offspring and, through effects on maternal behavior of offspring, mediate the transmission of these effects across generations. In this review we explore evidence for the influence of mother-infant interactions on the epigenome and consider evidence for and the implications of such epigenetic effects for human mental health.

Epigenetics and the Origins of Paternal Effects

Though there are multiple routes through which parents can influence their offspring, recent studies of environmentally induced epigenetic variation have highlighted the role of non-genomic pathways. In addition to the experience-dependent modification of DNA methylation that can be achieved via mother-infant interactions, there has been increasing interest in the epigenetic mechanisms through which paternal influences on offspring development can be achieved. Epidemiological and laboratory studies suggest that paternal nutritional and toxicological exposures as well as paternal age and phenotypic variation can lead to variations in offspring and, in some cases, grand-offspring development. These findings suggest a potential epigenetic germline inheritance of paternal effects. However, it may be important to consider the interplay between maternal and paternal influences as well as the experimental dissociation between experience-dependent and germline transmission when exploring the role of epigenetic variation within the germline as a mediator of these effects. In this review, we will explore these issues, with a particular focus on the potential role of paternally induced maternal investment, highlight the literature illustrating the transgenerational impact of paternal experiences, and discuss the evidence supporting the role of epigenetic mechanisms in maintaining paternal effects both within and across generations.

Coadaptation in mother and infant regulated by a paternally expressed imprinted gene

This study investigates how a targeted mutation of a paternally expressed imprinted gene regulates multiple aspects of foetal and post–natal development including placental size, foetal growth, suckling and post–natal growth, weaning age and puberty onset. This same mutation in a mother impairs maternal reproductive success with reduced maternal care, reduced maternal food intake during pregnancy, and impaired milk let–down, which in turn reduces infant growth and delays weaning and onset of puberty. The significance of these coadaptive traits being synchronized in mother and offspring by the same paternally expressed imprinted gene ensures that offspring that have extracted ‘good’ maternal nurturing will themselves be both well provisioned and genetically predisposed towards ‘good’ mothering.

Vasopressin, oxytocin and social behaviour

Understanding the neurobiology of social behaviour in mammals has been considerably advanced by the findings from two species of vole, one of which is monogamous and pair bonds whereas the other species is promiscuous and fails to form any long-lasting social relationships. The combination of neurobehavioural studies and molecular genetics has determined behavioural differences between the two species linked to the neural distribution of vasopressin 1A receptor in the male brain. More importantly, vasopressin 1A receptor gene transfer including the upstream regulatory sequence has enhanced male social affiliation in a non-monogamous species. Male affiliative bonding depends upon release of both vasopressin and dopamine in the ventral striatum enhancing the reward value of odour cues that signal identity.

How social experiences influence the brain

Social experiences throughout life influence gene expression and behavior, however, early in development these influences have a particularly profound effect. In mammals, mother-infant interactions are the primary source of social stimulation and result in long-term changes in offspring phenotype. This has previously been demonstrated in rodents and primates, however, recent studies in rats have advanced our understanding of how these influences are achieved at a mechanistic level, through epigenetic modification, and provide a model for studying the transmission of social behavior across generations. These studies emphasize the importance of a life-history approach to the study of brain development; incorporating information about genetic background, prenatal and postnatal maternal care received, and post-weaning social interactions of an individual, in addition to the social environment experienced by previous generations.

Social influences on neurobiology and behavior: Epigenetic effects during development

The quality of the social environment can have profound influences on the development and activity of neural systems with implications for numerous behavioral and physiological responses, including the expression of emotionality. Though social experiences occurring early in development may be particularly influential on the developing brain, there is continued plasticity within these neural circuits amongst juveniles and into early adulthood. In this review, we explore the evidence derived from studies in rodents which illustrates the social modulation during development of neural systems, with a particular emphasis on those systems in which a long-term effect is observed. One possible explanation for the persistence of dynamic changes in these systems in response to the environment is the involvement of epigenetic mechanisms, and here we discuss recent studies which support the role of these mechanisms in mediating the link between social experiences, gene expression, neurobiological changes, and behavioral variation. This literature raises critical questions about the interaction between neural systems, the concordance between neural and behavioral changes, sexual dimorphism in effects, the importance of considering individual differences in response to the social environment, and the potential of an epigenetic perspective in advancing our understanding of the pathways leading to variations in mental health.

Social Enrichment during Postnatal Development Induces Transgenerational Effects on Emotional and Reproductive Behavior in Mice

Across species there is evidence that the quality of the early social environment can have a profound impact on neurobiology and behavior. In the present study we explore the effect of communal rearing conditions (three dams with three litters per cage) during the postnatal period on offspring (F1) and grand-offspring (F2) anxiety-like and maternal behavior in Balb/c mice. Females rearing pups in communal nests exhibited increased levels of postpartum maternal care and communal rearing was found to abolish sex-differences in weaning weights. In adulthood, communally reared offspring were observed to display reduced anxiety-like behavior when placed in a novel environment. When rearing their own offspring under standard conditions, communally reared females demonstrated higher levels of motivation to retrieve pups, built higher quality nests, and exhibited higher levels of postpartum care compared to standard reared females. When exposed to an intruder male, communally reared females were more subordinate and less aggressive. F2 offspring of communally reared females were observed to engage in reduced anxiety-like behavior, have larger litter sizes and an increased frequency of nursing on PND 1. Analysis of neuropeptide receptor levels suggest that a communal rearing environment may exert sustained effects on behavior through modification of oxytocin and vasopressin (V1a) receptor densities. Though Balb-C mice are often considered “socially-incompetent” and high in anxiety-like behavior, our findings suggest that through enrichment of the postnatal environment, these behavioral and neuroendocrine deficits may be attenuated both within and across generations.

Epigenetics, brain evolution and behaviour

Molecular modifications to the structure of histone proteins and DNA (chromatin) play a significant role in regulating the transcription of genes without altering their nucleotide sequence. Certain epigenetic modifications to DNA are heritable in the form of genomic imprinting, whereby subsets of genes are silenced according to parent-of-origin. This form of gene regulation is primarily under matrilineal control and has evolved partly to co-ordinate in-utero development with maternal resource availability. Changes to epigenetic mechanisms in post-mitotic neurons may also be activated during development in response to environmental stimuli such as maternal care and social interactions. This results in long-lasting stable, or short-term dynamic, changes to the neuronal phenotype producing long-term behavioural consequences. Use of evolutionary conserved mechanisms have thus been adapted to modify the control of gene expression and embryonic growth of the brain as well as allowing for plastic changes in the post-natal brain in response to external environmental and social cues.

Increased body fat in mice with a targeted mutation of the paternally expressed imprinted gene Peg3

Peg3 encodes a C2H2 type zinc finger protein that is implicated in a novel physiological pathway regulating core body temperature, feeding behavior, and obesity in mice. Peg3+/− mutant mice develop an excess of abdominal, subcutaneous, and intra‐scapular fat, despite a lifetime of lower food intake than wild‐type animals. However, they start life with reduced fat reserves and are slower to enter puberty. These mice maintain a lower core body temperature, fail to respond to a cold challenge, and have lower metabolic activity as measured by oxygen consumption. Plasma leptin levels are significantly higher than in wild types, and Peg3+/− mice appear to have developed leptin resistance. Administration of exogenous leptin resulted in a significant reduction in food intake in wild‐type mice that was not observed in Peg3+/− mutants. This mutation, which is strongly expressed in hypothalamic tissue during development, has the capacity to regulate multiple events relating to energy homeostasis.

Genomic imprinting mediates sexual experience-dependent olfactory learning in male mice

Mammalian imprinted genes are generally thought to have evolved as a result of conflict between parents; however, recent knockout studies suggest that coadaptation between mother and offspring may have been a significant factor. We present evidence that the same imprinted gene that regulates mammalian maternal care and offspring development also regulates male sexual behavior and olfaction. We have shown that the behavior of male mice carrying a knockout of the imprinted gene Peg3 does not change with sexual experience and that the mice are consequently unable to improve their copulatory abilities or olfactory interest in female odor cues after mating experience. Forebrain activation, as indexed by female odor-induced c-Fos protein induction, fails to increase with sexual experience, providing a neural basis for the behavioral deficits that the male mice display. The behavioral and neural effects of the Peg3 knockout show that this imprinted gene has evolved to regulate multiple and varied aspects of reproduction, from male sexual behavior to female maternal care, and the development of offspring. Moreover, sexual experience-driven behavioral changes may represent an adaptive response that enables males to increase their reproductive potential over their lifespan, and the effects we have found suggest that the evolution of genomic imprinting has been influenced by coadaptation between males and females as well as between females and offspring.