Social influences on neurobiology and behavior: epigenetic effects during development

Abstract

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.

Figure 1. Illustration of the social modulation of oxytocin receptor levels in the rodent brain during postnatal and juvenile development

Social experiences occurring during the postnatal period, in the form of variation in mother-infant interactions, maternal separation, and communal nursing, and extending into juvenile development (late weaning, post-weaning variation in social housing), have been demonstrated to alter oxytocin receptor (OTR) levels in the brain. Indicated in the figure are findings highlighting these influences, which illustrate region-specific effects on OTR in response to the social environment. It is important to note that the impact of a particular social experience will vary dependent on the species, sex, and timing of the experience. The complexity of effects on OTR levels highlights the diverse pathways through which experiences occurring during development can alter functioning within neural systems which shape behavior. (BNST – bed nucleus of the stria terminalis; CeA – central amygdala; CP – caudate putamen; LS – lateral septum; MPOA – medial preoptic area; PVN –paraventricular nucleus; VMH – ventromedial hypothalamus).

Figure 2. Variations in early life maternal stimulation can alter offspring gene expression via epigenetic mechanisms

A) AVP exons 1, 2, and 3 (numbered white boxes) are separated from oxytocin exons (white box labeled OT) by a highly conserved intergenic region (IGR). CpG DNA methylation sites cluster in four islands (CGI 1–4; grey boxes marked i, ii, iii, iv), with DNA methylation at specific CpG sites within CGI3 (such as CpG10 marked by * which acts as a binding site for MeCP2) being the most significant for AVP mRNA expression. By PN10, maternal separation induces the phosphorylation of MeCP2 (via activation of the protein kinase CaMKII) preventing its functioning, reducing DNA methylation (M) and increasing AVP mRNA expression. These changes in methylation and gene expression persist into adulthood. B) In the intronic region between exons 1 and 2 (white boxes) of the CRH gene lies its regulatory region that contains a 21 bp sequence (NRSE) that is specifically bound to by the transcriptional repressor NRSF, which then recruits cofactors and induces epigenetic modification of gene expression. By day PN9, handled rat offspring show increased binding of NRSF to the NRSE that reduces CRH gene expression in the PVN permanently into adulthood. C) Exon 1 of the rat hippocampal GR gene contains multiple regulatory regions that are able to activate gene transcription including the brain-specific exon 1₇ promoter which contains an NGFI-A binding sequence (marked by *). High levels of tactile stimulation in the form of maternal LG increases the levels of intracellular 5-HT in the hippocampus which activates protein kinase and CREB signaling pathways leading to elevated levels of NGFI-A. When NGFI-A is bound to its binding site on the exon 1₇ promoter it recruits the HAT CREB-binding protein (CBP) and the DNA demethylase MBD2 to increase histone acetylation and decrease DNA methylation (M). This demethylation takes place by day PN6 and persists to adulthood.