Annual Research Review: Epigenetic mechanisms and environmental shaping of the brain during sensitive periods of development

Abstract

Experiences during early development profoundly affect development of the central nervous system (CNS) to impart either risk for or resilience to later psychopathology. Work in the developmental neuroscience field is providing compelling data that epigenetic marking of the genome may underlie aspects of this process. Experiments in rodents continue to show that experiences during sensitive periods of development influence DNA methylation patterns of several genes. These experience-induced DNA methylation patterns represent stable epigenetic modifications that alter gene transcription throughout the lifespan and promote specific behavioral outcomes. We discuss the relevance of these findings to humans, and also briefly discuss these findings in the broader contexts of cognition and psychiatric disorder. We conclude by discussing the implications of these observations for future research.

Figure 1

Epigenetic modifications in the CNS. Reversible and site-specific histone modifications occur at amino-acid residues of histone tails via histone modifying enzymes, some of which are depicted on the diagram. DNA methylation occurs at cytosine residues at the 5-position of the pyrimidine ring in a reaction catalyzed by DNA methyltransferases (DNMTs). DNA methylation is a reversible process, whereby several rounds of cell division without DNMT-mediated remethylation are necessary to erase epigenetic marks. Several active DNA demethylation pathways have also been proposed for post-mitotic cells, including the direct removal of methyl groups by a DNA demethylase (Bhattacharya, Ramchandani, Cervoni, & Szyf, 1999) or a Gadd45-coupled DNA repair-like process (Barreto et al., 2007; Ma et al., 2009). Together, these modifications provide a unique epigenetic signature that governs chromatin structure (active vs. closed) and thus gene transcription.

Figure 2

Effect of infant experience on DNA methylation of the Bdnf gene. Adult animals (at least 3 months old) that were maltreated as infants were found to have significant methylation of a regulatory region of the Bdnf gene (exon IV) in their prefrontal cortex in comparison to adults that had experienced either cross-foster care or remained with the biological mother (portrayed as the normal infancy group on the graph). Figure adapted from Roth et al., 2009a.

Figure 3

Effect of mother’s history on her maternal behavior. Left panel – Qualitative assessment of maternal behaviors directed toward infants in our maltreatment condition show that infants had overall experienced an adverse caregiving environment that was characterized by mainly abusive behaviors. Right panel – Qualitative assessment of maternal behaviors of females that had experienced our infant maltreatment regimen indicate that they grow up to display considerable abusive behaviors toward their own offspring. Please note that observation conditions in this experiment (homecage situated at eyelevel) also enabled us to determine whether females were displaying low vs. high nursing postures. Figure adapted from Roth et al., 2009a.

Figure 4

Effect of mother’s history on offspring DNA methylation patterns. Offspring of females that had been maltreated were found to have significantly higher levels of methylated Bdnf DNA in their prefrontal cortex (A) and hippocampus (B) in comparison to offspring from females that had a normal infancy. Data collected in panel A were from methylation-specific real-time PCR (2 Bdnf loci examined), and data collected in panel B were from direct bisulfite sequencing (Bdnf exon IV). (B) Cross-fostering of these offspring (Mal-Normal) did not completely rescue CNS DNA methylation, nor did it induce significant methylation in controls (Normal-Mal). Figure adapted from Roth et al., 2009a.