Epigenetic and Neurodevelopmental Consequences of Early Life Experience

Individual development is influenced by both genetic processes and environmental factors,
which interact throughout the lifespan. In mammals, early life parental care is particularly important in setting up developmental trajectories with long lasting consequences for physiology and behavior. In humans, early life stress which is often in the form of reduced parental care is associated with accelerated developmental outcomes and increased risk of mood disorders later in life. Research on neurobiological mechanisms mediating the impacts of early life parental care on these outcomes is generally completed in mice and rats, species which typically only provide maternal care in laboratory settings. Prairie voles are a laboratory rodent species which serve as a model of human-like social behaviors: they form monogamous pair bonds, and critically, both mothers and fathers provide parental care to the pups. In prairie voles and other rodents, animals raised with higher parental care are more social later in life. Prairie voles raised with high parental care are display more alloparental behavior as juveniles and have increased propensity to form a pair bond and provide high parental care to their own pups as adults.
One well studied mechanism which partially mediates the effects of early life parental care on social behavior later in life is the oxytocin system. Oxytocin is a neuropeptide hormone which regulates social behavior throughout the lifespan. Oxytocin acts primarily by binding to its one known receptor, the oxytocin receptor. In voles, the distribution of the oxytocin receptors in the brain differentiates between monogamous and non-monogamous species, and within prairie voles, the amount of oxytocin receptors in key brain regions is associated with species-typical social behaviors including pair bonding and parental care. While much work is done on the oxytocin system in prairie voles, many other neurobiological systems are involved in such complex behaviors.
This dissertation investigates how early life social experiences impact neurodevelopmental outcomes, in part by examining epigenetic regulation of gene expression. In Chapter 2, I examine how early life experience in the form of parental care impacts gene regulation of the oxytocin receptor. I examine two regions of the oxytocin receptor gene (Oxtr) promoter, a region termed MT2 and a region within exon 3. I find that while early nurture is associated with reduced DNA methylation in both MT2 and exon 3, only DNA methylation in MT2 is strongly associated with oxytocin receptor gene expression. Further, I identify a novel isoform of Oxtr which is under genetic control and is coregulated with the main transcript.
In Chapter 3, I use RNA-seq to identify genome-wide transcriptional changes associated with early nurture, which reveals differential gene expression in male offspring but not female offspring. I also examine neuroanatomical outcomes and find that in male offspring only, higher care by fathers leads to more excitatory synapses characterized by small-area terminals and shorter synaptic zones. I also find that in both sexes higher total parental care is associated with higher density of microglia. I then examine social behavior and find that male prairie voles raised with higher care by fathers is display more pup retrieval behavior as juveniles, while female offspring appear to display fewer pup retrievals. Finally, I show that high total parental care slows development, as indexed by epigenetic age.
In Chapter 4, I study the impact of adolescent social experiences on epigenetic age, a blood-derived metric for biological aging and healthspan, in humans. Using samples from the longitudinal KLIFF/VIDA study, I find that adolescents that experience peer struggles (i.e. lack of social connectedness, insecure attachments, etc.) have higher epigenetic age in midlife, indicating that positive social experiences are protective against biological aging and poor health outcomes. Further, the effect size of poor peer relationships on epigenetic age is comparable to that of lifetime history of cigarette smoking, suggesting that individual and public health outcomes are as highly influenced by social relationships as other environmental factors with known impacts on healthspan.