The role of DNA methylation in phenotypic outcomes of experiencing caregiver maltreatment
Date
2018
Authors
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Publisher
University of Delaware
Abstract
Caregiving received during development plays a critical role in programming brain development and behavioral trajectories. Receiving maltreatment by the caregiver can have grave, life-long consequences including poor physical health, cognitive dysfunction, and increased propensity to develop psychiatric illnesses. While the mechanisms through which early-life adverse experiences are able to induce long-term effects on the individual continue to be investigated, epigenetic alterations have emerged as a promising candidate. Epigenetic modifications, including DNA methylation, are capable of altering gene expression without altering the underlying genomic sequence. Therefore, alterations to the epigenome provide a way for experiences to produce changes at the molecular level that manifest into changes in brain function with implications for behavior. ☐ The Roth Lab employs a rodent model, the scarcity-adversity model of low nesting resources outside the home cage, to explore the neurobiological and behavioral consequences of experiencing caregiver maltreatment. This model involves exposing pups to brief but repeated bouts of maltreatment (30 minutes) daily from postnatal days 1-7. Using this model, we have discovered a number of behavioral and epigenetic aberrations induced by caregiver maltreatment. We hypothesize that the maltreatment-induced epigenetic alterations are causally related to behavioral outcomes. However, empirical data demonstrating a causal relationship between epigenetic alterations and behavior in the scarcity-adversity model are lacking. ☐ Female subjects are largely underrepresented in the scientific literature. However, it is well established that the implications of exposure to stress across the lifespan are sex-specific. Indeed, the Roth Lab has identified a number of sex differences in the consequences of maltreatment, with deleterious outcomes of maltreatment being more numerous in female subjects. For example, female rats subjected to maltreatment exhibit increased levels of adverse care toward their own offspring and altered behavior in the novel object and forced swim tests. Reasons underlying this sex disparity are unclear. While there are known sex differences in nurturing care provided toward offspring (dams lick their male pups more than the females) it is not known if sex differences exist in adverse caregiving. ☐ The goals of this dissertation were to: 1) examine the relationship between DNA methylation and phenotype; 2) explore the possibility for the epigenome-altering drug, zebularine, to rescue behavioral outcomes of maltreatment in adult animals; and, 3) explore reasons underlying sex differences in maltreatment outcomes. Chapter 1 reviews data regarding the influence of environmental factors on the epigenome of the female brain and associated behavioral outcomes, particularly in the context of environmental perturbations occurring during development. Experiments comprising this dissertation employed the scarcity-adversity model of low nesting resources outside the home cage. In experiments detailed in Chapter 2, females were subjected to the scarcity-adversity model as infants and then as adults administered zebularine at a dose and schedule previously shown to rescue DNA methylation. The number of adverse behaviors dams directed toward their offspring were recorded. We replicated our previous finding that dams with a history of maltreatment mistreat their own offspring and extended this to show that zebularine administration normalized maternal behavior in maltreated dams. Further, seven days of zebularine administration disturbed maternal behavior in animals with no history of maltreatment, such that these animals showed enhanced levels of adverse behavior toward their offspring relative to their vehicle-treated counterparts. ☐ To see if zebularine could normalize other behavioral aberrations induced by maltreatment, we next sought to examine the capacity for zebularine to normalize behavior in the novel object and forced swim tests in adult female animals. The same infant manipulations and drug regimen as used in Chapter 2 were utilized for experiments in Chapter 3. Following seven days of drug or vehicle administration, adult female animals were run through a battery of behavioral tests including the open field test, novel object recognition, and the forced swim test. In the forced swim test, maltreated females showed an increased latency to their first bout of immobility, and seven days of ICV zebularine treatment normalized this behavior. We did not find any group differences in the open field test or novel object recognition. Together, data from Chapters 2 and 3 demonstrate the capacity for behavioral outcomes of infant maltreatment to be rescued by a pharmacological intervention in adulthood. Further, these data provide support for a causal link between the epigenetic and phenotypic outcomes of experiencing maltreatment. ☐ Chapter 4 of this dissertation sought to examine potential sex differences in adverse care received in the scarcity-adversity model. To do this, adverse behaviors directed toward pups of each sex in the scarcity-adversity model were recorded. Results indicated that, in the maltreatment condition, female pups received more adverse behaviors from the dam relative to their male littermates. These data lend support to our hypothesis that outcomes of maltreatment in the scarcity-adversity model of low nesting resources are more numerous for female subjects because they experience higher levels of adverse behavior. ☐ These studies provide seminal evidence supporting a causal link between maltreatment-induced DNA methylation and behavioral outcomes in the scarcity-adversity model of low nesting resources. These experiments also show the experience-dependent nature of the behavioral impact of epigenome-modifying drugs, such as zebularine. Further, results highlight the importance of exploring sex differences in caregiving when interpreting data from models of early-life maltreatment.
Description
Keywords
Biological sciences, Psychology, Caregiver maltreatment, DNA methylation, Phenotypic outcomes