Caregiver experiences during early development profoundly affect development of the brain and behavior. Caregiver maltreatment imparts risk for later cognitive dysfunction and psychiatric disorders. An emerging idea is that epigenetic marking of the genome may underlie the genesis of these outcomes. However, this is based largely on correlational evidence and a causal relationship has not been established. Using a rodent model that we developed, we have shown that caregiver maltreatment induces aberrant methylation of DNA associated with the Brain-derived neurotrophic factor (Bdnf) gene within the prefrontal cortex (hypermethylation), amygdala (hypomethylation), and hippocampus (hypermethylation) of female rats. We have also shown that females when adult exhibit more anxiety-like behavior during gestation and mistreat their own offspring. Finally, we have shown that aberrant cortical Bdnf gene expression and DNA methylation patterns (hypermethylation) induced by caregiver maltreatment are reversible in adulthood by pharmacological manipulation of DNA methylation. The present project will utilize our rodent model to explore the central hypothesis that epigenetic gene changes are a basis for parenting behavior associated with caregiver maltreatment. The goal of the first aim is to determine whether pharmacological manipulation of DNA methylation improves behavior of maltreated-females. The goal of the second aim is to determine whether treatment of females with a demethylating agent at the time of maltreatment can prevent the emergence of aberrant methylation and maternal behavior. Finally, the goal of the third aim is to characterize gene-specific DNA methylation patterns in maltreated-females in brain regions associated with maternal behavior. These studies provide an innovative and informative approach for understanding the epigenetic consequences of exposure to an adverse caregiving environment. Furthermore, data generated from these studies will be the first to empirically establish a causal link between maltreatment-induced DNA methylation alterations and parenting behavior.

Public Health Relevance

This project explores an innovative hypothesis in evaluating the effects of maltreatment on maternal behavior and epigenetic mechanisms, giving us novel insight into typical and atypical behavioral development in females. This proposal will advance public health by elucidating molecular mechanisms of brain development relevant to the perpetuation of abusive caregiving.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Alvarez, Ruben P
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University of Delaware
Schools of Arts and Sciences
United States
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Keller, Samantha M; Doherty, Tiffany S; Roth, Tania L (2018) Pharmacological Manipulation of DNA Methylation in Adult Female Rats Normalizes Behavioral Consequences of Early-Life Maltreatment. Front Behav Neurosci 12:126
Doherty, Tiffany S; Roth, Tania L (2018) Epigenetic Landscapes of the Adversity-Exposed Brain. Prog Mol Biol Transl Sci 157:1-19
Boschen, K E; Keller, S M; Roth, T L et al. (2018) Epigenetic mechanisms in alcohol- and adversity-induced developmental origins of neurobehavioral functioning. Neurotoxicol Teratol 66:63-79
Walker, Claire-Dominique; Bath, Kevin G; Joels, Marian et al. (2017) Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential. Stress 20:421-448
Roth, Tania L (2017) Epigenetic Advances in Behavioral and Brain Sciences have Relevance for Public Policy. Policy Insights Behav Brain Sci 4:202-209
Doherty, Tiffany S; Blaze, Jennifer; Keller, Samantha M et al. (2017) Phenotypic outcomes in adolescence and adulthood in the scarcity-adversity model of low nesting resources outside the home cage. Dev Psychobiol 59:703-714