Poverty, inattention, abuse, and displacement are all examples of early-life stresses experienced by millions of children worldwide and within our own communities. Both human and rodent studies have associated early-life adversity (ELA) with hippocampal long-term memory impairments in later life.1–4 In contrast, exercise in rodents has been associated withimprovements in hippocampal long-term memory5–7 and changes in histone post-translational modifications (hPTM). 8–10 Our lab developed a mouse model of early-life exercise (early Ex) during the 4th-6th postnatal week that improves hippocampal memory11 and engages hPTMs to influence memory-associated gene expression.12 We discovered that exercise during the 4th postnatal week alone was sufficient to improve cognition despite a two-week cessation in running.11 Therefore, early Ex may target a critical window of hippocampal development to engage epigenetic mechanisms to offset the cognitive deficits associated with ELA. This dissertation investigates the efficacy of early Ex intervention to ameliorate ELA-induced cognitive deficits and the epigenetic mechanisms engaged by these early-life experiences. In chapter 1, we investigate the behavioral effects of ELA with or without early Ex intervention on short-term spatial memory, long-term spatial memory, and anxiety-like behavior. We discovered that early Ex intervention can alleviate long-term spatial memory deficits in middle-aged mice with a history of ELA. Chapter 2 describes our novel mouse model, Emx1-NuTRAP, for simultaneous isolation of neuronal translating mRNA and nuclei. Using this model, we identified genes that are epigenetically “primed” for expression during a learning stimulus. Additionally, we uncovered a histone lysine demethylase, Kdm7a, whose expression is increased by early Ex. In chapter 3, we study the expression of Kdm7a in dorsal hippocampus and medial prefrontal cortex. Additionally, we identified a signature of H3K27 methylation states following early Ex with or without prior ELA that suggested a potential role for Kdm7a activity. Finally, chapter 4 investigates early Ex and ELA translatomic signatures in adulthood. We identified candidate genes whose expression may be reversed by early Ex intervention. This body of work provides a foundation for examining the neuroepigenetic effects of early Ex intervention to offset ELA-induced cognitive deficits and provides targets for future therapeutic strategies.