Aerobic exercise is well know to promote neuroplasticity and hippocampal memory. More recent studies suggest that early-life exercise (EX) can lead to lasting improvements in hippocampal function; however, the molecular mechanisms of this phenomenon are not understood. Histone post translational modifications (HPTMs) are strong candidates for bridging the gap between environmental experiences and altered gene expression. Epigenetic mechanisms such as HPTMs can be persistent or transient and can have lasting influences on neuronal function. This dissertation investigates epigenetic mechanisms a possible explanation for the effect of EX on memory and develops tools for that investigation. In chapter 2 we develop a mouse model and a novel method for coupling epigenetic information and translating mRNA in hippocampal neurons. A Emx1-Cre2 mouse was crossed with a NuTRAP3 mouse to produce a transgenic line we call Emx1-NuTRAP. This mouse expresses a cassette in hippocampal neurons which labels both the nucleus and ribosomes in a way that allowed us to develop a novel method we call “SIT” (simultaneous isolation of nuclei in targeted cell types (INTACT) and translating ribosomal purification (TRAP)) to isolate both translating mRNA and intact nuclei from the same set of cells. We applied our lab’s EX model to the Emx1-NuTRAP mouse, followed by the SIT method from hippocampal tissue to identify an epigenetic and translational signature of EX as it relates to improved memory (Chapter 3). These data revealed activation of neuroplasticity genes engaged by EX, and implicated critical upstream regulators. Chapter 4 demonstrates that EX-induced epigenetic changes correlate with altered gene expression during consolidation that may underly EX-induced enabled memory. We discovered a distinct set of genes that had new histone PTMs after EX that have altered expression during memory consolidation. This suggests that neuronal chromatin in hippocampus may be “primed” by EX-induced new histone PTMs Finally, Chapter 5 describes a novel method for tracking the individual running of group housed juvenile mice. We constructed an RFID tracking system and correlate it with running using a software we developed in-house. This technique could be used to identify a threshold dose of EX for enabling of memory. Taken together, we lay the foundations for the study of epigenetics as a key underlying mechanism of EX enabled memory and identify candidate mechanisms with novel techniques.

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.