Amelia Cuarenta
Published: 2020
Total Pages: 132
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The data presented in the following chapters of this dissertation are meant to address how psychological and physiological stressors alter the retrotransposon, Line1, and how these changes may relate to behavioral outcomes with specific focus on biological sex as a covariate. A number of psychiatric disorders display a sex bias with women more often diagnosed with depression, anxiety and posttraumatic stress disorder (PTSD) while men are more often diagnosed with attention deficit hyperactivity disorder (ADHD) and substance abuse. Therefore, we hypothesized that early life stress would impact neonatal and juvenile development and that these changes may be dependent on biological sex (Chapter I). Specifically, we asked how exposure to stressful experiences early in life alters Line1 activity within the developing brain and if these adverse experiences resulted in altered Line1 DNA copy number within the genome. Line1 is a retrotransposon that has the ability to self-replicate via reverse transcription and insert itself into DNA, thereby increasing Line1 copy number throughout the genome. We present evidence that early life stress alters Line1 in a sex-specific manner in the neonatal hippocampus (Chapter II) suggesting that early life experiences have the propensity to affect Line1 activity altering the underlying genetic sequence. In Chapter III, we provide evidence that exposure to early life stress is capable of altering juvenile social behavior, indicating that early experiences have the propensity to affect long-lasting behavioral changes. Additionally, early life stress alters Line1 DNA copy number within the amygdala, consequently changing genetic sequences within this region during the juvenile stage of development. These data suggest that exposure to stressful experiences early in life has the capacity to alter genomic sequences within the brain in a region-specific manner, resulting in genomic heterogeneity. In Chapter IV, we then asked if a physiological stressor, binge alcohol consumption, alters Line1 activity. As preconception binge alcohol consumption has the capacity to influence social behavior of future offspring, we examined if Line1 is also altered in the offspring of parents that engaged in adolescent binge alcohol consumption. In addition, we examined how binge alcohol consumption influences Line1 activity in those offspring born from parents that engaged in adolescent alcohol consumption and if biological sex modified this response. We report that Line1 is altered in the offspring of parents that engaged in rapid alcohol intoxication during adolescence, and this response is influenced by biological sex. The data from this chapter suggest that some biological responses of engaging in adolescent alcohol consumption is transmitted to future offspring. As the frequency of Line1 retrotransposition is influenced by heterochromatin states, we then examined if early life stress alters the levels of topoisomerases, molecules implicated in modifying heterochromatin formation. In Chapter V, we find that experiencing stress early in life modifies some topoisomerases, proving a potential pathway by which early life stress can modify the activity of Line1 retrotransposition. Overall, our data demonstrates that psychological and physiological stressors alter Line1 activity and contributes to the idea that early life experiences have the capacity to reshape not only our epigenome but the underlying sequence as well.