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Abstract

We do not yet fully comprehend the biological mechanisms through which developmental experiences influence adult behavioral patterns. This is, in part, because maturation- and experience-dependent mechanisms of plasticity intersect dynamically to regulate the neural properties (e.g., cell number, subtype, functionality, connectivity) that constrain developmental learning. These neural properties are largely determined by the complement of protein-coding and noncoding RNAs transcribed from the genome. Transcription is regulated by transcription factors (TFs), proteins that coordinate the expression or repression of gene sets that orchestrate shifts in functional and structural cell properties through binding regulatory regions of the genome (i.e., enhancers, promoters, and repressors) and interacting with components of basic transcriptional machinery as well as other TFs. Due to their role in influencing cell-type-specific transcription, regulatory region accessibility profiles can be used to differentiate between cellular subtypes with a great deal of specificity. Epigenetic modifications, such as those on histone proteins, modulate regulatory region accessibility. Once such modification, H3K27ac, reliably denotes accessible regulatory regions. To determine the neural properties and identify the cellular subtypes that support and limit the learning of complex behavior, I performed chromatin immunoprecipitation for H3K27ac and high-throughput DNA sequencing (ChIP-Seq) on auditory forebrains of male and female zebra finches spanning developmental time points (post-hatch (P) day 23, P30, P60, and P67) at which song experience has differing influence on adult behavioral patterns. The first experimental chapter (Chapter 2) of this dissertation focuses on elucidating the biological prerequisites for developmental experience to be encoded such that it can influence adult behavioral patterns. The second experimental chapter (Chapter 3) of this dissertation focuses on understanding how developmental experience influences existing biology to prevent future experiences from altering established behavioral patterns. In each chapter, I investigate how regulatory region accessibility profiles differ between organisms differing in developmental state of receptivity (i.e. capable and incapable of learning) and age-matched animals of opposite sex. I identify transcription factor binding sites enriched in regulatory regions differing in accessibility between comparisons, identified putative genes under their regulation, and discuss the potential implications of these differences on brain development and function in the context of learning and memory formation. Additionally, in Chapter 3, I use age-matched male birds reared to P67 in environments controlling for experience and degree of social interaction to parse the roles of maturation and experience in establishing regulatory region accessibility profiles. In Chapter 4, I discuss an opportunity to leverage the obtained data to label and manipulate the putative cell populations responsible for memory encoding and present some preliminary data collected with this goal in mind. Finally, in Chapter 5 I discuss some interesting results that emerged from the collective analysis of this data and reflect on observations regarding the nature of bioinformatic analyses.

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