At the right time and place – identifying epigenetic and molecular determinants of a developmental learning window

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Summary. Despite the plethora of ways that developmental experience influences long-term patterns of behavior, our mechanistic understanding of how this occurs is limited. The long-term goal of this research program is to elucidate the intersection of maturational and experience-dependent mechanisms that support behavioral acquisition across development. The objective of this application is to identify the epigenetic and molecular signatures of select cells recruited for developmental learning in juveniles. Here, we build on our recent preliminary data that repeatable, spatially-discreet cell populations initiate a molecular response required for memory formation at an age when learning is possible, but not before, and differently between males and females. This provides a unique opportunity to track the changes that occur within a brain region as development proceeds and comes “on-line” for encoding experience such that it determines adult behavioral patterns. In contrast to the explosion of sequencing technology-based discoveries about brain cells in adults, only a few factors are known to track with developmental learning. Identifying the properties of individual cells and their networks as they shift functionally across juvenile development would be useful for discovery of other brain systems that undergo developmental functional fluctuations and ultimately to move towards remediation efforts and enrichment programs targeted for peak phases of developmental receptivity to experience. The central hypothesis is that epigenetic and molecular regulatory processes define individual cells and their relationships differently depending on an individual’s age and sex, creating combinations that support learning at the onset of a natural learning phase. The PI has expertise in mechanisms of brain development and behavior including epigenetics and molecular biology as means to find causal relationships of juvenile experience to adult behavior. The co-Investigator’s expertise in single cell sequencing methods and analysis is complementary. The objectives will be accomplished by pursing two specific aims 1) To identify properties of the auditory forebrain that support molecular activation required for behavioral effects, and 2) To predict cell responsivity based on baseline chromatin accessibility and RNA profiles. A combination of state-of-the-art sequencing methods, and innovative analysis across platforms and datasets, will discover new relationships between chromatin structure and RNA populations, new cell subtypes, and the relationships between them, that predict the ability to learn in sex-specific ways. Using a molecular marker for cells recruited for learning, we will then co-localize these baseline cell features with functional ones. The proposed research thus begins to fill a void in developmental neurobiology by applying an unprecedented level of detail to the structural organization of functional networks. Elucidating and establishing mechanisms underlying the organization of developing brain to encode experience is the key to breaking through to a new productive era for testing novel ways that maturation and experience-dependent processes shape neural networks to promote or limit learning.