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.
