Characterizing molecular profiles across puberty to identify the basis of sex-influenced gene expression from discrete brain cells.

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Introduction: Puberty plays an important role in altering brain dynamics, with both shared and distinct effects on males and females. The pubertal period consists of intense molecular, physiological and anatomical reorganization of the body, and represents a fundamental critical period associated with heightened brain plasticity. The vast hormonal-driven changes lay the framework for biological differences that persist throughout the lifespan. Importantly, the brain is comprised of numerous cell types and sub cell types that likely respond differently to these sex-specific hormonal changes. Tracking molecular changes in the brain in a regional, and cell-specific manner across puberty will give us enormous insight into how the brain reorganizes in response to this critical period, and ultimately how these changes may underlie sex differences in behavior and physiology. Main and Specific Objectives: The main aim of this research program is to track gene expression and DNA conformational changes within individual brain cells across the period of heightened plasticity induced by the hormonal surges during puberty. The long-term aim is to identify how these molecular changes result in sex-specific synaptic wiring patterns, in turn, influencing sex-specific behaviors. Specifically, we will use state-of-the-art single-cell omics techniques on complementary models, including rodent and human brains, and in vitro models, to profile the molecular changes that occur across this critical period and into adulthood. Methods: Well-characterized postmortem brain samples will be obtained from the Douglas-Bell Canada Brain Bank. These samples will come from healthy 14-17 year-old male and female donors with no history of psychiatric or neurological disorders. Given that studying human brain will only provide cross-sectional information, we will use rodents and cell models to generate data across time, thus producing trajectories of molecular changes. This will enable mapping cell-, regional- and sex-specific divergences in gene expression and DNA conformation across puberty. Cells will be subjected to various levels of male and female sex hormones, and collected along a time scale ranging from several minutes, to several days. Given that discrete cell types have both different, and sex-specific, availabilities of hormone receptors, for all models, cells will be studied at the individual level. State-of-the-art approaches routinely used in my laboratory will be employed to profile the transcriptomic and open chromatin profiles simultaneously. Impact: This research will molecularly characterize cells during the heightened brain plasticity associated with puberty, allowing us to better understand the nature of changes that occur to the structure and functional organization of the brain as it matures. These profiles will map out how male and female brains change during the pubertal period and elucidate some of the molecular underpinnings of sex-influenced behaviours.