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

表征整个青春期的分子谱，以确定离散脑细胞中受性别影响的基因表达的基础。

• 批准号: RGPIN-2022-03979
• 负责人: Nagy, Corina
• 金额: $ 2.04万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763667
• 关键词: Characterizing; molecular; profiles; across; puberty

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.

青春期在改变大脑动力学方面起着重要作用，对男性和女性都有共同和不同的影响。青春期包括身体的强烈分子，生理和解剖重组，代表了与大脑可塑性增强相关的基本关键时期。巨大的大脑驱动的变化奠定了贯穿整个生命周期的生物学差异的框架。重要的是，大脑由许多细胞类型和亚细胞类型组成，这些细胞类型和亚细胞类型可能对这些性别特异性激素变化有不同的反应。以区域和细胞特异性的方式跟踪青春期大脑中的分子变化，将使我们深入了解大脑如何在这个关键时期进行重组，以及最终这些变化如何成为行为和生理性别差异的基础。主要和具体目标：这项研究计划的主要目的是跟踪基因表达和DNA构象的变化在个体脑细胞在整个时期的可塑性提高诱导的激素激增在青春期。长期目标是确定这些分子变化如何导致性别特异性突触布线模式，进而影响性别特异性行为。具体来说，我们将使用最先进的单细胞组学技术在互补模型上，包括啮齿动物和人类大脑，以及体外模型，以描述在这个关键时期和成年期发生的分子变化。方法：将从道格拉斯-贝尔加拿大脑库获得充分表征的死后脑样本。这些样本将来自健康的14-17岁男性和女性供体，无精神病或神经系统疾病史。鉴于研究人类大脑只能提供横截面信息，我们将使用啮齿动物和细胞模型来生成跨时间的数据，从而产生分子变化的轨迹。这将使映射细胞，区域和性别特异性差异的基因表达和DNA构象在整个青春期。将细胞置于不同水平的雄性和雌性性激素中，并在沿着从几分钟到几天的时间范围内收集。鉴于离散细胞类型具有不同的和性别特异性的激素受体可用性，对于所有模型，将在个体水平上研究细胞。国家的最先进的方法，在我的实验室常规使用的转录组和开放的染色质同时配置文件。影响力：这项研究将从分子上表征与青春期相关的大脑可塑性增强期间的细胞，使我们能够更好地了解大脑成熟时结构和功能组织发生变化的性质。这些图谱将描绘出男性和女性大脑在青春期的变化，并阐明性别影响行为的一些分子基础。