Sex Differences in Astroglial Cells in Telencephalic Development and Plasticity

星形胶质细胞在端脑发育和可塑性方面的性别差异

• 批准号: RGPIN-2022-04898
• 负责人: Salmaso, Natalina
• 金额: $ 2.33万
• 依托单位: Carleton 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=761437
• 关键词: Sex; Differences; Astroglial; Cells; Telencephalic

Sex differences exist from neuroanatomy to behaviour. As such, characterising sex differences in the building of neural systems over development is essential to understanding the contributions of sex to systems level neuroscience in adult brain functions. A great deal of research has identified astroglial cells as critical players in all central nervous system functions, including in the development and maintenance of neurons and neuronal networks. Given the involvement of astroglial cells in neuronal network function, it is perhaps not surprising that astroglial cells also show sex differences in morphology, gene/protein expression patterns and functions. Indeed, astroglial cells express sex hormone receptors and show rapid responses to hormonal manipulations, however few studies have examined sex differences in astroglial cells in telencephalic development. We recently used translating ribosome affinity purification together with RNA sequencing (TRAPseq) to phenotype the entire astroglial translatome in males and females at key developmental time points and in adulthood. Overall, we found two distinct astroglial phenotypes between early and late development, independent of sex. However, the astroglial translatome also showed marked sex differences in gene expression patterns over development, many of which were generally related to synapses and synaptic formation. Peak sex differences occurred during the second postnatal week, with males appearing to reach the mature astroglial phenotype earlier than females. The mechanism which induces these sex differences remains unknown, although one might hypothesize that these sex differences would be related to circulating sex hormone levels. However, the second postnatal week marks a unique time in development where sex hormones are largely dormant, suggesting that our findings are likely not reflective of in situ hormone levels. Instead, we hypothesize that sex differences in astroglial gene expression patterns are more likely part of a developmental program induced by perinatal exposure to hormones involved in sexual differentiation and/or directly induced by sex-linked chromosomes. In Aim 1, we will investigate the contribution of sex chromosomes and/or the perinatal sex hormones to the sex-specific astroglial gene expression patterns we observed and our finding that males reach the "mature" or "late" phenotype earlier. In Aim 2, we will focus our studies to examine the functional outcome of one of the sex differences suggested by our dataset, specifically the astroglial induction of neuronal synapses by estradiol. To achieve this, we will employ a range of tools and techniques including transgenic models and TRAPseq. The findings generated by the proposed studies will contribute to our understanding of general patterns in cortical development, sex differences in development and, finally to continue to elucidate astroglial contributions to neuronal network development and function.

性别差异从神经解剖学到行为都存在。因此，在神经系统的发育过程中表征性别差异，对于理解性别对成人大脑功能的系统水平神经科学的贡献是至关重要的。大量研究表明，星形胶质细胞在中枢神经系统的所有功能中起着关键作用，包括在神经元和神经元网络的发育和维持中。鉴于星形胶质细胞参与神经元网络功能，星形胶质细胞在形态、基因/蛋白表达模式和功能上也表现出性别差异也许并不令人惊讶。事实上，星形胶质细胞表达性激素受体，并对激素操作表现出快速反应，但很少有研究考察端脑发育过程中星形胶质细胞的性别差异。我们最近使用翻译核糖体亲和纯化和RNA测序(TRAPseq)相结合的方法，在关键发育时间点和成年期对整个星形胶质细胞翻译组进行了表型分析。总体而言，我们发现在发育早期和晚期有两种不同的星形胶质细胞表型，与性别无关。然而，星形胶质细胞翻译组在发育过程中的基因表达模式也显示出显著的性别差异，其中许多通常与突触和突触形成有关。性别差异的高峰出现在出生后第二周，男性似乎比女性更早达到成熟的星形胶质细胞表型。导致这些性别差异的机制尚不清楚，尽管人们可能假设这些性别差异与循环性激素水平有关。然而，出生后的第二周标志着一个独特的发育时期，性激素在很大程度上处于休眠状态，这表明我们的发现可能不能反映原位的激素水平。相反，我们假设星形胶质细胞基因表达模式中的性别差异更有可能是由围产期暴露于与性别分化相关的激素和/或性染色体直接诱导的发育程序的一部分。在目标1中，我们将研究性染色体和/或围产期性激素对我们观察到的性别特异性星形胶质细胞基因表达模式的贡献，我们的发现是男性更早达到“成熟”或“较晚”的表型。在目标2中，我们将重点研究我们的数据集提出的性别差异之一的功能结果，特别是雌二醇诱导神经元突触的星形胶质细胞。为了实现这一目标，我们将使用一系列工具和技术，包括转基因模型和TRAPseq。这些研究的结果将有助于我们理解大脑皮层发育的一般模式、发育中的性别差异，并最终继续阐明星形胶质细胞对神经元网络发育和功能的贡献。