Sex Differences in Astroglial Cells in Telencephalic Development and Plasticity

从神经解剖学到行为，性别差异都存在。因此，描述发育过程中神经系统构建的性别差异对于理解性别对成人大脑功能系统级神经科学的贡献至关重要。大量研究已经确定星形胶质细胞在所有中枢神经系统功能中起着关键作用，包括神经元和神经元网络的发育和维持。考虑到星形胶质细胞参与神经网络功能，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可能并不奇怪。事实上，星形胶质细胞表达性激素受体，并对激素调控表现出快速反应，然而很少有研究检测星形胶质细胞在端脑发育中的性别差异。我们最近使用翻译核糖体亲和纯化和RNA测序（TRAPseq）对男性和女性在关键发育时间点和成年期的整个星形胶质翻译组进行表型分析。总的来说，我们发现在早期和晚期发育之间有两种不同的星形胶质细胞表型，与性别无关。然而，星形胶质翻译体在发育过程中也表现出明显的基因表达模式的性别差异，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，雄性似乎比雌性更早达到成熟的星形胶质细胞表型。引起这些性别差异的机制尚不清楚，尽管有人可能假设这些性别差异与循环性激素水平有关。然而，出生后的第二个星期标志着性激素在很大程度上处于休眠状态的一个独特时期，这表明我们的研究结果可能不能反映体内激素水平。相反，我们假设星形胶质细胞基因表达模式的性别差异更可能是由围产期暴露于参与性别分化的激素和/或由性连锁染色体直接诱导的发育程序的一部分。在Aim 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基因表达模式的贡献，以及我们发现雄性更早达到“成熟”或“晚期”表型。在Aim 2中，我们将集中研究我们的数据集所提示的性别差异之一的功能结果，特别是雌二醇对神经元突触的星形胶质诱导。为了实现这一目标，我们将采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对神经元网络发育和功能的贡献。

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.