Functional analysis of hippocampal astrocytes in the regulation of adult neurogenesis

神经干细胞和祖细胞（NSPCs）终生生成和整合新神经元是海马可塑性的关键过程，最终需要严格的控制机制。除了内在调控外，NSPCs及其后代还依赖于来自其直接细胞环境的外在信号。星形胶质细胞是成体海马干细胞生态的主要组成部分，并已被证明控制着神经发生的几个步骤，从NSPC增殖到新神经元的分化和成熟。越来越多的证据表明，星形胶质细胞在不同脑区之间的异质性表明，星形胶质细胞在脑内稳态和神经可塑性方面具有区域特异性。有趣的是，我们最近发现了成人海马齿状回区域内星形胶质细胞的多样性。在这里，三种主要的星形胶质细胞亚型可以通过它们的形态和对特定海马结构的亚定位来区分。此外，这些星形胶质细胞具有亚型特异性的分子特性，可以根据标记基因的表达进行区分。因此，我们假设这些形态、位置和分子差异解释了成人神经发生过程中不同的功能特性。为了验证我们的假设，我们的第一个目标是建立一个体外系统，在这个系统中，我们将评估NSPCs的增殖能力以及后代的分化和成熟是否会受到不同星形胶质细胞亚型共培养的影响。此外，我们希望全面揭示不同水平（从转录组、翻译组到蛋白质组）定义海马星形胶质细胞亚型的分子特征，并仔细研究这些亚型调节神经发生的机制。我们的研究将极大地促进我们对星形细胞多样性及其对神经发生和海马可塑性的各种重要性的理解。

The life-long generation and integration of new neurons by neural stem and progenitor cells (NSPCs) is a key process to hippocampal plasticity and ultimately requires strict control mechanisms. In addition to intrinsic regulation, NSPCs and their progeny are dependent on extrinsic signals derived from their direct cellular environment. Astrocytes are major components of the adult hippocampal stem cell niche and have been shown to control several steps of neurogenesis ranging from NSPC proliferation to differentiation and maturation of new neurons. Increasing evidence for astrocyte heterogeneity among different brain areas suggests that astrocytes contribute region-specifically to brain homeostasis and neural plasticity. Interestingly, we recently identified intra-regional astrocyte diversity in the adult dentate gyrus of the hippocampus. Here, three major astrocyte subtypes can be distinguished by their morphology and sub-localization to specific hippocampal structures. Furthermore, these astrocytes reveal subtype-specific molecular properties and can be discriminated based on marker gene expressions. We therefore hypothesize that these morphological, positional, and molecular differences account for different functional properties during the process of adult neurogenesis. To test our hypothesis, our first aim is to establish an in vitro system in which we will assess if NSPCs proliferation capacity as well as differentiation and maturation of progeny may be affected by co-cultures with different astrocyte subtypes. Furthermore, we want to comprehensively disclose the molecular profile on different levels (from transcriptome, to translatome to proteome) that defines hippocampal astrocyte subtypes and scrutinize the mechanisms, through which these subtypes modulate neurogenesis. Our research will significantly promote our understanding of astrocyte diversity and its miscellaneous importance for neurogenesis and hippocampal plasticity.