Functional heterogeneity and dynamic of astrocytes in the adult mouse hippocampus

大脑是神经元和神经胶质细胞之间的功能协作单位。在不同的大脑区域和发育阶段，这个单位的生理特性有所不同。在过去的几十年里，神经元的多样性得到了广泛的研究。最近的工作表明，星形胶质细胞在分子和功能上也是不同的，但对星形胶质细胞的异质性仍知之甚少。目前的研究大多集中在比较不同脑区或发育阶段的星形胶质细胞。然而，特定区域内星形胶质细胞的多样性是否以及在多大程度上有助于网络功能和可塑性尚未得到解决。使用遗传标记策略，我发现成年海马齿状回由形态不同的星形胶质细胞组成，这些星形细胞定位于特定的隔室。与普遍认为星形胶质细胞在未受损伤的成人大脑中是有丝分裂后的假设形成鲜明对比的是，初步实验显示，星形胶质细胞在成年齿状回中增殖。更令人惊讶的是，在特定刺激(自愿锻炼和衰老)的背景下，发现在形态上不同的星形胶质细胞表现出不同的增殖反应。在这里，我将追求一个新的假设，即齿状回是由分子和功能不同的星形胶质细胞组成的，其动力学是海马区适应不断变化的条件的关键调节器。不同星形胶质细胞亚型的“连接体”是什么？通过共聚焦显微镜和电子显微镜的结构分析和对不同生理条件下星形胶质细胞生成动力学的评估，将揭示星形胶质细胞亚型如何嵌入神经源性生态位，以及细胞相互作用和星形胶质细胞发生如何受到生理刺激的调节。成体星形胶质细胞的起源是什么？在目标2中，我将研究星形胶质细胞亚型和放射状胶质细胞样神经干细胞之间的潜在谱系关系。由于星形胶质细胞的结构异质性可能是其功能特性的反映，我的目标是通过单细胞测序识别星形胶质细胞亚型的分子指纹，作为目标3。该数据集将用于分析星形胶质细胞的不同分子特性，并为更好地靶向星形胶质细胞亚群寻找新的标记。总而言之，我的研究将极大地促进我们对同一区域星形胶质细胞的结构和分子多样性以及动态的理解。此外，它将为将来有选择地操纵星形胶质细胞亚型以解决其特定功能铺平道路。

The brain works as a functional co-operation unit between neurons and glial cells. This unit differs in its physiological properties in distinct brain regions and developmental stages. Neuronal diversity has been extensively investigated in the last decades. Recent works now suggests that also astrocytes are molecularly and functionally distinct, yet still very little is known about astrocyte heterogeneity. Most present studies focus on comparing astrocytes from different brain regions or developmental stages. However, if and to what extend astrocyte diversity within a specific region contributes to network function and plasticity has not been addressed yet. Using a genetic labeling strategy, I found that the adult hippocampal dentate gyrus is populated by morphologically distinct astrocytes that are localized to specific compartments. In sharp contrast to the prevailing assumption that astrocytes are postmitotic in the non-injured adult brain, preliminary experiments revealed proliferation of astrocytes in the adult dentate gyrus. Even more surprising was the finding that morphologically distinct astrocytes show a differential proliferation response in the context of specific stimuli (voluntary exercise and ageing). Here, I will pursue the novel hypothesis that the dentate gyrus is composed of molecularly and functionally distinct astrocytes whose dynamics are critical modulators for hippocampal adaption to changing conditions. What is the "connectome" of distinct astrocyte subtypes? Structural analysis by confocal and electron microscopy and assessment of the dynamics of astrocyte generation under distinct physiological conditions will reveal how astrocyte subtypes are embedded into the neurogenic niche and how cellular interactions and astrogenesis are modulated by physiological stimuli. What is the origin of adult generated astrocytes? In aim 2, I will investigate potential lineage relationships of astrocyte subtypes and radial glia-like neural stem cells. As structural heterogeneity of astrocytes may be a reflection of their functional properties, I aim to identify the molecular fingerprint of astrocyte subtypes by single-cell sequencing as aim 3. This data set will be used to analyse distinct molecular properties of astrocytes and to identify new markers for better targeting of astrocyte subgroups. Collectively, my studies will significantly promote our understanding of structural and molecular diversity and dynamic of astrocytes populating the same region. Furthermore, it will pave the way for selectively manipulating astrocyte subtypes in the future to address their specific functions.