Functional analysis of hippocampal astrocytes in the regulation of adult neurogenesis

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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.