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A21: Activity-dependent molecular control of the progression through the distinct precursor cell stages of adult hippocampal neurogenesis

Project leader: Prof. Dr. G. Kempermann

The key interest of the research group is how the multi-stage process of adult hippocampal neurogenesis is regulated, in particular with respect to molecular changes in response to behavioural activity. In our first funding period, we had followed the hypothesis that changes in redox potential in the neural precursor cells represents a fundamental switch underlying a multitude of regulatory events. We discovered that hypoxia induces a transient surge in intrinsic reactive oxygen species (ROS), which by itself is sufficient to trigger proliferation and survival.

We will now take a broader perspective, making use of the excellent opportunities for studies at the level of the transcriptome that the SFB provides. Building upon our previous work, we will examine how physical activity affects gene expression in cells at distinct stages of adult neurogenesis, focussing on precursor cell stages that can be isolated by FACS. Such sytematic representation of gene expression over the course of a defined developmental pathway, which is clearly regulated by activity, has not yet been performed. We hypothesize that exercise accelerates progression through programs characterized by transcription factor profiles, which in turn are associated with the stage-specific and coordinated activation of effector genes. We will relate ex vivo findings to parallel in vitro investigations, where we follow transcriptional changes during neuronal development in the adult hippocampus under standard conditions as well as manipulations mimicking aspects of activation in vitro (e.g. by addition of potassium chloride, glutamate, and growth factors). This will allow us to determine and compare “activity profiles” in vitro and ex vivo and from the comparison better judge, which regulatory mechanisms define the “stages” and “cell types” of adult neurogenesis. Validation experiments will confirm the assumed leading role of such pathways.

Extending ongoing work on modelling “neurogenesis” based on transcriptome networks, we will work on providing the framework to put candidate genes into the greater context. We will expand our online annotation and analysis platform MANGO (Mammalian adult neurogenesis gene ontology). As a final step, we will in an exemplary manner demonstrate how activity-dependent Notch signalling as neurogenic regulator is related to other molecular changes in vitro and in vivo. 

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Funding program:

DFG