Investigating the role of cell-autonomous ROS status in the regulation of hippocampal neural precursor cells in adult mice

Adult hippocampal neurogenesis entails a continued recruitment of neural precursor cells (NPCs) into active cell cycle and their progressive transition into post-mitotic granule cells. These adult born neurons integrate into the existing circuitry and confer structural plasticity, which aids in key hippocampal functions. For sustained neurogenesis, the cell cycle entry of the NPCs has to be tightly controlled. Environmental cues strongly, and differentially, regulate this checkpoint. Voluntary physical activity represents such an established strong stimulus that results in enhanced proliferation within the neurogenic niche. However, mechanistic insights into the maintenance and regulation of quiescence and the responsiveness of the NPCs to acute physical activity, as a form of adaptive neurogenesis, are yet to be elucidated. In my doctoral studies, we identified redox regulation as a key pathway regulating the cellular state equilibrium. I further explored the role of cellular oxidative stress in the neurogenic course and in adaptive neurogenic responses. Our results show that non-proliferative precursors within the hippocampal dentate gyrus, unlike in other stem cell systems, are marked by high levels of cellular reactive oxygen species (ROS). Using cytometric methodologies, ex vivo bioassays and transcriptional profiling, we revealed that classifying cells based on intracellular ROS content identified functionally defined sub-populations of adult NPCs. We propose that a drop in intracellular ROS content precedes the transition of cellular states, specifically from quiescence to active proliferation. Acute physical activity involves the activation of non- proliferating cells through a transient Nox2-dependent ROS surge in high-ROS, quiescent NPCs. In the absence of Nox2, baseline neurogenesis was unaffected, but the activity- dependent response was abolished. These findings shed new light on the discrete cellular events, which maintain the homeostasis between distinct cellular states of NPCs within the adult murine hippocampus.

Level thesis:degree_level

thesis.doctoral

Grantor dc:publisher

Technische Universität Dresden

Year

2020

Author dc:creator

• Adusumilli, Vijaya

Contributors dc:contributor

• Kempermann, Gerd
• Karl, Mike O.

• Adult neurogenesis
• neural stem cells
• quiescent stem cells
• redox regulation
• Adulte Neurogenese
• neurale Stammzellen
• ruhende Stammzellen
• Redox-Regulation