Epigenetic control of hippocampal stem cells: modulation by hyperactivation, glucocorticoids and aging

The adult brain has the ability to structurally and functionally adapt to changes in its environment. Examples of these adaptations are the addition of new neurons to neurogenic regions such as the hippocampal dentate gyrus, termed adult hippocampal neurogenesis, and alterations in neuronal connections at synaptic sites. Both of these forms of plasticity are heavily regulated at multiple molecular levels, not all of which are fully understood.
Concerning AHN, a number of crucial events occur before newly born neurons in the adult hippocampus can functionally contribute to the pre-existing network. Exit of the neural precursor cells (NPCs) from their quiescent state, proliferation, fate decisions and selection through apoptosis are the changes that together control the neurogenic cascade. This plethora of events can all take place within a time-span of several days, and as such require rapid yet carefully orchestrated changes in the molecular machinery of these cells. This coordinated action can be achieved through multiple layers of molecular control, many of which are epigenetic, such as alterations in gene promoter DNA methylation and microRNA-mediated control of mRNA translation. Furthermore, specific alterations in any of these layers of molecular control, and in the corresponding cellular phenotypes, can also be induced by cell extrinsic factors such as circuit hyper-activation, alterations in glucocorticoids or during aging.
Therefore, the overall aim of this thesis is the identification of novel epigenetic mechanisms governing phenotypical changes of NPCs and newborn neurons such as quiescence, proliferation, apoptosis and differentiation, induced by these aforementioned cell extrinsic factors.