Benutzerspezifische Werkzeuge

A23: Regulation of adult neurogenesis by noradrenaline

Project leader: Prof. Dr. A. Storch

 

The rostro-caudal gradual loss of cellular diversity and neuroprogenitor cell (NPC) proliferation within the periventricular regions (PVRs) of the ventricular system of the adult brain points to the presence of restrictive factors inhibiting the quiescent non-proliferating neuroblast-like cells within the non-neurogenic regions of the caudal PVRs. The stimulation of these NPCs in brain regions in close proximity to systems which are affected in neurodegenerative diseases is of great interest for establishing orthotopic regenerative therapies by recruiting endogenous NPCs. The search for such factors led to the observation of differential expression of noradrenaline [NA] within neurogenic and non-neurogenic PVRs of the adult mouse brain with NA expression inversely correlating with NPC proliferation. Preliminary experiments consistently demonstrate strong inhibitory effects of NA on adult NPC proliferation in vitro. These effects are specifically mediated through adrenergic receptor signaling. Intraventricular infusion of NA shows a strong decrease in proliferation of NPCs in the adult subventricular zone (SVZ) while blocking of adrenergic receptor signaling led to an increase of proliferation of quiescent NPCs within non-neurogenic regions of the caudal PVRs.

In the project, we propose to dissect the role and molecular mechanisms of NA in regulating adult neurogenesis in neurogenic and non-neurogenic regions. We plan to intraventricularly infuse NA and its antagonists by using minipumps to determine proliferation and neurogenesis in the neurogenic and non-neurogenic regions within the adult mouse brain in vivo. Depletion of endogenous NA by destroying NAergic neurons will be used as an alternative method to investigate the role of endogenous NA in adult neurogenesis. Isolated NPCs derived from adult SVZ and PVRs will serve as in vitro models to further define the pharmacology of NA actions. The results will contribute to the understanding of the regulation of adult neurogenesis in neurogenic and non-neurogenic brain regions. This knowledge might help (i) to better understand the effects of noradrenergic compounds and (ii) to generate novel endogenous regenerative approaches in neurodegenerative diseases.

 

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Funding program:

DFG