Freie Universität Berlin
Charité University Medicine Berlin
Humboldt University Berlin
Max-Delbrück-Center for Molecular Medicine, Berlin-Buch
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GRK 1123:

Cellular Mechanisms of Learning and Memory Consolidation
in the Hippocampal Formation

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This Research Training Group is funded by the German Research Council DFG

©2006, FU Berlin
GRK 1123

Imprint & Disclaimer
AG Ahnert-Hilger AG Behr AG Braunewell AG Haucke AG Heinemann
AG Kempermann AG Kempter/Schmitz AG Kuhl AG Multhaup AG Nitsch

PD Dr. med. Gerd Kempermann
Max-Delbrück-Centrum für Molekulare Medizin
Research Group "Neuronal Stem Cells"
Robert-Rössle-Str. 10
13125 Berlin-Buch
gerd.kempermann@mdc-berlin.de


Title

Experience-dependent induction of neurogenesis-associated genes in precursor cell stages during adult hippocampal neurogenesis

Question of the project

Adult hippocampal neurogenesis is regulated in an activity-dependent manner. At present it is not known how the regulatory influence is mediated to the precursor cells in the adult dentate gyrus

Scientific background

Learning stimuli and the experience of a complex environment stimulate adult hippocampal neurogenesis (Gould et al. 1999; Van Praag et al. 1999) . From a heterogeneous pool of precursor cells new neurons are recruited. The proliferation of the precursor cells is also regulated in an activity-dependent way. "Learning" influences adult hippocampal neurogenesis on the level of precursor cells and induces a further maturation of immature cells within the neuronal lineage into mature granule cell neurons (Gould et al. 1999; Kempermann et al. 1997; Kronenberg et al. 2003) . The details of this development and its regulation are still unknown.

Phosphorylated CREB (cAMP response element binding protein) is of particular interest in this context, because it activates BDNF (brain derived neurotrophic factor) (Nakagawa et al. 2002a; Nakagawa et al. 2002b) . BDNF appears to be a key regulator in adult hippocampal neurogenesis with influences on both cell survival and differentiation. CREB is expressed and posphorylated in a subpopulation of proliferative cells in the subgranular zone of the dentate gyrus, the region, in which the precursor cells reside that drive adult hippocampal neurogenesis. Many very different factors can lead to a phosphorylation of CREB. It is not known, which of these might be involved in a learning-induced recruitment of new neurons. The literature on the regulation of synaptic plasticity, for example suggests that NMDA receptor activation can cause phosphorylation of CREB and thereby modulate the consecutive trophic action of BDNF (and other factors) (Korte et al. 1997) . From our own research we have preliminary evidence that a number of plasticity-dependent genes exist, which are upstream of CREB, are expressed in immature neuronal precursor cells, and which might be inducible by learning stimuli. We hypothesize that gene activation upstream of CREB is necessary for the initiation of an experience-dependent regulation of adult hippocampal neurogenesis. In the proposed project, we intend to identify such genes.


Previous work of the group in the field

We have recently identified six distinct stages during the development of new granule cells from precursor cells in the adult hippocampus (Brandt et al. 2003; Filippov et al. 2003; Kronenberg et al. 2003; Steiner et al. 2003) . Four of these are on the level of precursor cells, which seem to differ in their proliferative activity and possibly lineage restriction. We also found that the experience-dependent recruitment of new neurons affects relatively late precursor cells (type-3 cells) (Kronenberg et al. 2003) . pCREB is presumably active in these cells and only for a relatively short time. An activity-dependent up-regulation of immediate early genes (c-fos, zif268, and homer 1A) is not found in the immature cells; these genes are only induced in mature neurons (Jessberger et al. 2003) . On the other hand, we have found that transcription factor Prox1 is induced very early in adult neurogenesis (Brandt et al. 2003) . Experience of an enriched environment leads to an early increase in Prox1-positive cells (Kronenberg et al. 2003) . Prox1 remains expressed throughout the life of the granule cell. We hypothesize that Prox1 acts downstream of pCREB, but this remains to be shown in vitro and in vivo. The sequence might also be variable. We further hypothesize that neurogenesis-associated genes are activated upstream of pCREB, modulating the cAMP-dependent (and probably NMDA-receptor-dependent) response. We are currently conducting a linkage analysis and have so far identified three candidate gene loci associated with the baseline regulation of adult hippocampal neurogenesis. Identified candidate genes will be examined in detail.

Goals

Goal of the proposed study is to examine the activity-dependent regulation of candidate genes in those precursor cell populations that are thought to be responsible for generating the increase in new neurons. The hypothesis is that a restriction point can be identified at which survival-promoting genes are up-regulated in precursor cells and neuronal maturation is initiated.

Methods

Dissertation topics


Cooperation with other Members  


Scholarship Holders:

 

AG Ahnert-Hilger AG Behr AG Braunewell AG Haucke AG Heinemann
AG Kempermann AG Kempter/Schmitz AG Kuhl AG Multhaup AG Nitsch