Differential 24 h responsiveness of Prox1–expressing precursor cells in adult hippocampal neurogenesis to physical activity, environmental enrichment, and kainic acid–induced seizures

doi:10.1016/j.neuroscience.2008.04.023

Neuroscience

Volume 154, Issue 2, 23 June 2008, Pages 521-529

https://doi.org/10.1016/j.neuroscience.2008.04.023 Get rights and content

Abstract

Regulation of adult hippocampal neurogenesis in mice responds to behavioral stimuli, including physical activity (RUN) and the exposure to enriched environments (ENR). If studied after days or weeks, these stimuli and the pathological stimulus of kainic acid–induced seizures (KA) show differential effects on different developmental stages of adult neurogenesis. The question thus arose, whether such differential effects would also be apparent under very acute conditions. To further refine our method for identifying key restriction points in adult neurogenesis we here used the first expression of granule cell–specific transcription factor prospero-related homeobox 1 (Prox1) to identify lineage-determined progenitor cells in a nestin–green fluorescent protein (GFP) reporter gene mouse and labeled proliferating precursor cells with bromodeoxyuridine (BrdU). Twenty-four hours after the stimulus adult neurogenesis showed a very similar response to the three paradigms, in that cell proliferation increased. Detailed analysis, however, revealed the following new results: (1) KA, but not RUN and ENR stimulated the division of radial glia-like type-1 cells, (2) KA led to the disappearance of proliferative undetermined progenitor cells (type-2a), (3) only RUN increased proliferation of type-2a cells, (4) ENR and KA, in contrast, acted on lineage-determined progenitor cells (type-2b and type-3) even under acute conditions, and (5) only in the case of KA the short-term stimulus resulted in measurably increased survival of newborn neurons 4 weeks later. These results confirm and specify the idea that in the course of neuronal development in the adult hippocampus, precursor cells acutely sense and distinguish various forms of “activity” differentially and translate these stimuli into defined responses based on their stage of development.

Section snippets

Animals and housing conditions

The experiment was done in transgenic mice expressing the green fluorescent protein (GFP) driven by regulatory elements of the nestin gene (Nestin-GFP mice). The generation of these mice has been described elsewhere (Yamaguchi et al., 2000). They were bred at the animal facility of the Max Delbrück Center for Molecular Medicine (MDC). All appropriate local and federal regulations of animal welfare were followed. Every attempt was made to minimize the number and suffering of animals used in the

Prox1 expression in adult hippocampal neurogenesis

Prox1 expression was found in all mature granule cells (Fig. 1); here the overlap with neuronal marker NeuN was complete but not all Prox1-positive cells were NeuN-positive. Prox1 was completely absent from the radial glia-like type-1 precursor cells. In contrast, 77.8%±2.7 of all type-2 cells co-expressed Prox1. DCX can be used to identify cells from the intermediate progenitor cell stage (type-2b) to the immature postmitotic maturation phase. We found that essentially all DCX-positive cells

Discussion

The present study fills some interesting gaps in our previously developed scheme, how different models of “activity” might differentially affect the regulation of adult hippocampal neurogenesis. The most important advance is the finding that these effects are already visible only 24 h after the onset of the stimulus (albeit not to their full extent). This not only speaks in favor of the idea of a very sensitive and swift response it also highlights that it is acutely dividing cells that respond

Conclusion

In summary, our new results confirm under the condition of acute stimulation that different stages of neuronal development in the adult hippocampus differentially respond to RUN, ENR, and KA. We show that in physiological situations (RUN and ENR) this immediate response is not (yet) translated into lasting changes on the level of net neurogenesis. The pathological stimulus KA, in contrast, exerts a lasting effect on adult neurogenesis even after one single bout of seizures.

Acknowledgments

The authors would like to thank Ruth Zarmstorff for her outstanding technical assistance. The study was sponsored by Volkswagenstiftung. B.S. is a Rahel Hirsch fellow of the Charité, University Medicine Berlin.

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Cellular neuroscienceDifferential 24 h responsiveness of Prox1–expressing precursor cells in adult hippocampal neurogenesis to physical activity, environmental enrichment, and kainic acid–induced seizures

Abstract

Section snippets

Animals and housing conditions

Prox1 expression in adult hippocampal neurogenesis

Discussion

Conclusion

Acknowledgments

Trends Cogn Sci

Mol Cell Neurosci

Neuron

Mol Cell Neurosci

Brain Res Dev Brain Res

Neuron

Exp Neurol

Trends Neurosci

Trends Neurosci

Neurobiol Aging

Neurobiol Dis

Cell Stem Cell

Neuron

Mol Cell Neurosci

Potential role for adult neurogenesis in the encoding of time in new memories

Nat Neurosci

Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures

Proc Natl Acad Sci U S A

Running in pregnancy transiently increases postnatal hippocampal neurogenesis in the offspring

Proc Natl Acad Sci U S A

Serotonin depletion in the adult rat produces differential changes in highly polysialylated form of neural cell adhesion molecule and tenascin-C immunoreactivity

J Neurosci Res

Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons

Eur J Neurosci

Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus

J Neurosci

Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina

Nat Genet

Fluoxetine targets early progenitor cells in the adult brain

Proc Natl Acad Sci U S A

Cellular neuroscience
Differential 24 h responsiveness of Prox1–expressing precursor cells in adult hippocampal neurogenesis to physical activity, environmental enrichment, and kainic acid–induced seizures