Neural stem cells continuously generate new functional neurons in the dentate gyrus of the adult mammalian brain. Evidence is accumulating that adult neurogenesis contributes to learning and memory processes as well as to the regulation of mood. Moreover, dysregulation of neurogenesis is evolving as a significant contributor to neuropsychiatric symptoms in ageing and neurodegenerative diseases. The overall goal of our laboratory is to under of two central following questions:
a) Adult neurogenesis contributes to plasticity in the hippocampal network. Dysregulation of adult neurogenesis is associated with cognitive and behavioral deficits. How is the generation of new neurons from adult neural stem cells adjusted to optimize function of the hippocampal network?
b) The adult central nervous system shows only limited regenerative capacity. How can stem cells be harnessed for repair in neurological diseases?
My laboratory is tackling these questions by focusing on the identification of the signaling pathways and of the genetic programs that control the generation of new neurons in the adult hippocampus using a combination of techniques molecular biology, cell biology, biochemistry, epigenetics, virology, histology, and mouse genetics. We expect that our research will significantly contribute to the development of experimental strategies for the treatment neuropsychiatric diseases as they identify pathways that could be targeted for enhancement of neurogenesis under pathological conditions and for the recruitment of stem cells for repair of the central nervous system.
The ability of NSCs to generate new neurons throughout life depends on the tight balance of stem cell maintenance and differentiation. Incomplete maintenance and premature differentiation will result in depletion of the NSC pool and consequently will lead to decreased levels of neurogenesis over time. Increased stem cell maintenance at the expense of neuronal differentiation will impair the ability of NSCs to generate neurons at a rate necessary for proper hippocampal function. Using virus-mediated gene transfer, mouse genetics, and in vitro stem cell cultures we recently found that Notch-signalling (Ehm et al., 2010), and Wnt-signalling activity (Lie et al. 2005; Kuwabara et al. 2009, Karalay et al. 2011) control the balance between stem cell maintenance and differentiation. In ongoing projects we are using a proteomic approach to identify pathways that interact with Notch- and Wnt-signalling on the transcriptional level to regulate stem cell behaviour.
There is increasing evidence that neural network activity matches the rate of adult neurogenesis to the physiological needs of the network. We are interested in understanding how network activity is translated into developmental programs in adult neurogenesis. We are using retrovirus mediated gene-transfer, behavioral manipulations, immunhistochemistry, biochemical and molecular approaches to identify transcriptional pathways downstream of neural activity and their targets in newborn neurons. We have recently identified SoxC proteins (Haslinger et al. 2009) and CREB (Jagasia et al., 2009; Herold et al., 2011, Merz et al., 2011) as potential transcriptional regulators that control adult neurogenesis downstream of network activity. Intriguingly, loss of SoxC- or CREB-activity result in impaired differentiation, maturation and survival of newborn neurons. In ongoing projects we are in vivo using transcriptome analysis to identify the genetic network downstream of SoxC and CREB in activity-dependent neurogenesis.
Adult neurogenesis and neural stem cells hold great promise for the treatment of neuropsychiatric diseases. A major challenge, however, is the identification and validation of molecular targets that allow the specific modulation of adult neurogenesis and the recruitment of stem cells for repair. We are currently investigating how ageing and neurodegeneration affect the generation of new hippocampal neurons. Ongoing projects are investigating in particular the effect of ageing and disease on mitochondria – a key organelle for neuronal development and survival. In a parallel project, we are testing whether the activity of key pathways in neurogenesis are perturbed in animal models for ageing, neurodegenerative and neuropsychiatric diseases and whether modulation of the respective pathways can reconstitute neurogenesis and hippocampal function. We expect that these studies will provide insight into pathophysiological mechanisms in neuropsychiatric diseases and that they will identify molecular targets for the development of novel treatment strategies.
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