Neurogenesis occurs in adult brain in discrete regions in creatures as diverse as mammals, amphibians, birds and reptiles. Its occurrence in adult mammals is firmly established in the hippocampus and the subventricular zone surrounding the lateral ventricles. Neurogenesis in adult brain may be regarded as one aspect of neural plasticity and altered hippocampal neurogenesis may play a pathophysiological role in disease states and in the therapeutic action of certain drugs. For example administration of all classes of antidepressants tested to date enhance hippocampal neurogenesis by stimulating the proliferation of neural progenitor cells and tricyclic antidepressants can reverse stress-induced reductions in neural progenitor proliferation in the hippocampus. Hippocampal neurogenesis may also be altered in other disease states including cerebral ischemia, seizures and Alzheimer's disease. Yet despite its undoubted existence and possible role in disease states the functional significance of hippocampal neurogenesis in adult brain remains unclear. One major limitation in identifying functional roles for neurogenesis in the adult remains the lack of methods to selectively perturb neurogenesis. Here we propose to develop a system to selectively target a cytotoxic agent, the diphtheria toxin A chain (DT-A) to adult CNS stem cells using a recently described system that relies on transgene regulation by lac repressor. This system will allow an inducible ablation of nestin lineage neural stem cells and thus of neurogenesis at any age in adult animals and will permit the effects of altered neurogenesis in the adult to be assessed independent of secondary affects on the non-progenitor population.
| De Gasperi, Rita; Rocher, Anne B; Sosa, Miguel A Gama et al. (2008) The IRG mouse: a two-color fluorescent reporter for assessing Cre-mediated recombination and imaging complex cellular relationships in situ. Genesis 46:308-17 |
| Wen, Paul H; De Gasperi, Rita; Sosa, Miguel A Gama et al. (2005) Selective expression of presenilin 1 in neural progenitor cells rescues the cerebral hemorrhages and cortical lamination defects in presenilin 1-null mutant mice. Development 132:3873-83 |
