The Role of Notch1 in adult Hippocampal Neurogenesis and function

Neurogenesis occurs throughout life in the hippocampal subgranular zone (SGZ) and is potently stimulated by exercise, but the underlying mechanisms are still poorly defined. Notch1 is a master regulator of developmental neurogenesis, yet its role in adult hippocampal neurogenesis is unclear. To test the hypothesis that cell-intrinsic Notch1 is critical to both basal and exercise-induced SGZ neurogenesis, we generated Nestin-creERT2/R26R-YFP/Notch1loxP/loxP (Notch1 iKO) mice to inducibly ablate Notch1 in Nestin-expressing stem and progenitor SGZ cells. The total number of YFP+ SGZ cells increased over time in wild type littermates, but not in Notch1 iKO mice. Morphological and phenotypic analyses revealed that fewer YFP+ DG neurons were generated over time in Notch1 iKO mice due to smaller pools of YFP+ stem-like and progenitor cells. Likewise, neural progenitors isolated from Notch1 iKO mice were incapable of forming new neurospheres with extended passaging. While non-running Notch1 iKO mice had fewer YFP+ SGZ cells relative to wild type littermates, Notch1 iKO mice given 30 days access to a running wheel had equal number of YFP+ SGZ cells relative to controls, suggesting that running rescued total YFP+ SGZ cell number independent of Notch1. However, running did not rescue YFP+ stem-like cell number in Notch1 iKO mice, suggesting that the putative stem-like SGZ cells make little contribution to adult hippocampal neurogenesis in these conditions. From these data, we conclude that Notch1 in Nestin+ stem and progenitor cells is critical to maintain basal adult hippocampal neurogenesis, but is not critical for exercise-induced neurogenesis. Neurogenesis has also been implicating in depression and behavioral response to antidepressants. To determine if reduced neurogenesis contributed to depression- or anxiety-related behavior, we assessed several measures of depression and anxiety in Notch1 iKO mice. We found that Notch1 iKO mice did not differ from WT mice in their behavior, suggesting that reduced neurogenesis is not associated with mood disturbances.