Regulation of Hippocampal Neurogenesis and Behavior by Noggin

Hippocampus (HIP)-dependent cognition is regulated by a variety of different types of environmental stimuli, but the mechanisms by which the environment initiates and/or modulates behavior are not fully understood. Adult inbred mice display wide variability in performance on HIP-dependent cognitive tasks, and there is highly significant negative correlation between levels of endogenous BMP signaling in the HIP and baseline cognitive performance. Further, exposure to exercise or environmental enrichment increases expression of the BMP-inhibitor, noggin, in the HIP and attenuates BMP signaling concurrent with enhanced cognitive performance and increased neurogenesis. Similarly, antidepressants increase neurogenesis in association with behavioral changes, and these changes are mediated by an increase in noggin expression and a reduction in BMP signaling in the ventral hippocampus. Reducing BMP signaling in adult mice by ventricular infusion, transgenic overexpression, or viral overexpression of noggin in the HIP reproduces many effects of exercise on cognitive and affective behavior and on neurogenesis. In the HIP, noggin is localized within dentate granule neurons (GC),and membrane depolarization promotes noggin release from cultured GC. Sonic hedgehog signaling promotes even greater levels of release of noggin by cultured GC. Disruption of cilia (IFT88 knockout) or inhibition of transport to cilia (Rab8a/b knockdown) depletes noggin from cultured GC. In toto these observations suggest that BMP signaling plays a central role in regulating both neurogenesis and HIP-dependent behavior, that BMP signaling is regulated by activity-dependent release of noggin by GC, and that cilia regulate noggin expression and release by GC. This proposal will test the hypotheses that: 1) Release of noggin by dentate gyrus GC is a crucial link between environmental stimuli and both cellular changes in the hippocampal neurogenic niche, and hippocampus-dependent behavior. 2) Environmental signals transduced through primary cilia and neuronal activity cooperatively regulate expression and release of noggin to regulate neural progenitor proliferation. 3) The DG circuitry is structured to support the transfer of information between largely parallel cortical and subcortical systems via interactions between mature and immature neurons. Activity-dependent release of noggin alters this functional connectivity leading to changes in hippocampus-dependent behavior