(Revised text) This proposal seeks to identify and investigate molecular pathways that modulate adult neurogenesis in response to environmental stimuli. Following formative periods of early development, ongoing neurogenesis persists in the dentate gyrus (DG) of the hippocampus and contributes to learning, memory, and regulation of emotion. Adult neurogenesis can be modulated by environmental influences and experiences, including electroconvulsive shock (ECS) and voluntary running. Enhanced learning has been demonstrated in rodent models of wheel running, while electroconvulsive therapy is used in humans to effectively treat depressive disorders. Previous work has implicated a small number of molecules in transducing external stimuli into neurogenic effects, but few novel pathways outside of already well-established neurogenic factors have been functionally identified. Additionally, a major obstacle has been an inability to investigate biological pathways specifically within neurogenic cell types. Therefore, molecular mechanisms that facilitate environmentally induced neurogenesis in adult DG remain largely unknown. To address the question of how molecular machinery in DG and specifically within newly formed neurons facilitates neurogenesis in response to extrinsic signals, I will utilize two complementary methods. Firstly, I propose that independent sources of data in the fields of epigenetics and neurodevelopmental disease can be integrated to inform a targeted screening of candidate genes likely to contribute to environmentally induced neurogenesis. I will characterize functional roles for candidate genes found to have altered expression in DG after ECS and/or wheel running. Secondly, I will utilize a novel Nestin-CreERT2/RiboTag mouse line to capture and characterize the translational profiles of enriched populations of newborn neurons as they mature in a voluntary wheel running paradigm, and genes of interest identified through this analysis will be functionally assessed. This research will yield significant insight into the inner workings of developing neurons at the interface of environment and neuroplasticity. Additionally, novel mechanisms and pathways discovered may represent valuable targets for future regenerative treatments of brain injury and CNS disorders.
(Revised text) The research plan described in the proposal entitled 'Elucidating Molecular Mediators of Environmentally Induced Neurogenesis' aims to characterize novel mechanisms by which stem cells in the brain create new neurons in response to environmental experiences. Altered neurogenesis is of central importance in neurodevelopmental disorders, aging, and brain injury, which have significant environmental contributions in addition to genetic risk factors. Identifying externally tractable neurogenic substrates can directly inform advancement of future therapies for significant human health issues.
