Grant: $256,499 - National Institutes of Health - Aug. 17, 2009
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Award Description: The goal of this supplemental proposal is to expand the experiments in R01 NS064025A1 entitled, ¿Newborn Neurons in the Adult Hippocampal Network¿ (PI: Linda Overstreet-Wadiche) by incorporating new techniques into the study of the survival of adult-generated granule cell (GC) neurons. We propose to establish an organotypic slice culture preparation for studying the circuit connectivity and survival of newborn GCs. This methodology will allow us manipulate synaptic activity in a controlled manner and perform genetic manipulations that are not feasible using the in vivo methods proposed in the parent grant. As shown in our preliminary data, organotypic slice cultures also allow us to track newborn cells over time. The main hypothesis is the same as the parent grant; that the long-term fate of adult generated neurons is controlled by GABAergic synaptic input. In Aim 1, we will use live retrograde tracing methods to identify synaptically-coupled neurons. This provides an alternative approach for determining the identity of the interneuron subtype(s) that are poised to translate network activity into regulation of newborn GC. In the course of this aim we will also determine whether cell autonomous or non-cell autonomous factors control the synaptogenesis of newborn neurons. That is, whether the sequence of synaptic integration of newborn GCs is maintained when the opportunity for synaptic reorganization is provided during slice preparation. In Aim 2, we will determine how GABAergic input to newborn GCs controls their survival in the slice culture preparation. This aim will complement the experiments proposed in Aim 3 of the parent grant and facilitate future studies of the downstream survival signals that are generated by synaptic GABAergic depolarization. Briefly, we will enhance the survival of newborn GCs by driving GABAergic synaptic activity within the slice, and we will negate activity-dependent enhanced survival by blocking GABAergic depolarization of newborn GCs. In addition to accelerating the tempo of research initiated in the parent grant by establishing an in vitro system that is amenable to genetic manipulation, the research plan also promotes job creation by enabling a senior research associate to be hired. The senior research associate has extensive experience investigating mechanisms of neuronal survival, particularly in studying the signal transduction cascades underlying neuronal support via depolarization, neurotrophins and neuropeptides in an avian autonomic neuronal culture system. Establishing an intact mammalian system for studying neuronal survival is a natural progression of their research interests and will significantly enhance their appeal on the job market at the end of the funding period.
Project Description: Same as above
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Aug. 17, 2009. Help expand these official descriptions using the wiki below.