The factors involved in competition among inputs for a postsynaptic target, growth and stabilization of winning inputs, and the role of innervation in coordinated maturation of synaptic partners are not well delineated. In part this situation stems from the protracted nature of these events in most neural systems. We have revealed that innervation of cells in the auditory brainstem by large nerve terminals called calyces of Held is a good model system to study these events. Small terminals compete, then a single winning input grows to envelop the cell body of its target within 48 hours, between postnatal (P) days 2-4. We will take advantage of this constrained time frame to study onset and offset of gene expression using microarray technology. We propose here to analyze data from dense temporal sampling of gene expression surrounding P2-4 in daily intervals using exon microarrays. From genes whose individual expression profile is temporally linked to synaptogenesis events at P2-4, we will select 25 candidates for validation by using quantitative real-time PCR, immunohistochemistry and in situ hybridization. More complex analyses, such as gene cluster or alternative splicing-based methods, will yield an additional list of genes from which another 25 candidates will be selected for validation. These activities will require recruitment to fill two new positions. Through a new collaboration with Jiang Qian, PhD, at Johns Hopkins University, a postdoctoral fellow will be hired to assist Dr. Qian with microarray analyses. At West Virginia University, a research technician will be hired to facilitate high throughput validation of selected candidate genes. These newly created jobs, along with requested equipment to more efficiently perform qPCR experiments, will accelerate the tempo of scientific research. This application is submitted in accordance with grant Notice Number: NOT-09-058 and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competittivce Revision Applications.
Disorders of information processing in the brain characterize a range of neurologic pathologies that can be traced to improper formation of neural circuits during early development. The proposed studies are designed to discover general principles that underlie neural circuit formation. Therefore, insights from this work may underpin therapeutic strategies for deficits in hearing, such as auditory processing disorder and dyslexia.
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