The proposed experiments are directed at elucidating the mechanism of survival in activity-deprived auditory neurons. As with central neurons in all other sensory systems, brainstem auditory neurons require afferent input for maintenance and survival. Elimination of this input results in the death of 30- 60 percent of cochlear nucleus neurons in neonatal chicks and mice. Thus, the proposed studies concern the role of phosphorylation and activation of the transcription factor calcium/cAMP response element binding protein (CREB) in the subpopulation of cochlear nucleus neurons that survive activity deprivation. The experiments will address two groups of questions about the interactions among activity deprivation, intracellular calcium changes, CREB phosphorylation and activation, and neuronal survival. The hypothesis driving these experiments posits that following activity deprivation cochlear nucleus neurons show increased phophorylation/activation of CREB in the response to increased intracellular calcium. This phosphorylation is mediated by calcium-dependent activation of calcium/calmodulin dependent kinases and protein kinase A. Once phosphorylated, CREB results in the transcription of genes containing the calcium/cAMP response element within their promoter region, and the protein products of some of these genes allow the neurons to survive activity deprivation. The proposed experiments, grouped into two specific aims, will characterize the mechanisms of CREB phosphorylation and the role of this phosphorylation in neuronal survival. Neuronal survival is a critical issue in patients with sensory deficits. A significant fraction of the U.S. population suffers from profound hearing loss of early onset. There is agreement that early intervention is the most effective strategy for successful treatment. Understanding the mechanisms of neuronal survival following early sensorineural hearing loss may influence the success of restorative therapies for the congenitally hearing-impaired. During neural development, critical periods occur in which central structures are more sensitive or receptive to changes in afferent input. One potential benefit to understanding how central neurons survive activity deprivation will be to prolong these critical periods, thus improving success rates of early intervention therapy on patients with congenital hearing deficits. The proposed experiments would contribute information about how central auditory neurons survive in the absence of afferent input.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
7R01DC005012-03
Application #
6682286
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Freeman, Nancy
Project Start
2001-08-01
Project End
2006-07-31
Budget Start
2003-01-01
Budget End
2003-07-31
Support Year
3
Fiscal Year
2002
Total Cost
$321,133
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455