(Verbatim from applicant?s abstract): Impairment of learning and memory is a common phenomenon associated with advancing age, although the underlying mechanisms are not clearly understood. Based on previous reports of age-correlated increases in dynorphin expression in the brain and on studies of effects of dynorphin in vivo and in vitro, we are investigating a possible role of the endogenous opioid neuropeptide dynorphin in age-associated decline in mental health. We have recently found that moderately aged prodynorphin knockout mice perform significantly better than similarly aged wild-type mice in a spatial learning and memory task, suggesting an important role of this peptide in causing memory dysfunction. We hypothesize that age-related alterations in hippocampal dynorphin levels contribute substantially to functional impairment of learning and memory by altering glutamate neurotransmission or other synaptic activities. To test this hypothesis, we propose a set of behavioral assays to assess hippocampal-dependent learning and memory processes in dynorphin knockout mice and wild-type mice of varying ages. In addition, we will supplement the behavioral studies with electrophysiological analysis and anatomical characterization of specific sites within hippocampus where dynorphin is localized. These experiments will allow us to determine the functional role of hippocampal dynorphin in modulating neuronal activity associated with learning and memory processes, which may lead to novel therapeutic strategies for the treatment of learning and memory dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30MH065055-04
Application #
6797146
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (20))
Program Officer
Curvey, Mary F
Project Start
2002-09-17
Project End
2006-09-16
Budget Start
2004-09-17
Budget End
2005-09-16
Support Year
4
Fiscal Year
2004
Total Cost
$47,946
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Nguyen, Xuan V; Liu, Mei; Kim, Hyoung-Chun et al. (2009) Effects of prodynorphin deletion on striatal dopamine in mice during normal aging and in response to MPTP. Exp Neurol 219:228-38