While several cellular mechanisms that underlie learning and memory have been well-studied, little is known about the genetic components that contribute to proper memory formation, retention, and retrieval. A special class of genes called immediate early genes (IEGs) is rapidly expressed in neurons in response to activity, and has been implicated in learning and memory. We have initiated a genome-wide analysis of Drosophila melanogaster brains in order to discover novel IEGs that may underlie memory. Our preliminary results have revealed 278 candidate IEGs that are expressed differently in the Drosophila brain after exposure to sensory stimulation, and we have used a high-throughput behavior screen to implicate 28 of these genes so far in learning and memory. In addition to the classical IEGs that are rapidly up-regulated in response to neuronal activity, we have also identified 87 genes that are down-regulated immediately following stimulation, several of which we have implicated in memory using our behavior screen. The goal of this proposal is to delineate the molecular mechanisms by which 6 novel IEGs that we identified, that are conserved in humans, are necessary for learning and memory. We have selected 3 up-regulated genes (CG11964, sallimus, and Amylase distal) and 3 down-regulated genes (Heat-shock-protein-70Ab, Heat-shock-protein- 70Ba, and maggie) that have a variety of molecular functions, which should provide an understanding of the diverse molecular and cellular mechanisms necessary for memory formation and retrieval. We will validate that our IEGs are critical for learning using standard Drosophila tools and techniques such as alternative allele lines and deficiency stocks, and we will map expression of the genes in the brain using RNA probes and antibodies to delineate specific regions that are needed for several different types of learning. We will also investigate a potential developmental role for the genes by knocking down gene expression with RNAi following development. The outcome of our studies will specify the methods by which these 6 specific novel genes are critical for proper memory function. Our results will also provide a greater understanding of normal learning and memory mechanisms, as well as potential therapeutic targets for neurological diseases that result in memory loss.

Public Health Relevance

This proposal will investigate molecular mechanisms of learning and memory, using Drosophila as a model to understand the role of six proteins that are conserved in humans and whose activities show dramatic regulation of expression with external activity. We have used behavior testing to show that these six proteins are necessary for specific types of learning, and we will uncover the cellular processes that link these genes to memory. Our results will provide insight into the process of normal learning, as well as potential therapeutic targets and a greater understanding of pathological conditions of memory loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS084741-02
Application #
8699046
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mamounas, Laura
Project Start
2013-07-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Zoology
Type
Earth Sciences/Resources
DUNS #
City
Riverside
State
CA
Country
United States
Zip Code
92521