The molecular basis of LTM formation appears to be evolutionarily conserved. In particular, simple forms of learning appear to reflect the conserved cellular functions of neurons, while more complex behavioral tasks reflect the diversity of neuronal systems (anatomy) across species. Nonetheless, memory of these complex tasks appears to invoke a common underlying synaptic plasticity. Consequently, we have capitalized on the economy-of-scale and the availability of genetic tools in Drosophila to focus on the discovery of the downstream genes involved in LTM Via a combination of DNA microarrays and a behavioral screen for single-gene mutants with defective memory, we have identified several genetic components of a novel biological pathway involved in the cellular transport of newly transcribed mRNAs and their subsequent local translocation. Importantly, in vivo biological validation has been achieved for two of these genes, pumilio and staufen. ? ? We propose to focus on this pathway via the following specific aims: ? ? 1. Molecular-genetic confirmation of selected genes in the pumilio/staufen pathway (staufen, oskar, moesin, pumilio, orb, elF2g, elFSc): We plan (i) genetic complementation with existing alleles and (ii) temporal and spatial rescue to establish a role for each of these genes in memory formation. ? ? 2. Protein expression studies of selected genes in the pumilio/staufen pathway: Immunostaining for most of these developmental genes never has been reported for the adult CNS. We will do so, with particular focus on subcellular co-localization experiments. ? ? 3. DNA microarray screen after cell purification: Studies focused on the neural substrates of olfactory memory continue to suggest the focus to be neurons of the mushroom bodies. Using a novel method, we plan to purify MB neurons from trained flies for DNA microarray experiments. We expect the signal from transcriptionally responsive genes to be greater in RNA isolated from this purified population of cells, thereby detecting additional neuronal participants of the pumilio/staufen pathway. ? ? Mechanisms of memory formation are remarkably conserved. Work in animal model systems can therefore greatly inform our understanding of human cognitive dysfunction. We will take advantage of the economy-of-scale and the molecular-genetic tools available in Drosophila to establish this novel biological pathway underlying memory formation. Our work in Drosophila will fuel studies of vertebrate homologs and eventually will contribute to our understanding of various forms of cognitive dysfunction in humans. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH066910-02
Application #
6783417
Study Section
Genetics Study Section (GEN)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2003-08-01
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
2
Fiscal Year
2004
Total Cost
$380,719
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
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Matsuno, Motomi; Horiuchi, Junjiro; Tully, Tim et al. (2009) The Drosophila cell adhesion molecule klingon is required for long-term memory formation and is regulated by Notch. Proc Natl Acad Sci U S A 106:310-5
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Wang, Yalin; Chiang, Ann-Shyn; Xia, Shouzhen et al. (2003) Blockade of neurotransmission in Drosophila mushroom bodies impairs odor attraction, but not repulsion. Curr Biol 13:1900-4