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. ? ?
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