Dubnau Laboratory

Introduction
Our long-term goal is to understand how animals remember past experiences. The behavioral properties and cellular mechanisms of memory are highly similar across animal phyla. This means that many features of memory can be studied in simple organisms that are easy to manipulate (Fly Learning Movie). The immensely powerful genetic techniques that are feasible in fruit flies make for an ideal "model system" to study this problem. Work in the lab consists of a diverse array of experimental approaches. The first is to identify genetic pathways that are involved in Pavlovian learning and memory. With this strategy, we have identified a number of genes involved in the sub-cellular transport of mRNAs and the local control of their translation (Dubnau et al., 2003; Chen et al., 2008). We hypothesize that these genes are involved in selectively modifying specific synaptic connections in response to environmental experience. Ongoing work is designed to investigate this hypothesis in mechanistic detail (Pumilio project). A second area of focus in the lab is investigation of anatomical circuitry underlying memory (Functional Anatomy). We have taken advantage of the suite of methods available in Drosophila to spatially restrict genetic manipulations to specific neuronal sub-types. This class of experimentation includes spatially restricting the expression of individual genes within a specific neuronal circuits (Blum et al., 2009) as well as spatially restricting the expression of proteins that directly impact neuronal function such as neurotransmission. With this approach we can quickly take sub-regions of the brain "offline" and then moments later bring them "online" again. This technique allows us to dissect the complex circuitry that is involved in learning, in memory storage, and even in memory recall (Dubnau et al., 2001). With these methods, we have established that short-term and long-term memory rely on distinct neural circuits.
A third area of focus in the Dubnau lab is to use behavior genetic approaches to investigate the “Psychology of memory”. Many of the classically observed psychological features of memory formation, decay and consolidation appear to be conserved across phyla. But little is known about the underlying mechanisms. As an example, we have established a robust assay of inhibitory extinction learning (Extinction project). This brings the genetic methods available in flies to bear on this behavioral model of exposure therapy for post-traumatic stress disorder (link to Qin and Dubnau, 2009, submitted). Finally, we have developed a novel strategy to identify networks of gene interaction (IntelligentFlyDesign Project). One of the great challenges to understanding genetic impact on human disease is that clinical outcomes often are influenced by interactions among groups of genes. Despite its widespread relevance, mechanisms by which multi-gene interactions modulate phenotype are ill understood because almost all mechanistic studies of gene interaction are limited to pair-wise studies. We have developed and implemented a novel approach in Drosophila, using the biologically important and clinically relevant cAMP pathway as a model. Our approach uses the power of selective breeding to evolve combinations of alleles capable of suppressing the learning defect of mutations in the rutabaga adenylyl cyclase gene. With this approach, we have identified a number of rutabaga suppressors and also are identifying higher order gene interactions that impact olfactory memory in Drosophila (Cressy et al., 2009 in preparation).
"How to collect 60,000 fly heads"