Dr. Shouzhen Xia, Cold Spring Harbor Laboratory
Title: NMDA receptors and long-term memory consolidation in Drosophila
Abstract: Recent neuroscience research on memory consolidation has been attempting to identify the physical basis of LTM (long-term memory) storage - the engram. Cellular and molecular experiments have yielded the prevalent view that the engram for a given particular behavioral task is encoded as changes in synaptic structure/function distributed in an unknown fashion across an ill-defined neural circuit/network. The engram - the combined stable changes to circuit/network function - thus constitutes the stabilized long-term memory trace which is consolidated from and outlasts the earlier ephemeral memory traces. Although short-lasting memory traces have recently been identified in the fly and worm, the engram has not been identified for any given behavior task in vertebrates or invertebrates. Olfactory memory in Drosophila is a simple associative memory defined in a simple, accessible insect brain. Combined with powerful genetic tools, the search for the engram represents a feasible experimental objective. This study first provides a clear demonstration of a role for NMDA receptor function during adult associative learning in Drosophila by combining specificity of anti-sense RNA knockdown for dNR1 with a rapid induction of transgenic expression using Drosophila heat shock promoter. Acquisition of an odor-footshock association was impaired significantly by inducible and transient knockdown of dNR1, while long-term memory was blocked completely. Until recently, although many neuroscientists have begun to expect that invertebrate behavioral plasticity may be mediated by evolutionarily conserved molecular/cellular mechanisms, NMDA receptor-dependent synaptic plasticity was not believed to exist in the nervous systems of invertebrates. Our results confirm for the first time this expectation for invertebrates and, more generally, has yielded the most acute genetic knockdown of NR1 in any model system, thereby establishing its functional role in adult plasticity. We then demonstrate an adult-specific requirement for NMDARs outside of the mushroom body during LTM consolidation. dsRNA-mediated silencing of dNR1 or dNR2 in cholinergic R4m subtype large-field neurons of the ellipsoid body (EB; a substructure of the central complex which is believed to be a control center for many different behavioral outputs) specifically disrupts LTM consolidation but not retrieval. This observation thus identifies the anatomical region (i.e., EB), wherein the engram must reside. Most importantly, the involvement of a brain region other than the mushroom body, where olfactory learning occurs, during memory consolidation suggests for the first time the existence of a system-level memory consolidation in an invertebrate, implying that the transfer of memory from one brain location to another during memory consolidation is evolutionarily conserved, in spite of huge anatomical (circuit) differences between flies and mammals.