国立研究開発法人情報通信研究機構 未来ICT研究所("NICT神戸")
　吉原基二郎研究室（記憶神経生物学プロジェクト）

Connecting synaptic plasticity to memory using Drosophila feeding circuit and Drosophila embryonic neuromuscular junction.

My lab is trying to ask a fundamental question “How do we remember?” by studying synaptic physiology in the fruit fly, Drosophila. I believe that memory is stored as a series of neurons connected through strengthened synapses, in which sequential firing of the neurons allows recall of specific events (Fig. 1). Therefore, understanding mechanisms of synaptic modification is a key to understanding mechanisms underlying memory. Taking advantage of a combination of synaptic physiological methods on highly plastic Drosophila embryonic neuromuscular synapses (neuromuscular junction, NMJ) and sophisticated Drosophila genetics, we have proposed a novel hypothesis, “local feedback model” as a potential molecular and cellular basis of memory formation (Yoshihara et al., 2005, Science 310: 858-863; Fig. 2). In this model, I postulate that mutual intensification between presynaptic and postsynaptic cells by a positive feedback loop at single synapses keeps individual synapses potentiated, leading to eventual morphological change and perpetually strengthened synapses, storing memory. In my lab, we are testing this working hypothesis to answer the question “how do we remember?”, by a novel approach using a pair of feeding command neurons, Feeding neuron (Fdg neuron; Fig. 3).  We have performed behavioral screening on NP lines (Yoshihara and Ito, 2000, Drosoph. Inf. Serv., 83, 199-202) to establish a new system to connect synaptic plasticity to memory, and finally identified the Fdg neuron (Flood, Iguchi et al., 2013, Nature, 499: 83-87), which is ideal for neurophysiological analysis of classical conditioning demonstrated by Ivan Pavlov (Fig. 4) to connect synaptic plasticity to memory mechanism. We are now establishing novel protocols of Pavlovian conditioning to “witness” memory formation as real-time synaptic change in an experimental system I have devised for simultaneous observation of the brain and behavior of a single fruit fly (Yoshihara, 2012, JoVE; 62, 3625; Fig. 5). Through these novel approaches using Drosophila allowing us to perform comprehensive genetic analyses, we are trying to understand basic principle on molecular and cellular mechanism of memory formation.
We are continuing detailed analysis on synaptic plasticity of neuromuscular synapses as a simple cellular model for comparison with central synapses in the brain (this study was supported by NIH R01 grant of U.S.A.). In addition to the plasticity projects, we are also studying basic mechanism of synaptic transmission, which is not fully understood yet.  For these synaptic transmission projects, we are taking advantage of Drosophila embryonic neuromuscular synapses, which is suitable for quantitative synaptic physiology even in lethal mutants, as shown in our previous works on function of synaptic molecules (Yoshihara et al., 1999,  J. Neurosci. 19: 2432-2441; Yoshihara et al., 2000,  J. Neurosci. 20: 8315-8322; Yoshihara and Littleton, 2002 Neuron, 36, 897-908; Yoshihara et al., 2010, Proc. Natl. Acad. Sci. USA, 107, 14869-14874).  We are collaborating with the lab of Prof. J. Troy Littleton at MIT for these neuromuscular projects.