学習・記憶の細胞基盤—シナプス・アンサンブルを可視化・操作する技術の創出

Optical Erasure of the Synaptic Ensemble that Underlies Learning and Memory

記憶はどこに保存されているのか。各種イメージングや光遺伝学・薬理遺伝学の発展に伴い，高い時空間解像度で記憶情報の脳内表現を可視化できるようになったが，記憶の脳内表現とシナプスとの関連は相関関係以上の知見を得ることができなかった。この問題を克服するために，われわれはシナプス光プローブを開発し，記憶を光操作する技術の開発に取り組んできた。記憶を直接操作することで明らかになった知見を概説する。

Abstract

Dentritic spines are small membrane protrusions. Their regulation is thought to be important for memory storage, but the links between dentric spines and memory have been largely correlational because of a luck of techniques for manipulating individual spines. To overcome this problem, we have developed a novel synaptic optoprobe, AS-PaRac1, which is unique not only because it specifically labels recently potentiated spines, but also because it becomes possible to selectively shrink spines containing AS-PaRac1. This indicates that AS-PaRac1 can be use to specifically visualize the recently “written spines”and that the erasure of these spines is possible upon excitation with blue light. Using in vivo two-photon imaging, synaptic potentiation was visualized during active remodeling of the neocortex. Upon learning a motor skill, AS-PaRac1 expression was induced in a relatively small number of neurons, in which approximately 8% of spines were tagged by AS-PaRac1. The labeled spines were broadly distributed throughout the dendritic tree. Excitation with blue light induced shrinkage of learning related spines and disrupted the acquired motor learning. In contrast, the erasure of a similar number of learning-irrelevant spines did not affect task performance. This novel light-dependent tool will open up new areas of memory research, and will additionally shed light on the neural networks that determine who we are.