Using Enhancer-Driven Gene Expression (EDGE) to Study the Circuitry of Memory

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Like electronic circuits, understanding neural circuitry requires manipulating particular circuit elements while recording from others.
While recent years have seen the development of molecular tools capable of recording and manipulating neural activity both acutely and in the steady state, targeting such tools to single circuit elements (i.e. single neuronal cell types) remains an unsolved problem. The only means to do so is by co-opting the genetic elements that specify diverse neural cell types, but while most genes express in the brain, they tend to express in many different cell types, so native promoters are not specific enough. We have used an approach called Enhancer-Driven Gene Expression (EDGE) based on identifying individual distal sequence elements which tell the promoter where and to express (enhancers) that are uniquely active in a target sample and using them to make synthetic promoters specific to the target. We present the results of applying EDGE to the entorhinal cortex, showcasing the kinds of “circuit-breaking” experiments these tools make possible.