Neural circuitry of the mammalian neocortex: which neurons are connected to each other, and how can these patterns of connectivity be altered by experience?

Abstract

Neurons in the cerebral cortex communicate with each other using highly specified, hierarchical rules of connectivity. There are more than 30 cell types in the neocortex, and these cell types can be differentiated by their developmental lineage, projection target, or expression of marker genes. Previous studies have attempted to reveal the logic of neural circuits by low-throughput anatomical or electrophysiological methods. Here we propose to develop and employ a novel protein complementation strategy to chemically tag synapses defined by pre- and post-synaptic cell identity. Cell contacts made between genetically specified pre- and post-synaptic neurons will enable assembly of a fluorescence-activating protein that triggers a 20,000-fold increase in fluorescence upon dye application. The outstanding signal-to-noise and spectral properties of the dye will enable quantitative and in vivo analysis of cell-type specific synapses in the mammalian neocortex. The long-term goal of this proposal is to develop chemical biology tools for a complete index of cell-type specific synaptic contacts in health and disease states.

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