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A molecular calcium integrator reveals a striatal cell-type driving aversion

By Christina K. Kim, Mateo Lopez Sanchez, Paul Hoerbelt, Lief E Fenno, Robert C. Malenka, Karl Deisseroth, Alice Y. Ting

Posted 02 Nov 2020
bioRxiv DOI: 10.1101/2020.11.01.364174

The ability to record transient cellular events in the DNA or RNA of cells would enable precise, large-scale analysis, selection, and reprogramming of heterogeneous cell populations. Here we report a molecular technology for stable genetic tagging of cells that exhibit activity-related increases in intracellular calcium concentration (FLiCRE). We used FLiCRE to transcriptionally label activated neural ensembles in the nucleus accumbens of the mouse brain during brief stimulation of aversive inputs. Using single-cell RNA sequencing, we detected FLiCRE transcripts among the endogenous transcriptome, providing simultaneous readout of both cell-type and calcium activation history. We identified a cell-type in the nucleus accumbens activated downstream of long-range excitatory projections. Taking advantage of FLiCRE′s modular design, we expressed an optogenetic channel selectively in this cell-type, and showed that direct recruitment of this otherwise genetically-inaccessible population elicits behavioral aversion. The specificity and minute-resolution of FLiCRE enables molecularly-informed characterization, manipulation, and reprogramming of activated cellular ensembles. ### Competing Interest Statement A.Y.T. and M.I.S. have filed a patent covering some components used in this study (US provisional application 62/906,373; CZB file CZB-123S-P1; Stanford file S19-269; KT file 103182-1132922-002400PR).

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