A Molecular Calcium Integrator Reveals a Striatal Cell Type Driving Aversion

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From: Cell(Vol. 183, Issue 7)
Publisher: Elsevier B.V.
Document Type: Report
Length: 339 words

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Keywords calcium; light; transcription factor; neural activity; striatum; aversion; single-cell RNA sequencing; optogenetics Highlights * FLiCRE enables fast light- and calcium-gated molecular labeling of active neurons * Combining FLiCRE with optogenetic tagging identifies functionally coupled circuits * FLiCRE readout with single-cell RNA sequencing links cell type with activity * A FLiCRE-driven opsin reveals the behavioral function of activated neurons Summary 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. Author Affiliation: (1) Department of Genetics, Stanford University, Stanford, CA 94305, USA (2) Chan Zuckerberg Biohub, San Francisco, CA 94158, USA (3) Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA (4) Department of Bioengineering, Stanford University, Stanford, CA 94035, USA (5) Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA (6) Department of Biology, Stanford University, Stanford, CA 94305, USA * Corresponding author Article History: Received 30 March 2020; Revised 18 September 2020; Accepted 6 November 2020 (miscellaneous) Published: December 11, 2020 (footnote)7 These authors contributed equally (footnote)8 Lead Contact Byline: Christina K. Kim (1,7), Mateo I. Sanchez (1,2,7), Paul Hoerbelt (3), Lief E. Fenno (3,4,5), Robert C. Malenka (3), Karl Deisseroth [deissero@stanford.edu] (3,4,5,*), Alice Y. Ting [ayting@stanford.edu] (1,2,6,8,**)

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Gale Document Number: GALE|A648923404