In the study of complex mammalian behaviours, technological limitations have prevented spatiotemporally precise control over intracellular signalling processes. Here we report the development of a versatile family of genetically encoded optical tools (‘optoXRs’) that leverage common structure–function relationships1 among G-protein-coupled receptors (GPCRs) to recruit and control, with high spatiotemporal precision, receptor-initiated biochemical signalling pathways. In particular, we have developed and characterized two optoXRs that selectively recruit distinct, targeted signalling pathways in response to light. The two optoXRs exerted opposing effects on spike firing in nucleus accumbens in vivo, and precisely timed optoXR photostimulation in nucleus accumbens by itself sufficed to drive conditioned place preference in freely moving mice. The optoXR approach allows testing of hypotheses regarding the causal impact of biochemical signalling in behaving mammals, in a targetable and temporally precise manner.
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We thank B. Kobilka, B. Knutson, M. P. Bokoch, T. Sudhof, R. Malenka and the Deisseroth Laboratory for comments and discussion. We appreciate the gifts of pCNGA2-C460W/E583M from J. W. Karpen, pcDNA3.1-β2AR from B. Kobilka and pDT-α1AR from C. Hague. We thank T. Jardetzky for use of a Biotek Synergy4 plate reader. R.D.A. is supported by a NIH/NIMH National Research Service Award and the Stanford Medical Scientist Training Program. K.R.T. is supported by a NARSAD Young Investigator Award. K.D. is supported by CIRM, McKnight, Coulter, Klingenstein, Keck, NSF, NIMH, NIDA, the NIH Pioneer Award, the Albert Yu and Mary Bechmann Foundation and the Kinetics Foundation.
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Airan, R., Thompson, K., Fenno, L. et al. Temporally precise in vivo control of intracellular signalling. Nature 458, 1025–1029 (2009). https://doi.org/10.1038/nature07926
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