Temporally precise in vivo control of intracellular signalling.
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 relationships 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.
Airan
Raag D
RD
Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
Thompson
Kimberly R
KR
Fenno
Lief E
LE
Bernstein
Hannah
H
Deisseroth
Karl
K
D000818:Animals; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005818:Genetic Engineering; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism* / Q000528:radiation effects; D051379:Mice; D009714:Nucleus Accumbens / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D013329:Structure-Activity Relationship; D013997:Time Factors
C547713:ADRA1A protein, human; C547714:Adra1a protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018340:Receptors, Adrenergic, alpha-1; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D012243:Rhodopsin