Genetically encoded dopamine sensors based on green fluorescent protein (GFP) enable high-resolution imaging of dopamine dynamics in behaving animals. However, these GFP-based variants cannot be readily combined with commonly used optical sensors and actuators, due to spectral overlap. We therefore engineered red-shifted variants of dopamine sensors called RdLight1, based on mApple. RdLight1 can be combined with GFP-based sensors with minimal interference and shows high photostability, permitting prolonged continuous imaging. We demonstrate the utility of RdLight1 for receptor-specific pharmacological analysis in cell culture, simultaneous assessment of dopamine release and cell-type-specific neuronal activity and simultaneous subsecond monitoring of multiple neurotransmitters in freely behaving rats. Dual-color photometry revealed that dopamine release in the nucleus accumbens evoked by reward-predictive cues is accompanied by a rapid suppression of glutamate release. By enabling multiplexed imaging of dopamine with other circuit components in vivo, RdLight1 opens avenues for understanding many aspects of dopamine biology.
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All DNA plasmids and viruses used in this study have been deposited in NCBI (accession numbers MK751449 and MK751450) and ADDGENE, and can be obtained either from the Tian laboratory at UC Davis, Addgene or the Canadian neurophotonics platform viral (https://tools.neurophotonics.ca/) core under a material-transfer agreement. All source data present in this manuscript are available from https://github.com/lintianlab/RdLight1. Source data are provided with this paper.
Custom MATLAB code is available via https://github.com/lintianlab/RdLight1.
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This work was supported by NIH DP2MH107056 (L.T.); BRAIN Initiative awards U01NS090604, U01NS013522 (L.T. and M.V.Z), U01NS103571 (L.T) and U01NS094375 (J.B.); a Rita Allen Young Investigator Award (L.T.) and R01DA045783 (J.D.B.); the Olga Mayenfisch Foundation (T.P.); and the Novartis Foundation for medical-biological research (T.P.). We thank D. Jullie (UCSF) for advice and providing striatal neuronal culture. We thank J. Zhang and C.-H. Chen for advice on FACS experiments.
L.T. and G.O.M. are co-founders of Seven Biosciences.
Peer review information Nina Vogt was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Outline and summary.
a, Fluorescence emission spectra of dLight1.3b variants carrying red-shifting mutations in their GFP component. Fluorescence emission was measured in the 450-650 nm wavelength range both in the absence of DA (dotted lines) and upon addition of 100 μM DA to the medium (continuous lines). n = 4 cells from 3 cultures. b, Representative image showing membrane expression profile of the initial variant of the red dopamine sensor, carrying the original amino acid linkers from JRGECO1a. The experiments were repeated at least twice with similar results. c, linker screening results from a library of 264 variants in which the two aminoacid pairs flanking cpmApple were randomized (as shown in inset). Red and blue vertical bars indicate fluorescence changes (∆F/F) in response to 100 μM DA; significance values of ∆F/F are shown by colored bars and scale. n = 3 trials, two-tailed t test. d, optimization of the RdLight1 fluorescence response was achieved by selectively mutating residue F129 into a subset of amino acids. Fluorescence change (∆F/F) was measured in HEK293 cells in response to bath-applied 100 μM DA. n = 4 cells from 2 cultures. **p<0.01, ****p<0.0001, two-tailed t test. The experiments were repeated at least twice with similar results. Data are shown as mean ± SEM.
Confocal imaging of RdLight1 in transfected HEK293 cells. a, b, Frame scan imaging performed in the presence of both blue (488 nm) and green (561 nm) light after (a) or before (b) bath-application of DA. Blue light did not significantly increase the fluorescence response of RdLight1 to DA. Average ∆F/F=-0.006±0.003 (baseline), 0.53±0.03(DA), 0.69±0.06(DA+blue light, One-way Anova, ***P=0.0005, n.s P=0.1224, n=5 cells from two cultures (a). Average ∆F/=0.002±0.001 (baseline+blue light), 0.83±0.06(DA+blue light), 0.69±0.08(DA), One-way Anova, ***P=0.0007, n.s P=0.0678, n=5 cells from two cultures, mean±SEM (b). c, Representative line scan imaging at acquisition rate of 1000 Hz. Bursts of 488nm laser (150 ms duration at 1Hz) was applied followed by application of DA. Laser powers used were: 24779.4 W/cm2 for 561nm laser, 16373.7 W/cm2 for 488nm laser. Experiments were performed six times with similar results.
a, b, Titration curves are shown for the response to DA or NE both in HEK293 cells and in cultured neurons. Data points were fit with a one-site specific binding curve to obtain EC50 values. Data are shown as mean ± SEM. n = 7 cells from 2 cultures for both HEK293 cells and neurons. The response of RdLight to NE at 1mM is significantly lower than that to DA (P=4.8x10 -8, paired t-test (two sided). c, The specificity of RdLight1 was tested by performing titrations of a panel of different neurotransmitters on the sensor expressed in HEK293 cells. Quantification of responses to each concentration of ligand are shown as mean ± SEM. n = 12 cells from 2 cultures. Neurotransmitters tested were: norepinephrine (NE), epinephrine (EPI), acetylcholine (ACH), glutamate (GLU), histamine (HIS), serotonin (5HT). The experiments were repeated at least twice with similar results.
a, cAMP response curve to a titration of the D1 agonist SKF81297 in HEK293 cells transfected with RdLight1 compared to human D1-dopamine receptor (DRD1, positive control) or enhanced green fluorescence protein (GFP, negative control). No significant cAMP response was produced by RdLight1 (n=3 independent experiments, **p=0.0033, ***p=0.00053, one-way ANOVA, Dunnett’s post-hoc test). b, cAMP response curves of a cell line endogenously expressing DRD1 (U2OS). Overexpression of RdLight1 did not alter the endogenous cAMP response to SKF81297 (n=3 independent experiments, p=0.944, two-way ANOVA). c, Expression of RdLight1 (red) in cultured primary striatal neurons did not affect cAMP responses to vehicle, SKF81297 or the adenylate cyclase activator Forskolin, compared to mock-transfected conditions (black), as measured by the green genetically encoded cAMP sensor cADDis (n=10 neurons from three cultures, P=0.744 (unpaired t-test, two-tailed). d, TIRF imaging of RdLight1 response (red) and of a static Alexa-647-conjugated anti-Flag antibody label to delineate sensor expression on cell surface (far-red channel). Quantification of RdLight1 response to a DRD1 agonist (SKF81297), which was immediately abolished by applying antagonist (SCH23390) (n=3 independent experiments). e, RdLight1 internalization is significantly reduced compared to wild type DRD1 as assayed via flow cytometry (% internalized receptor: RdLight1, 4.82 ± 6.42 %; DRD1, 31.9 ± 2.74 %, n=4 independent experiments, p=0.0006 (unpaired t-test, two-tailed). f, g, Representative TIRF microscopy images of HEK293 cells transfected with beta-arrestin-2 and DRD1 or RdLight1. DRD1 and RdLight1 were labeled with an Alexa-647 conjugated anti-flag antibody. Conditions before and after addition of DRD1 agonist SKF81297 are shown. Experiments were performed three times with similar results. h, i, Quantification of beta-arrestin-2 recruitment on the cell membrane from f, g. Under these conditions RdLight1 triggers significantly lower beta-arrestin-2 recruitment than DRD1. RdLight1, 6.8 ± 4.2 (n=8 cells); DRD1, 1.3 ± 0.5 (n=7 cells), P=0.0029 (unpaired t-test, two-tailed). All values shown are mean±SD.
Extended Data Fig. 6 Multiplex imaging of drug selectivity at two dopamine receptor subtypes and characterization of RdLight1 and nLight1.3 coexpression.
a, Combined fluorescence emission spectra of DRD1-based (dLight1.5) and DRD1-based (RdLight1) sensors used for multiplex imaging experiments. Fluorescence emission was measured in the 450-700 nm wavelength range both in the absence of DA (dotted lines) and upon addition of 100 μM DA to the medium (continuous lines). n = 4 cells from 3 cultures. b, c, Dose-response curves were obtained by performing multiplex imaging during titrations of the DRD1-selective agonist A77636 or the DRD2-selective agonist Quinpirole on a coculture of two HEK293 cell populations expressing either RdLight1 (red) or dLight1.5 (green). Maximal fluorescence responses at each applied concentration were quantified and plotted. n = 6 cells from 3 cultures. Data are shown as mean ± SEM. d–f, Characterization of RdLight1 and nLight1.3 coexpression. d, Flow cytometry analysis of cells transfected with RdLight1 (n=13928 cells), nLight1.3(n=25798 cells), or both (n=33049 cells) showed that co-transfection significantly increased both basal green and basal red-fluorescence. Violin plots show the distribution of the log value of fluorescence, on top of the boxplot of the same data. P=2.2X10-16 Two-sided Student’s t-test. e, f, In a perfusion experiment, confocal time-lapse imaging revealed that the response of nLight1.3 to NE when expressed alone (n=8) can be slightly decreased when cotransfected with RdLight1 (n=7 cells), which could possibly due to increased basal green fluorescence from RdLight1 co-transfection. A slight increase in the amplitude of response in RdLight1 was noticed when co-transfected (n=7 cells), but not significant. P=0.04 and 0.16, Two-sided Student’s t-test for the value when NE or DA applied. Traces were plotted as mean +/- sem, with center line as mean value and shade the s.e.m.
Two-photon bleaching measurements of RdLight were acquired from acute brain slices. Fluorescence of RdLight was excited at 1020 nm with a Ti: sapphire laser (Ultra II, Coherent) that was focused by an Olympus 40×, 0.8NA water immersion objective. Emitted fluorescence photons were separated by a 620/60 nm filter. Scan area was 60 μm×60 μm, and the scan rate was 30 frames/s. Light intensity was kept at 8.7 mW across measurements. Burst electrical stimulation was performed with a metal bipolar electrode that has a tip spacing of 255 μm (PI2ST30.01A5, Microprobes for life science) every 100 s. Amplitude of the pulses was 4 V, width was 0.3 ms and a total number of 40 pulses was applied at a frequency of 80 Hz. As shown in the figure, photobleaching was continuously measured in a 1 h duration. Overall fluorescence in all the 3 tested slices declined about 17.2±3.1%, mean ± SEM. The experiments were repeated in 3 slices from two mice with similar results.
a, List of all in vivo experiments in which RdLight1 was expressed in NAc simultaneously with a green indicator. b, Representative stitched image for each experiment collected on an epifluorescence microscope using a 4x objective. All sections (except for the D1-Cre example) are collected in horizontal planes. The D1-Cre example is in the coronal plane. Each section shows the most ventral section with a fiber punch hole. Scale bar: 1 mm. c, Overlaid reconstruction map of the estimate location of recordings for each experiment. Histology results were not available for one subject in the TH-Cre experiment since the subject died prior to the end of the experiment. Brain atlas outlines in this figure were reproduced with permission from (Paxinos and Watson, 2005).
To further validate the dip observed in the glutamate signal in NAc following the reward click in Fig. 4, we performed two complementary experiments. a, Only iGluSnFR was expressed in NAc and imaged using a 400 μm fiber during the pavlovian approach task. b, c, similar patterns to Fig. 4b,c, demonstrating a dip following the reward click was observed when only iGluSnFR was expressed and monitored. d–f, To control for pH changes or other artifacts, we expressed a variant of iGluSnFR (SF-iGluSnFR.R75A) with a mutation to the binding sites that destroyed glutamate binding, along with RdLight1. While similar to Fig 4b,c RdLight1 signal was preserved, the dip in the glutamate signal disappeared. Experiments for each panel were repeated independently for n=2 rats with similar results.
Extended Data Fig. 10 In vivo signal-to-noise ratio comparison between RdLight1 and dLight1.3b, and effect of dLight1.1 or RdLight1 expression in NAc on motivated approach behavior.
a, Peak response to an unpredicted click signaling immediate reward delivery. Signals were collected using fiber photometry across n=6 rats with dLight1.3b expressed in NAc and n=7 rats with RdLight1 expressed in the same coordinates. RdLight1 signals demonstrated significantly higher signal-to-noise ratio (SNR). A one-sided t-test was used to assess statistical significance (p=8.04x10^-3). Box plot shows the mean and quartiles of the data with whiskers representing the range of observations. b, To investigate the effect of dopamine indicators on behavior, we compared two cohorts of rats expressing either dLight1.1 (n=8) or RdLight1 (n=6) in NAc to a control group (n=6) expressing neither. Similar to the experimental paradigm for the in vivo photometry experiments, rats are placed in an operant chamber with a speaker and a reward delivery port. An auditory click indicating an immediate delivery of a sucrose pellet is played at random intervals. Rats with either of the indicators expressed in NAc show no difference to the control group in their latency to approach and retrieve the reward following the click. A kolmogorov-smirnov test was used to compare the latency distributions.
Multiplex imaging of drug-target engagement in HEK293 cells. The movie shows live multiplex confocal imaging of two populations of HEK293 cells that were individually transfected for dLight1.5 or RdLight1 and then cocultured. The fluorescence response of the two sensors to different DA-receptor drugs are shown. The following drugs, in chronological order, were sequentially bath-applied to the cells: A77636, quinpirole, SCH-23390 and sulpiride. Scale bar, 10 μm. Images were acquired at 3.13 s per frame. The experiments were repeated three times with similar results
Multiplex imaging of NE and DA in a neuron–astrocyte coculture. Multiplex confocal imaging of neurons and astrocytes, related to Fig. 1g,h. Cells were grown in a coculture and transduced together with the following AAVs: AAV1.GFAP.nLight1.3 and AAV.hSynapsin1.RdLight1. The cells were imaged 14 d after AAV transduction. During imaging, DA, NE, the DRD1 antagonist SCH-23390 and the B2AR antagonist ICI118551 were sequentially applied to the cell bath while the fluorescence of both sensors was being recorded. The molecular specificity of the two sensors allowed the in vitro optical dissection of DA from NE, while the subtype-specific antagonists selectively reversed the fluorescence responses. Images were acquired at 3.13 s per frame. The experiments were repeated three times with similar results.
Fluorescent fold change calculated from raw data and used to plot graphs displayed in the figure
Fluorescent signals of RdLight1, iGluSnFR and GCaMP6 responses to field stimuli
Fluorescent signals of RdLight1 and GCaMP in response to light stimuli or behavior
Fluorescent signals of RdLight1, iGluSnFR and GCaMP in response to behavior
Emission scan and sensor screening
Fluorescence signals of RdLight in response to blue/yellow light illumination
In situ titration of RdLight1 and specificity
cAMP production in three types of cells, internalization and β-arrestin recruitment assay
Emission spectrum, in situ titration of RdLight1 and nLight1.3 to ligands and drugs
Fluorescence signal of RdLight in response to field stimuli in acute striatal slice
Fluorescent traces comparing iGluSnFR, iGluSnFR(mut) and RdLight1 responses to unpredicted reward cue
Fluorescent traces comparing dLight SNR to RdLight in response to unpredicted reward cue
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Patriarchi, T., Mohebi, A., Sun, J. et al. An expanded palette of dopamine sensors for multiplex imaging in vivo. Nat Methods 17, 1147–1155 (2020). https://doi.org/10.1038/s41592-020-0936-3
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