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Constraints on the subsecond modulation of striatal dynamics by physiological dopamine signaling

Nature Neuroscience volume 27, pages 1977–1986 (2024)Cite this article

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Abstract

Dopaminergic neurons play a crucial role in associative learning, but their capacity to regulate behavior on subsecond timescales remains debated. It is thought that dopaminergic neurons drive certain behaviors by rapidly modulating striatal spiking activity; however, a view has emerged that only artificially high (that is, supra-physiological) dopamine signals alter behavior on fast timescales. This raises the possibility that moment-to-moment striatal spiking activity is not strongly shaped by dopamine signals in the physiological range. To test this, we transiently altered dopamine levels while monitoring spiking responses in the ventral striatum of behaving mice. These manipulations led to only weak changes in striatal activity, except when dopamine release exceeded reward-matched levels. These findings suggest that dopaminergic neurons normally play a minor role in the subsecond modulation of striatal dynamics in relation to other inputs and demonstrate the importance of discerning dopaminergic neuron contributions to brain function under physiological and potentially nonphysiological conditions.

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Fig. 1: Simultaneous monitoring of dopamine and electrophysiological activity in the ventral striatum.
Fig. 2: Small effect of inhibiting VTA dopaminergic neurons on reward-evoked striatal spiking activity.
Fig. 3: Population-level decoding discriminates striatal neuron reward responses with and without dopamine.
Fig. 4: Strong effect of activating VTA GABAergic neurons on reward-evoked striatal spiking activity.
Fig. 5: Small effect of artificial reward-matched dopamine transients on spontaneous striatal activity.
Fig. 6: Supra-reward dopamine signals modulate reward-evoked striatal spiking activity.

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Data availability

The data that support the findings of this study are available from the Zenodo repository via https://doi.org/10.5281/zenodo.8237324 (ref. 60).

Code availability

The MATLAB code used for analyzing data is available at https://github.com/sotmasman/Dopamine-constraints

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Acknowledgements

S.C.M. was supported by National Institutes of Health grants no. NS100050, no. NS125877, no. DA042739 and no. DA005010, and NSF NeuroNex Award no. 1707408. C.L. was supported by National Institutes of Health grant no. 5T32DA024635 and National Institute of General Medical Sciences grant no. T32GM008042.

Author information

Author notes

  1. Kwang Lee

    Present address: Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea

  2. Theresia Dafalias

    Present address: Graduate Program for Neuroscience, Boston University, Boston, MA, USA

  3. These authors contributed equally: Charltien Long, Kwang Lee.

Authors and Affiliations

  1. Department of Neurobiology, University of California, Los Angeles, CA, USA

    Charltien Long, Kwang Lee, Long Yang, Theresia Dafalias, Alexander K. Wu & Sotiris C. Masmanidis

  2. Medical Scientist Training Program, University of California, Los Angeles, CA, USA

    Charltien Long

  3. California Nanosystems Institute, University of California, Los Angeles, CA, USA

    Sotiris C. Masmanidis

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Contributions

C.L., K.L. and S.C.M. designed the study. C.L., K.L., A.K.W. and T.D. collected the data. C.L., K.L., L.Y. and S.C.M. analyzed the data and interpreted the results. C.L., K.L. and S.C.M. prepared the manuscript.

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Correspondence to Sotiris C. Masmanidis.

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Extended data

Extended Data Fig. 1 Reward response of electrophysiologically classified cell types in the ventral striatum.

a. Percentage of each cell type that showed a significant reward response. b. Mean firing rate of one putative FSI (left) and TAN (right) unit during reward delivery. Data in this figure represent mean ± SEM (shading). c. Selectivity index of a population of 774 MSNs, 136 FSIs, and 95 TANs during reward delivery. Selectivity of neural activity is calculated relative to baseline.

Extended Data Fig. 2 GRIN lens imaging of dopamine dynamics in the ventral striatum.

a. Experimental approach. Miniscope placed above GRIN lens for imaging (not pictured). b. dLight fractional fluorescence change for R trials (black) and R + L trials (orange). Translucent traces represent a random sample of 20 individual pixel responses for each trial type; opaque traces represent the mean signal across all pixels. c. Frequency plot of pixel mean peak fluorescence change for R (black) and R + L (orange) trials relative to mean reward response (black dashed line) (n = 2339 pixels, paired two-sided t-test, t = 117, P < 0.0001). d. Comparison plot of pixel mean peak fluorescence in R and R + L trials (n = 2339 pixels). Line of identity in black.

Extended Data Fig. 3 Effect of VTA dopaminergic neuron inhibition on reward-evoked striatal firing rates.

a. Mean firing rate changes for neurons of each cell type (eNpHR3 animals: n = 435 MSN, 73 FSI, 58 TAN; control animals: n = 339 MSN, 63 FSI, 37 TAN; one-way ANOVA, cell type x group effect: F5,999 = 6.937, P < 0.0001). Post-hoc Sidak’s test comparing eNpHR3 animals and controls: MSN (P = 0.25), FSI (P < 0.0001), TAN (P = 0.99). Data represent mean ± SEM. b. Mean firing rate changes for neurons of each cell type group by ML position. One-way ANOVA: MSN ML position effect (F3,431 = 3.193, P = 0.02), FSI ML position effect (F3,69 = 0.869, P = 0.46), TAN ML position effect (F3,54 = 0.474, P = 0.70). Post-hoc Tukey’s test for MSN: P = 0.0529 for 1.05 mm vs. 1.45 mm. Data in this figure represent mean ± SEM. c. Mean firing rate changes for neurons of each cell type group by DV position. One-way ANOVA: MSN DV position effect (F3,431 = 4.557, P = 0.004), FSI DV position effect (F3,69 = 0.904, P = 0.44), TAN DV position effect (F3,54 = 1.002, P = 0.40). Post-hoc Tukey’s test for MSN: P = 0.005 for 4.4 mm vs. 5.0 mm, P = 0.02 for 4.7 mm vs. 5.0 mm. Data represent mean ± SEM. d. Comparison of TAN pause duration in eNpHR3 expressing animals across R and R + L trial types (n = 29 TANs, paired two-sided t-test, t = 0.3825, P = 0.7). Data represent mean ± SEM.

Extended Data Fig. 4 Effect of VTA dopaminergic neuron inhibition on spontaneous striatal activity.

a. Top: Experimental approach. Bottom: Task schematic. b. dLight fractional fluorescence change (mean ± SEM) from one eNpHR3-expressing mouse and one opsin-free control mouse. c. Mean laser-evoked dLight fluorescence (n = 5 eNpHR3 and 3 control mice, unpaired two-sided t-test, t = 4.2, **P = 0.005). d. Total percentage of neurons significantly modulated by laser relative to baseline (n = 46 out of 589 cells in eNpHR3 group, n = 25 out of 344 cells in control group, chi square test, χ2 = 0.09, P = 0.8, df = 1). e. Maximum selectivity index per neuron (n = 589 cells in the eNpHR3 group, n = 344 cells in the control group, unpaired two-sided t-test, t = 1.1, P = 0.3). Selectivity of neural activity is calculated relative to baseline. Lines represent mean ± SD, dots represent individual cells. f. Firing rate changes (mean ± SEM) by cell type (eNpHR3 animals: n = 435 MSN, 73 FSI, 58 TAN; control animals: n = 261 MSN, 44 FSI, 25 TAN; one-way ANOVA, cell type x group effect: F5,890 = 4.303, P = 0.0007). Post-hoc Sidak’s test comparing eNpHR3 and controls: MSN (P = 0.78), FSI (P = 0.45), TAN (P = 0.37). g. Top: Selectivity index of 589 neurons pooled across 5 eNpHR3-expressing mice, and 344 neurons pooled across 3 control mice. Bottom: Percentage of neurons significantly modulated by the laser relative to baseline. h. Mean accuracy of SVM decoder trained using 50 neurons to discriminate laser-evoked from baseline activity. Magenta dashed line indicates the 95 % confidence interval of decoder performance trained on trial-shuffled data. Top: eNpHR3 group. Bottom: control group. Shaded area represents the SD across 50 random drawings of neurons. i. Maximum decoder accuracy (mean ± SD across 50 drawings) by neuron number (two-way ANOVA, group effect: F1,784 = 8, P = 0.004, neuron number effect: F7,784 = 116, P < 0.0001). Post-hoc Sidak’s test: **P = 0.005 for n = 50 neurons; other comparisons between eNpHR3 and control group not significant.

Extended Data Fig. 5 Effect of dopaminergic neuron inhibition during reward anticipation.

a. Top: Targeted areas in the striatum. Bottom: task schematic. b. Fractional fluorescence change from one eNpHR3-expressing mouse (mean ± SEM). c. Mean cue-evoked fluorescence (n = 4 eNpHR3 and 5 control mice, two-way RM ANOVA, group effect: F1,14 = 1.6, P = 0.2, trial effect: F1,14 = 5, P = 0.04). d. Mean anticipatory lick rate (n = 5 eNpHR3 and 6 control mice, two-way RM ANOVA, group effect: F1,14 = 15, P = 0.0016, trial effect: F1,14 = 0.1, P = 0.8). e. Top: Neuronal selectivity index (SI) from eNpHR3 expressing mice (n = 124 ventral-striatal neurons from 2 mice, n = 77 dorsal-striatal neurons from 2 mice). Middle: SI from control mice (n = 111 ventral-striatal neurons from 3 mice, n = 105 dorsal-striatal neurons from 2 mice). Bottom: Time course of percent neurons significantly modulated by the laser. f. Total percent neurons selective for trial type pooled by recording location (n = 18/124 ventral striatal cells in eNpHR3 group, n = 19/111 ventral striatal cells in control group, chi-square test, χ2 = 0.3, P = 0.6, df = 1; n = 9/77 dorsal striatal cells in eNpHR3 group, n = 13/105 dorsal striatal cells in control group, chi-square test, χ2 = 0.02, P = 0.9, df = 1). g. Mean accuracy (± SD of 50 drawings) of decoder trained using 50 neurons pooled across ventral and dorsal striatum to discriminate trial type. Magenta dashed line indicates 95 % confidence interval of decoder performance trained on trial-shuffled data. h. Maximum decoder accuracy (mean ± SD of 50 drawings) as a function of number of neurons drawn (two-way ANOVA, group effect: F1,588 = 214, P < 0.0001, neuron number effect: F5,588 = 194, P < 0.0001). Post-hoc Sidak’s test: P < 0.01 for all neuron numbers. i. Maximum decoder accuracy (mean ± SD of 50 drawings) using 50 neurons by recording location (one-way ANOVA, group x recording location effect: F3,196 = 72, P < 0.0001). Post-hoc Sidak’s test: P < 0.001 for all pairwise comparisons.

Extended Data Fig. 6 Effect of activating VTA GABAergic neurons on spontaneous striatal spiking activity.

a. Top: Experimental approach. Bottom: task schematic in which 0.5 s pulsed laser stimulation is delivered in the absence of reward or other stimuli. b. Top: dLight fractional fluorescence change signal during laser stimulation from one Vgat-Chrimson mouse. Bottom: Mean firing rate of one neuron. Data represent mean ± SEM. c. Top: Selectivity index of 379 neurons pooled across 3 Vgat-Chrimson mice. Bottom: Percentage of neurons that were significantly modulated by the laser relative to baseline, as a function of time. d. Top: Mean accuracy of an SVM decoder trained using 50 neurons to discriminate laser-evoked from baseline activity. Shaded area represents the SD across 50 random drawings of neurons. Magenta line indicates the 95 % confidence interval of decoder performance trained on trial-shuffled data. Bottom: Maximum decoder accuracy as a function of neuron number (one-way ANOVA, neuron number effect: F7,392 = 441, P < 0.0001). Post-hoc Sidak’s test: P < 0.0001. Data represent the mean and SD across 50 random drawings of neurons.

Extended Data Fig. 7 Factor increase in dopamine effects on neuron firing rates.

a. Changes in MSN firing rates compared to baseline as a function of factor increase in dopamine. n = 26 sessions from 9 Chrimson-expressing mice, and n = 12 sessions from 4 control mice. Chrimson group MSN data are positively correlated with the factor increase in dopamine (Pearson r = 0.6, P = 0.0033). Dashed line represents the highest value seen in the control data. Blue line represents the linear fit to the Chrimson data. b. Changes in FSI firing rates compared to baseline as a function of factor increase in dopamine (Pearson r = 0.005, P = 0.98). Dashed line represents the highest value seen in the control data. c. Changes in TAN firing rates compared to baseline as a function of factor increase in dopamine (Pearson r = 0.12, P = 0.55). Dashed line represents the highest value seen in the control data.

Extended Data Fig. 8 Assessing sources of variability in estimating the factor increase in dopamine.

a. Experimental approach of the dLight photometry depth test. b. Reward-evoked dLight fractional fluorescence change signal from one Chrimson-expressing mouse. The plots are color-coded by photometry fiber depth from bregma. c. Laser-evoked dLight fractional fluorescence change signal from one Chrimson-expressing mouse. The plots are color-coded by photometry fiber depth from bregma. d. Factor increase in dopamine (the ration of laser-evoked to reward-evoked dLight signal amplitudes) calculated from data at different photometry fiber depths. Data are from n = 2 mice. e. Recalibrated versus original factor increase in dopamine. The recalibrated factor used only the first 10 % of reward trials (n = 26 sessions from 9 Chrimson-expressing mice, paired two-sided t-test, t = 2.1, P = 0.04). f. Maximum decoder accuracy per recording session, as a function of recalibrated factor increase in dopamine. The decoder was trained using 50 neurons to discriminate laser-evoked from baseline activity. Chrimson group data are positively correlated with the factor increase in dopamine (Pearson r = 0.9, P < 0.0001). Dashed line represents the highest value seen in the control data. Blue line represents the linear fit to the Chrimson data.

Extended Data Fig. 9 Effect of supra-reward dopamine signals on activity of different putative striatal cell types.

a. Top: Experimental approach. Bottom: Task schematic. All data in this figure are from the supra-reward condition (4 mice exhibiting over 80 % decoding accuracy in Fig. 6e). b. Mean firing rate of an FSI and TAN. Data in b, e, i-k represent mean ± SEM. c. Percent of selective cells. d. Mean ± SD of maximum absolute value of selectivity index (n = 322 MSN, 63 FSI, 31 TAN, one-way ANOVA, cell type effect: F2,413 = 18, P < 0.0001). Post-hoc Sidak’s test: ****P < 0.0001. e. Mean firing rate changes for each cell type (Chrimson animals: n = 322 MSN, 63 FSI, 31 TAN; control animals: n = 308 MSN, 42 FSI, 17 TAN; one-way ANOVA, cell type x group effect: F5,777 = 8.416, P < 0.0001). Post-hoc Sidak’s test for eNpHR3 vs controls: MSN (P = 0.12), FSI (P = 0.0005), TAN (P = 0.40). f. Top: Selectivity index of 322 MSNs from 4 Chrimson-expressing mice. Bottom: Percentage of neurons selective for trial type over time. g. Same as f for 63 FSIs. h. Same as f for 31 TANs. i. Mean neuron firing rate changes by ML position. One-way ANOVA, position effect: MSN (n = 322, F3,318 = 6, P = 0.0005), FSI (n = 63, F3,59 = 2, P = 0.12), TAN (n = 31, F3,27 = 0.22, P = 0.88). Post-hoc Tukey’s test for MSN: P = 0.004 for 1.05 mm vs. 0.65 mm, P = 0.001 for 1.05 mm vs. 1.45 mm, P = 0.004 for 1.05 mm vs. 1.85 mm. j. Same as i but by DV position. One-way ANOVA, position effect: MSN (n = 322, F3,318 = 3.027, P = 0.03), FSI (n = 63, F3,59 = 1.848, P = 0.15), TAN (n = 31, F3,27 = 1.599, P = 0.21). Post-hoc Tukey’s test for MSN: P = 0.02 for 4.1 mm vs. 4.4 mm. k. TAN pause durations (n = 24 neurons, paired two-sided t-test, t = 2.5, P = 0.02).

Extended Data Fig. 10 Effect of dopaminergic neuron activation during auditory stimulus processing in ventral striatum.

a. Top: Experimental approach. Bottom: task schematic in which neutral auditory tone trials (T) are compared to laser-paired tone trials (T + L). b. Fractional fluorescence change signal from one Chrimson-expressing mouse (top) and one opsin-free control mouse (bottom) on tone (T) and laser-paired tone (T + L) trials (mean ± SEM). c. Percentage of neurons per animal that were selective for T versus T + L trials, as a function of dopamine tone amplification factor (an amplification factor of one corresponds to tone-matched dopamine levels). n = 4 Chrimson-expressing and 2 control mice (Pearson r = 0.8, P = 0.18). Dashed line represents the highest value seen in the control data. d. Maximum decoder accuracy per animal, as a function of dopamine tone amplification factor. The decoder was trained using 50 neurons to discriminate R from R + L trials. n = 4 Chrimson-expressing and 2 control mice (Pearson r = 0.9, P = 0.12). Dashed line represents the highest value seen in the control data. e. Mean firing rate of two putative MSNs on T and T + L trials. Data are from the supra-reward condition (mice exhibiting over 80 % decoding accuracy in panel d). Data represent mean ± SEM. f. Top: Selectivity index of 226 neurons pooled across 2 Chrimson-expressing mice. Bottom: Percentage of neurons that were significantly selective for T versus T + L trials, as a function of time. Data are from the supra-reward condition (mice exhibiting over 80 % decoding accuracy in panel d).

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Long, C., Lee, K., Yang, L. et al. Constraints on the subsecond modulation of striatal dynamics by physiological dopamine signaling. Nat Neurosci 27, 1977–1986 (2024). https://doi.org/10.1038/s41593-024-01699-z

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