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# Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior

## Abstract

The persistence of negative affect in pain leads to co-morbid symptoms such as anhedonia and depression—major health issues in the United States. The neuronal circuitry and contribution of specific cellular populations underlying these behavioral adaptations remains unknown. A common characteristic of negative affect is a decrease in motivation to initiate and complete goal-directed behavior, known as anhedonia. We report that in rodents, inflammatory pain decreased the activity of ventral tegmental area (VTA) dopamine (DA) neurons, which are critical mediators of motivational states. Pain increased rostromedial tegmental nucleus inhibitory tone onto VTA DA neurons, making them less excitable. Furthermore, the decreased activity of DA neurons was associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA DA neurons was sufficient to restore baseline motivation and hedonic responses to natural rewards. These findings reveal pain-induced adaptations within VTA DA neurons that underlie anhedonia-like behavior.

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### Extended Data Fig. 7 CFA does not alter intake of water during the sucrose two-bottle choice experiment.

a. 5% and 30% sucrose significantly increased consummatory protrusions as compared to water, with similar trend being seeing with 60% sucrose as well (ANOVA Friedman’s test, **** p < 0.0001; two-tailed Dunn’s multiple comparisons post hoc: 5% sucrose versus water, ** p = 0.0036; 30% sucrose versus water, * p = 0.0423, n = 5 rats). No changes are observed in number of ingestive licks or the length of the lick between different concentrations. b. Volume of water consumed is not changed after the CFA injection during either 5% (CFA (n = 13 rats), SAL (n = 12 rats)), 30% (CFA (n = 12 rats) and SAL (n = 13 rats)) or 60% (CFA (n = 15 rats), SAL (n = 12 rats)) sucrose two-bottle choice. c. CFA decreases 5% sucrose preference during two-bottle choice (open bars -baseline, filled bars – 48 hours post CFA/SAL. two-way ANOVA for repeated measures, time: F1, 23 = 2.339, p = 0.1398; interaction (time x treatment): F1, 23 = 4.446, p = 0.0461; Sidak’s post hoc within group: CFA (n = 13) baseline versus 48 hours post CFA, * p = 0.03), while it has no effect on 30% or 60% sucrose preference. d. CFA decreases latency to withdrawal from a noxious stimulus resulting in hyperalgesia (two-way ANOVA for repeated measures, 5% sucrose (CFA (n = 13 rats), SAL (n = 12 rats)), time: F1,23 = 91.75, p < 0.0001; interaction (time x treatment): F1,23 = 63.86, p < 0.0001; Sidak’s post hoc for each group as compared to the group’s baseline session: **** p < 0.0001; 30% sucrose (CFA (n = 12 rats) and SAL (n = 13 rats)) time: F1,23 = 40.71, p < 0.0001; interaction (time x treatment): F1,23 = 20.02, p = 0.0002; Sidak’s post hoc for each group as compared to the group’s baseline session: **** p < 0.0001; 60% sucrose 60% (CFA (n = 15 rats), SAL (n = 12 rats)) time: F1,25 = 72.34, p < 0.0001; interaction: F1,25 = 43.85, p < 0.0001; Sidak’s post hoc for each group as compared to the group’s baseline session: **** p < 0.0001). The data are presented as the mean ± s.e.m.

### Extended Data Fig. 8 Chemogenetic stimulation of VTA DA neurons does not alter water intake in two-bottle choice test.

a. Chemogenetic activation of DA containing neurons in the VTA does not alter sucrose preference in two-bottle choice test. b. CFA induced hyperalgesia is not altered by activation of VTA DA neurons (two-way ANOVA for repeated measures, time: F2, 48 = 148.2, p < 0.0001; interaction (time x treatment): F6, 48 = 19.30, p < 0.0001; Sidak’s post hoc for each group as compared to the group’s baseline session: **** p < 0.0001; n (hM3Dq SAL + CNO) = 7 rats, n (hM3Dq CFA + CNO) = 7 rats, n (hM3Dq CFA + VEH) = 7 rats, n (m-Cherry CFA + CNO) = 6 rats). c. Chemogenetic activation of DA containing neurons in the VTA does not alter water consumption in two-bottle choice test. d. Representative coronal section of VTA DREADD expressing neurons. Blue – DAPI; Red – m-Cherry (Gq DREADD); Green – TH (DA neurons). e. Spread of overlay of individual animal viral expression across VTA in DREADD and control m-Cherry injected TH-cre animals. The data are presented as the mean ± s.e.m.

### Extended Data Fig. 9 Chemogenetic stimulation of RMTg GABA neurons does not alter sucrose preference in two-bottle choice test.

a-d. Chemogenetic activation of RMTg GABA cells does not alter preference for 60% or 5% sucrose or water consumption in two-bottle choice test. e. Sucrose consumption presented as percent change of baseline (5% sucrose (n (m-Cherry) = 6 rats, n (hM3Dq) = 7 rats) two tailed unpaired t test, * p = 0.0105; 60% sucrose (n (m-Cherry) = 6 rats, n (hM3Dq) = 7 rats) two tailed unpaired t test p = 0.0610). f. Representative coronal section of RMTg Gq DREADD expressing neurons. Blue – DAPI; Red – m-Cherry (Gq DREADD); Green – GAD 67 (GABA neurons). g. Spread of overlay of individual animal viral expression across RMTg in DREADD and control m-Cherry injected GAD-cre animals. The data are presented as the mean ± s.e.m. h-j. PPR is not correlated with the evoked amplitude of initial response at any inter-pulse interval. The data are presented as regression line and 95% confidence interval.

### Extended Data Fig. 10 Chemogenetic inhibition of RMTg-VTA GABAergic pathway does not alter sucrose preference in two-bottle choice test.

a-b. Chemogenetic inhibition of RMTg GABA cells projecting to VTA does not alter sucrose preference or water consumption in two-bottle choice test. c. Sucrose consumption presented as percent change of baseline (two-way ANOVA for repeated measures, time: F1, 20 = 20.89, p = 0.0002; interaction (time x treatment): F2,20 = 6.236, p = 0.0079; Sidak’s post hoc within group: hM3Di + CFA + CNO(n = 8) versus hM3Di + CFA + VEH (n = 8), **** p < 0.0001) d. Representative coronal section of RMTg Gi DREADD expressing neurons. Blue – DAPI; Red – m-Cherry (Gi DREADD); Green – GAD 67 (GABA neurons). e. Representative coronal section of cannula placement in the VTA. Blue – DAPI; Red – m-Cherry (Gi DREADD); Green – TH (DA neurons). f. Spread of overlay of individual animal viral expression across RMTg in DREADD and control m-Cherry injected GAD-cre animals. i. Schematic representation of cannula placement in the VTA for local delivery of aCSF or CNO. The data are presented as the mean ± s.e.m.

## Supplementary information

### Supplementary Information

Supplementary Figs. 1–5 with legends.

### Supplementary Video 1

Hedonic protrusions, 60% sucrose.

### Supplementary Video 2

Exaggerated swallowing, 60% sucrose.

### Supplementary Video 3

Aversive quinine gapes.

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Markovic, T., Pedersen, C.E., Massaly, N. et al. Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior. Nat Neurosci 24, 1601–1613 (2021). https://doi.org/10.1038/s41593-021-00924-3