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Ventral arkypallidal neurons inhibit accumbal firing to promote reward consumption

Nature Neuroscience volume 24, pages 379–390 (2021)Cite this article

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Abstract

The nucleus accumbens shell (NAcSh) and the ventral pallidum (VP) are critical for reward processing, although the question of how coordinated activity within these nuclei orchestrates reward valuation and consumption remains unclear. Inhibition of NAcSh firing is necessary for reward consumption, but the source of this inhibition remains unknown. Here, we report that a subpopulation of VP neurons, the ventral arkypallidal (vArky) neurons, project back to the NAcSh, where they inhibit NAcSh neurons in vivo in mice. Consistent with this pathway driving reward consumption via inhibition of the NAcSh, calcium activity of vArky neurons scaled with reward palatability (which was dissociable from reward seeking) and predicted the subsequent drinking behavior during a free-access paradigm. Activation of the VP–NAcSh pathway increased ongoing reward consumption while amplifying hedonic reactions to reward. These results establish a pivotal role for vArky neurons in the promotion of reward consumption through modulation of NAcSh firing in a value-dependent manner.

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Fig. 1: NAcSh inhibition is causally related to reward consumption.
Fig. 2: A subpopulation of VP neurons innervates projection neurons and interneurons in the NAcSh.
Fig. 3: VP neurons make inhibitory, monosynaptic contacts onto NAcSh neurons.
Fig. 4: Activation of vArky terminals inhibits NAcSh firing in vivo.
Fig. 5: vArky calcium activity is correlated with duration of reward consumption.
Fig. 6: Closed-loop activation of vArky terminals promotes reward consumption.
Fig. 7: Selective vArky inhibition attenuates consumption-related inhibition of NAcSh firing and reduces length of reward consumption bouts.
Fig. 8: vArky activation enhances reward value and vArky calcium activity scales with reward palatability.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request. Analysis code will be provided from authors upon request.

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Acknowledgements

We thank A. V. Kravitz for assistance with fiber photometery and in vivo electrophysiology experiments and M. C. Stander for excellent technical help. We thank A. V. Kravitz and I. Monosov for critical reading of the manuscript. Graphics used in schematics of experiments were adapted from https://scidraw.io/. Research was supported by intramural funds from the US National Institute of Child Health and Human Development (to C.E.L.P.) and internal funds from the McDonnell Center for Systems Neuroscience (to B.M.-A.) and Department of Anesthesiology at Washington University in St Louis (to M.C.C.), the Brain and Behavior Research Foundation (NARSAD Young Investigator Grant 27197 to M.C.C.), National Institutes of Health National Institute on Drug Abuse (R21-DA047127, R01-DA049924 to M.C.C.), a Whitehall Foundation Grant (2017-12-54 to M.C.C.) and a Rita Allen Scholar Award in Pain (to M.C.C.).

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Author notes

  1. These authors contributed equally: Yvan M. Vachez, Jessica R. Tooley.

Authors and Affiliations

  1. Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St Louis, MO, USA

    Yvan M. Vachez, Jessica R. Tooley, Kavitha Abiraman, Tom Earnest, Elizabeth Godynyuk & Meaghan C. Creed

  2. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA

    Bridget Matikainen-Ankney, Eric Casey, Tom Earnest, Elizabeth Godynyuk & Meaghan C. Creed

  3. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Leana M. Ramos, Hanna Silberberg & Claire E. Le Pichon

  4. Department of Anatomy and Neurobiology, University of Maryland, Baltimore, MD, USA

    Olivia Uddin

  5. Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA

    Lauren Marconi

  6. Departments of Neuroscience and Biomedical Engineering, Washington University School of Medicine, St Louis, MO, USA

    Meaghan C. Creed

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Contributions

Y.M.V., K.A. and M.C.C. wrote the paper with input from all authors. Y.M.V., J.R.T., L.M., L.M.R., H.S. and T.E. performed anatomical experiments. Y.M.V., K.A. and M.C.C. performed patch-clamp physiology. M.C.C., J.R.T. and O.U. performed in vivo electrophysiology. Y.M.V., J.R.T. and E.G. performed fiber photometry. Y.M.V., J.R.T., E.C. and K.A. performed behavioral experiments. B.M.-A. engineered custom hardware for behavioral experiments and B.M.-A. and T.E. developed the analytical methods. Data were analyzed by Y.M.V., J.R.T., K.A. and M.C.C. Work was supervised by B.M.-A., C.E.L.P. and M.C.C.

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Correspondence to Meaghan C. Creed.

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Extended data

Extended Data Fig. 1 NAcSh units are activated by reward approach.

a-b, Top: examples of approach-activated and approach-inhibited single units from the same mouse, aligned to drinking onset. Raster and PSTH of units activated and inhibited during reward approach; bottom = mean ± SEM. c, Summary of approach-related responses of n=32 multi-units from 6 mice; 6.25% decrease, 25.0% increase, 68.75% no change, and normalized firing rate changes in response to approach (mean increase = 1.81 ± 0.20, mean decrease = 0.79 ± 0.09; mean ± sem (d) Euler diagram showing overlap of functionally defined NAcSh units.

Extended Data Fig. 2 NAcSh inhibition promotes reward consumption without inducing a place preference or locomotor effects.

a, Histology showing viral infection and optic fiber placement (scale bar = 1 mm). b, Arch stimulation increased total drinking time (Arch No Stim: 217.93±21.57 sec, Arch Stim: 267.95±22.93 sec, t14 = 3.77, p = 0.002; eYFP No Stim: 24.422±30.03 sec, eYFP Stim: 231.43±25.55 sec, t7 =1.68, p=0.14), (c) number of bouts (Arch No Stim: 48.88±4.29, Arch Stim: 53.63±4.69 sec, t14 = 2.47, p = 0.038; eYFP No Stim: 43.21±5.40, eYFP Stim: 44.13±6.00, t7 =0.88, p=0.41) and (d) mean bout length (Arch No Stim: 4.63 ± 0.37 sec, Arch Stim: 5.16±0.46 sec, t14 = 2.27, p = 0.040; eYFP No Stim: 5.836 ± 0.847 sec, eYFP Stim:5.836±0.847, t7 =2.28, p = 0.06). (e) Arch3 inhibition did not induce a place preference in a RTPP task (eYFP: -11.92±7.71%, Arch: 1.06±5.96, t19=1.22, p=0.24) or (f) alter locomotor activity in an open field task (eYFP No Stim: 320.97±13.41 m, eYFP Stim: 323.41±12.02 m, Arch No Stim: 353.12±22.46 m, Arch Stim: 374.07±21.34 m, FStimxVirus;1,19=1.33, p=0.26). n=12/15, eYFP/Arch3). All data is represented as mean ± IQ range. *p<0.05, **p < 0.01.

Extended Data Fig. 3 Retrograde viral tracing reveals vArky fibers preferentially in the NAcSh.

(a) rAAV-Cre was injected in the NAcSh, DIO-ChR2 was injected into the VP and serial sections were taken of known VP projection sites. (b-c) 5x and 20x overview of ChR2-labeled terminals in the NAcSh and infected cell bodies in the VP (n=4 sections/brain region, 6 mice). (d) 10x representative images of serial sections (top) and 20x confocal images of canonical VP projection areas. (e) Quantification of total axonal length, normalized to VP. Intensity and axonal length in the NAcSh was significantly greater than any area examined. Abbreviations: Nucleus accumbens shell (NAcSh), ventral pallidum (VP), medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), basolateral amygdala (BLA) lateral habenula (LHb), mediodorsal thalamus (MDThal), subthalamic nucleus (STN), ventral tegmental area (VTA). F=148.4 p<0.001, Ffluorescence=148.4, p = 0.0016 with Bonferroni correction for multiple comparisons applied. Data presented as mean ± IQ range. Scale bars=25 µm.

Extended Data Fig. 4 Topography of release properties of VP inputs to NAcSh.

a, Merged fluorescent image of recorded tomato-expressing neuron adjacent to EYFP-labeled terminals from the VP during patch-clamp experiments. b, 4x image of ChR2-injection site in VP and terminal fields in the NAc in each of three reporter lines. Amplitude (c) and PPR (d) of oIPSC expressed as location of recorded neuron within the NAcSh in D1-MSNs (n=118 cells/11 mice), D2-MSNs (n=117 cells/12 mice), PVs (n=112 cells/12 mice), and CINs (n=104 cells/10 mice), scale bar = 50 µm.

Extended Data Fig. 5 Properties of NAcSh neurons and in vivo responses to activation of vArky terminals.

a, Location of recording arrays in the NAcSh. b–d, Units were classified according to peak-valley width (n = 9 pMSNs, 14 pINS, 32 multi-units from 6 mice, pMSN: 462.8±27.96 µs, pIN: 242.01±26.27 µs), CV (pMSN: 1.77±0.254, pIN: 1.23±0.17) and firing rate (pMSN: 0.40±0.11 Hz, pIN: 3.53±1.20 Hz, data shown as mean ± IQ range). e–h, representative waveform and PSTH of single neural examples in response to 15 ms of vArky stimulation. Scale bar = 500µs, 50µV.

Extended Data Fig. 6 Lick behavior of individual subjects, as a function of high- vs. low-vArky calcium signals.

a, Single-subject heat map of arkypallidal fluorescence signal across high GCaMP (top) and low GCaMP (bottom) trials aligned to reward consumption onset. b, Lick behavior of high- vs. low-vArky calcium trials of all individual GCaMP-injected subjects. c, Single-subject heat map of fluorescence signal of GFP mouse. d, Lick behavior of high- vs. low-VP signal trials of all GFP-injected subjects, (e) Average lick behavior of high and low-VP signal trials of all GFP-injected mice (AUC lick probability high signal trials: 3.16±0.65, AUC lick probability low signal trials: 2.94±0.49, mean ± IQ range).

Extended Data Fig. 7 Calcium activity in the NAcSh decreases upon reward consumption onset.

a-b, GCaMP injection in the NAcSh, representative traces (scale bar: 10 sec, 1 z-score) and histology (n=6/6 GCaMP/GFP mice, scale bar = 1 mm). c, Single-subject heat map of NAcSh GCaMP signal and (d) combined signal from all subjects (n=6/6 GCaMP/GFP) aligned to reward consumption onset (mean AUC GCaMP: -2.58±0.65, GFP: -0.14±1.40, t11=2.87, p=0.015, mean ± IQ range).

Extended Data Fig. 8 vArky calcium activity increases during sucrose pellet consumption but not locomotor events.

a, vArky fluorescence signal was recorded during free-access consumption of sucrose pellets. b, Representative heat map and normalized calcium signal aligned to sucrose pellet retrieval in GCaMP (left) and GFP (right) expressing mice. c, AUC was significantly greater in the two seconds following pellet retrieval in GCaMP-expressing mice relative to GFP controls (AUC GCAMP: 3.687 ± 0.756, AUC GFP: 0.238 ± 1.378, t16=2.1944, p=0.0433). d-f, Fluorescence responses aligned to locomotor arrests (mean AUC GCaMP: -1.467±0.2994, GFP: -0.3198±1.071, t16=1.127, p=0.27), locomotor initiations (n=704/677 events, AUC GCaMP: -0.818±0.638, GFP: -0.619±1.210, t16=0.150, p=0.88) and peaks in locomotor speed (n=1309/1221 events, mean AUC GCaMP: 0.1294±0.2945, GFP:0.4977±0.3022, t16=0.873, p=0.396). Data mean ± IQ range.

Extended Data Fig. 9 Histological verification, ICSS and RTPP behavioral controls for vArky optogenetic stimulation.

a, Infection site in VP and terminal fields in NAcSh; scale bar=50µm. b, Verified placements of optic fibers. c, Distance traveled in an open field task (n=12 eYFP, 18 ChR2, eYFPNoStim: 121.62±22.63, eYFPStim : 122.15±21.75, p=0.96, ChR2NoStim: 124.48±16.22, ChR2Stim: 121.83±14.18, Fstim•virus=0.050, p=0.825). d, Preference for the stimulation-paired side of a chamber in a real-time place preference task (n=12 eYFP, 18 ChR2, eYFP: -4.36±4.32%, ChR2: -1.13±5.83) and representative heatmaps. *p<0.05, **p<0.01. All data presented as mean ± sem.

Extended Data Fig. 10 Input-output curves of vArky neuronal responses to current injections ex vivo.

a, Ai14 reporter mice were injected with retro-cre in the NAcSh to selectively label vArky neurons. b, Merged fluorescent image of Ai14-expressing vArky neurons during patch-clamp experiments (n=12 neurons from 9 mice). c, The mean number of action potentials per second in response to successive current injection (0 to 200 pA) is plotted (error bars: sem). d, Representative traces in response to 50, 100, 150, and 200 pA current injections. Scale bar: 10mV, 100ms.

Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2.

Reporting Summary

Supplementary Video 1

Example video of iDisco-processed and light sheet–imaged brain hemispheres. Retro-Cre was injected in the NAcSh and DIO-ChR2 was injected in the VP to visualize vArky neurons.

Supplementary Video 2

Example of orofacial taste reactivity test, with and without vArkypallidal stimulation.

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Vachez, Y.M., Tooley, J.R., Abiraman, K. et al. Ventral arkypallidal neurons inhibit accumbal firing to promote reward consumption. Nat Neurosci 24, 379–390 (2021). https://doi.org/10.1038/s41593-020-00772-7

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