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What does dopamine mean?

Nature Neurosciencevolume 21pages787793 (2018) | Download Citation

Abstract

Dopamine is a critical modulator of both learning and motivation. This presents a problem: how can target cells know whether increased dopamine is a signal to learn or to move? It is often presumed that motivation involves slow (‘tonic’) dopamine changes, while fast (‘phasic’) dopamine fluctuations convey reward prediction errors for learning. Yet recent studies have shown that dopamine conveys motivational value and promotes movement even on subsecond timescales. Here I describe an alternative account of how dopamine regulates ongoing behavior. Dopamine release related to motivation is rapidly and locally sculpted by receptors on dopamine terminals, independently from dopamine cell firing. Target neurons abruptly switch between learning and performance modes, with striatal cholinergic interneurons providing one candidate switch mechanism. The behavioral impact of dopamine varies by subregion, but in each case dopamine provides a dynamic estimate of whether it is worth expending a limited internal resource, such as energy, attention, or time.

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References

  1. 1.

    Ungerstedt, U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. Suppl. 367, 95–122 (1971).

  2. 2.

    Sacks, O. Awakenings. (Duckworth, London, 1973).

  3. 3.

    Marshall, J. F., Levitan, D. & Stricker, E. M. Activation-induced restoration of sensorimotor functions in rats with dopamine-depleting brain lesions. J. Comp. Physiol. Psychol. 90, 536–546 (1976).

  4. 4.

    Berridge, K. C., Venier, I. L. & Robinson, T. E. Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: implications for arousal and anhedonia hypotheses of dopamine function. Behav. Neurosci. 103, 36–45 (1989).

  5. 5.

    Salamone, J. D. & Correa, M. The mysterious motivational functions of mesolimbic dopamine. Neuron 76, 470–485 (2012).

  6. 6.

    Mazzoni, P., Hristova, A. & Krakauer, J. W. Why don’t we move faster? Parkinson’s disease, movement vigor, and implicit motivation. J. Neurosci. 27, 7105–7116 (2007).

  7. 7.

    Schultz, W. Responses of midbrain dopamine neurons to behavioral trigger stimuli in the monkey. J. Neurophysiol. 56, 1439–1461 (1986).

  8. 8.

    Schultz, W. & Romo, R. Dopamine neurons of the monkey midbrain: contingencies of responses to stimuli eliciting immediate behavioral reactions. J. Neurophysiol. 63, 607–624 (1990).

  9. 9.

    Montague, P. R., Dayan, P. & Sejnowski, T. J. A framework for mesencephalic dopamine systems based on predictive Hebbian learning. J. Neurosci. 16, 1936–1947 (1996).

  10. 10.

    Schultz, W., Apicella, P. & Ljungberg, T. Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task. J. Neurosci. 13, 900–913 (1993).

  11. 11.

    Sutton, R. S. & Barto, A. G. Reinforcement Learning: an Introduction. (MIT Press: Cambridge, Massachusetts, 1998).

  12. 12.

    Cohen, J. Y., Haesler, S., Vong, L., Lowell, B. B. & Uchida, N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 482, 85–88 (2012).

  13. 13.

    Eshel, N., Tian, J., Bukwich, M. & Uchida, N. Dopamine neurons share common response function for reward prediction error. Nat. Neurosci. 19, 479–486 (2016).

  14. 14.

    Steinberg, E. E. et al. A causal link between prediction errors, dopamine neurons and learning. Nat. Neurosci. 16, 966–973 (2013).

  15. 15.

    Hamid, A. A. et al. Mesolimbic dopamine signals the value of work. Nat. Neurosci. 19, 117–126 (2016).

  16. 16.

    Yagishita, S. et al. A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science 345, 1616–1620 (2014).

  17. 17.

    Berke, J. D. & Hyman, S. E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515–532 (2000).

  18. 18.

    Beeler, J. A. A role for dopamine-mediated learning in the pathophysiology and treatment of Parkinsonas disease. Cell Rep. 2, 1747–1761 (2012).

  19. 19.

    Wise, R. A. Dopamine, learning and motivation. Nat. Rev. Neurosci. 5, 483–494 (2004).

  20. 20.

    Leventhal, D. K. et al. Dissociable effects of dopamine on learning and performance within sensorimotor striatum. Basal Ganglia 4, 43–54 (2014).

  21. 21.

    Wyvell, C. L. & Berridge, K. C. Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward “wanting” without enhanced “liking” or response reinforcement. J. Neurosci. 20, 8122–8130 (2000).

  22. 22.

    Cagniard, B. et al. Dopamine scales performance in the absence of new learning. Neuron 51, 541–547 (2006).

  23. 23.

    Shiner, T. et al. Dopamine and performance in a reinforcement learning task: evidence from Parkinson’s disease. Brain 135, 1871–1883 (2012).

  24. 24.

    McClure, S. M., Daw, N. D. & Montague, P.R. A computational substrate for incentive salience. Trends Neurosci. 26, 423–428 (2003).

  25. 25.

    Schultz, W. Multiple dopamine functions at different time courses. Annu. Rev. Neurosci. 30, 259–288 (2007).

  26. 26.

    Gonon, F. et al. Geometry and kinetics of dopaminergic transmission in the rat striatum and in mice lacking the dopamine transporter. Prog. Brain Res. 125, 291–302 (2000).

  27. 27.

    Aragona, B. J. et al. Preferential enhancement of dopamine transmission within the nucleus accumbens shell by cocaine is attributable to a direct increase in phasic dopamine release events. J. Neurosci. 28, 8821–8831 (2008).

  28. 28.

    Owesson-White, C. A. et al. Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens. J. Neurochem. 121, 252–262 (2012).

  29. 29.

    Yapo, C. et al. Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons. J. Physiol. (Lond.) 595, 7451–7475 (2017).

  30. 30.

    Freed, C. R. & Yamamoto, B. K. Regional brain dopamine metabolism: a marker for the speed, direction, and posture of moving animals. Science 229, 62–65 (1985).

  31. 31.

    Niv, Y., Daw, N. D., Joel, D. & Dayan, P. Tonic dopamine: opportunity costs and the control of response vigor. Psychopharmacology (Berl.) 191, 507–520 (2007).

  32. 32.

    Strecker, R. E., Steinfels, G. F. & Jacobs, B. L. Dopaminergic unit activity in freely moving cats: lack of relationship to feeding, satiety, and glucose injections. Brain Res. 260, 317–321 (1983).

  33. 33.

    Cohen, J.Y., Amoroso, M.W. & Uchida, N. Serotonergic neurons signal reward and punishment on multiple timescales. eLife 4, e06346 (2015).

  34. 34.

    Floresco, S. B., West, A. R., Ash, B., Moore, H. & Grace, A. A. Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat. Neurosci. 6, 968–973 (2003).

  35. 35.

    Grace, A. A. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat. Rev. Neurosci. 17, 524–532 (2016).

  36. 36.

    Phillips, P. E., Stuber, G. D., Heien, M. L., Wightman, R. M. & Carelli, R. M. Subsecond dopamine release promotes cocaine seeking. Nature 422, 614–618 (2003).

  37. 37.

    Wassum, K. M., Ostlund, S. B. & Maidment, N. T. Phasic mesolimbic dopamine signaling precedes and predicts performance of a self-initiated action sequence task. Biol. Psychiatry 71, 846–854 (2012).

  38. 38.

    Howe, M. W., Tierney, P. L., Sandberg, S. G., Phillips, P. E. & Graybiel, A. M. Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Nature 500, 575–579 (2013).

  39. 39.

    Satoh, T., Nakai, S., Sato, T. & Kimura, M. Correlated coding of motivation and outcome of decision by dopamine neurons. J. Neurosci. 23, 9913–9923 (2003).

  40. 40.

    Howe, M. W. & Dombeck, D. A. Rapid signalling in distinct dopaminergic axons during locomotion and reward. Nature 535, 505–510 (2016).

  41. 41.

    da Silva, J. A., Tecuapetla, F., Paixão, V. & Costa, R. M. Dopamine neuron activity before action initiation gates and invigorates future movements. Nature 554, 244–248 (2018).

  42. 42.

    du Hoffmann, J. & Nicola, S. M. Dopamine invigorates reward seeking by promoting cue-evoked excitation in the nucleus accumbens. J. Neurosci. 34, 14349–14364 (2014).

  43. 43.

    Hart, A. S., Rutledge, R. B., Glimcher, P. W. & Phillips, P. E. Phasic dopamine release in the rat nucleus accumbens symmetrically encodes a reward prediction error term. J. Neurosci. 34, 698–704 (2014).

  44. 44.

    Soares, S., Atallah, B. V. & Paton, J. J. Midbrain dopamine neurons control judgment of time. Science 354, 1273–1277 (2016).

  45. 45.

    Ikemoto, S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res. Rev. 56, 27–78 (2007).

  46. 46.

    Syed, E. C. et al. Action initiation shapes mesolimbic dopamine encoding of future rewards. Nat. Neurosci. 19, 34–36 (2016).

  47. 47.

    Floresco, S. B., Yang, C. R., Phillips, A. G. & Blaha, C. D. Basolateral amygdala stimulation evokes glutamate receptor-dependent dopamine efflux in the nucleus accumbens of the anaesthetized rat. Eur. J. Neurosci. 10, 1241–1251 (1998).

  48. 48.

    Jones, J. L. et al. Basolateral amygdala modulates terminal dopamine release in the nucleus accumbens and conditioned responding. Biol. Psychiatry 67, 737–744 (2010).

  49. 49.

    Cachope, R. Selective activation of cholinergic interneurons enhances accumbal phasic dopamine release: setting the tone for reward processing. Cell Rep. 2(1), 33–41 (2012).

  50. 50.

    Threlfell, S. et al. Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 75, 58–64 (2012).

  51. 51.

    Grace, A. A. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41, 1–24 (1991).

  52. 52.

    Moyer, J. T., Wolf, J. A. & Finkel, L. H. Effects of dopaminergic modulation on the integrative properties of the ventral striatal medium spiny neuron. J. Neurophysiol. 98, 3731–3748 (2007).

  53. 53.

    Jędrzejewska-Szmek, J., Damodaran, S., Dorman, D. B. & Blackwell, K. T. Calcium dynamics predict direction of synaptic plasticity in striatal spiny projection neurons. Eur. J. Neurosci. 45, 1044–1056 (2017).

  54. 54.

    Morris, G., Arkadir, D., Nevet, A., Vaadia, E. & Bergman, H. Coincident but distinct messages of midbrain dopamine and striatal tonically active neurons. Neuron 43, 133–143 (2004).

  55. 55.

    Brown, M. T. et al. Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning. Nature 492, 452–456 (2012).

  56. 56.

    Yamanaka, K. et al. Roles of centromedian parafascicular nuclei of thalamus and cholinergic interneurons in the dorsal striatum in associative learning of environmental events. J. Neural Transm. (Vienna) 125, 501–513 (2018).

  57. 57.

    Shen, W. et al. M4 muscarinic receptor signaling ameliorates striatal plasticity deficits in models of L-DOPA-induced dyskinesia. Neuron 88, 762–773 (2015).

  58. 58.

    Nair, A. G., Gutierrez-Arenas, O., Eriksson, O., Vincent, P. & Hellgren Kotaleski, J. Sensing positive versus negative reward signals through adenylyl cyclase-coupled GPCRs in direct and indirect pathway striatal medium spiny neurons. J. Neurosci. 35, 14017–14030 (2015).

  59. 59.

    Stocco, A. Acetylcholine-based entropy in response selection: a model of how striatal interneurons modulate exploration, exploitation, and response variability in decision-making. Front. Neurosci. 6, 18 (2012).

  60. 60.

    Franklin, N. T. & Frank, M. J. A cholinergic feedback circuit to regulate striatal population uncertainty and optimize reinforcement learning. eLife 4, e12029 (2015).

  61. 61.

    Nougaret, S. & Ravel, S. Modulation of tonically active neurons of the monkey striatum by events carrying different force and reward information. J. Neurosci. 35, 15214–15226 (2015).

  62. 62.

    Schultz, W. Predictive reward signal of dopamine neurons. J. Neurophysiol. 80, 1–27 (1998).

  63. 63.

    Lammel, S. et al. Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57, 760–773 (2008).

  64. 64.

    Poulin, J. F. et al. Defining midbrain dopaminergic neuron diversity by single-cell gene expression profiling. Cell Rep. 9, 930–943 (2014).

  65. 65.

    Morales, M. & Margolis, E. B. Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat. Rev. Neurosci. 18, 73–85 (2017).

  66. 66.

    Matsumoto, M. & Hikosaka, O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 459, 837–841 (2009).

  67. 67.

    Pasquereau, B. & Turner, R. S. Dopamine neurons encode errors in predicting movement trigger occurrence. J. Neurophysiol. 113, 1110–1123 (2015).

  68. 68.

    Redgrave, P., Prescott, T. J. & Gurney, K. Is the short-latency dopamine response too short to signal reward error? Trends Neurosci. 22, 146–151 (1999).

  69. 69.

    Bromberg-Martin, E. S., Matsumoto, M. & Hikosaka, O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68, 815–834 (2010).

  70. 70.

    Dodson, P. D. et al. Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in Parkinsonism. Proc. Natl. Acad. Sci. USA 113, E2180–E2188 (2016).

  71. 71.

    Lerner, T. N. et al. Intact-brain analyses reveal distinct information carried by SNc dopamine subcircuits. Cell 162, 635–647 (2015).

  72. 72.

    Parker, N. F. et al. Reward and choice encoding in terminals of midbrain dopamine neurons depends on striatal target. Nat. Neurosci. 19, 845–854 (2016).

  73. 73.

    Kim, C. K. et al. Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain. Nat. Methods 13, 325–328 (2016).

  74. 74.

    Menegas, W., Babayan, B. M., Uchida, N. & Watabe-Uchida, M. Opposite initialization to novel cues in dopamine signaling in ventral and posterior striatum in mice. eLife 6, e21886 (2017).

  75. 75.

    Brown, H. D., McCutcheon, J. E., Cone, J. J., Ragozzino, M. E. & Roitman, M. F. Primary food reward and reward-predictive stimuli evoke different patterns of phasic dopamine signaling throughout the striatum. Eur. J. Neurosci. 34, 1997–2006 (2011).

  76. 76.

    Knutson, B., & Greer, S. M. Anticipatory affect: neural correlates and consequences for choice. Phil. Trans. R. Soc. Lond. B 363, 3771–3786 (2008).

  77. 77.

    Bartra, O., McGuire, J. T. & Kable, J. W. The valuation system: a coordinate-based meta-analysis of BOLD fMRI experiments examining neural correlates of subjective value. Neuroimage 76, 412–427 (2013).

  78. 78.

    Ferenczi, E. A. et al. Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science 351, aac9698 (2016).

  79. 79.

    Bertran-Gonzalez, J. et al. Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol. J. Neurosci. 28, 5671–5685 (2008).

  80. 80.

    Redgrave, P., Prescott, T. J. & Gurney, K. The basal ganglia: a vertebrate solution to the selection problem? Neuroscience 89, 1009–1023 (1999).

  81. 81.

    Beeler, J. A., Frazier, C. R., & Zhuang, X. Putting desire on a budget: dopamine and energy expenditure, reconciling reward and resources. Front. Integr. Neurosci. 6, 49 (2012).

  82. 82.

    Anderson, B. A. et al. The Role of dopamine in value-based attentional orienting. Curr. Biol. 26, 550–555 (2016).

  83. 83.

    Chatham, C. H., Frank, M. J. & Badre, D. Corticostriatal output gating during selection from working memory. Neuron 81, 930–942 (2014).

  84. 84.

    Shenhav, A., Botvinick, M. M. & Cohen, J. D. The expected value of control: an integrative theory of anterior cingulate cortex function. Neuron 79, 217–240 (2013).

  85. 85.

    Aarts, E. et al. Striatal dopamine mediates the interface between motivational and cognitive control in humans: evidence from genetic imaging. Neuropsychopharmacology 35, 1943–1951 (2010).

  86. 86.

    Westbrook, A. & Braver, T. S. Dopamine does double duty in motivating cognitive effort. Neuron 89, 695–710 (2016).

  87. 87.

    Manohar, S. G. et al. Reward pays the cost of noise reduction in motor and cognitive control. Curr. Biol. 25, 1707–1716 (2015).

  88. 88.

    Wunderlich, K., Smittenaar, P. & Dolan, R. J. Dopamine enhances model-based over model-free choice behavior. Neuron 75, 418–424 (2012).

  89. 89.

    Nicola, S. M. The flexible approach hypothesis: unification of effort and cue-responding hypotheses for the role of nucleus accumbens dopamine in the activation of reward-seeking behavior. J. Neurosci. 30, 16585–16600 (2010).

  90. 90.

    Eban-Rothschild, A., Rothschild, G., Giardino, W. J., Jones, J. R. & de Lecea, L. VTA dopaminergic neurons regulate ethologically relevant sleep-wake behaviors. Nat. Neurosci. 19, 1356–1366 (2016).

  91. 91.

    Haber, S. N., Fudge, J. L. & McFarland, N. R. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J. Neurosci. 20, 2369–2382 (2000).

  92. 92.

    Reddi, B. A. J. & Carpenter, R. H. S. The influence of urgency on decision time. Nat. Neurosci. 3, 827–830 (2000).

  93. 93.

    Thura, D. & Cisek, P. The basal ganglia do not select reach targets but control the urgency of commitment. Neuron 95, 1160–1170.e5 (2017).

  94. 94.

    Turner, R. S. & Desmurget, M. Basal ganglia contributions to motor control: a vigorous tutor. Curr. Opin. Neurobiol. 20, 704–716 (2010).

  95. 95.

    Hikosaka, O., Nakamura, K. & Nakahara, H. Basal ganglia orient eyes to reward. J. Neurophysiol. 95, 567–584 (2006).

  96. 96.

    Kelly, P. H. & Moore, K. E. Mesolimbic dopaminergic neurones in the rotational model of nigrostriatal function. Nature 263, 695–696 (1976).

  97. 97.

    Cousins, M. S., Atherton, A., Turner, L. & Salamone, J. D. Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task. Behav. Brain Res. 74, 189–197 (1996).

  98. 98.

    Redish, A. D. Vicarious trial and error. Nat. Rev. Neurosci. 17, 147–159 (2016).

  99. 99.

    Rabinovich, M. I., Huerta, R., Varona, P. & Afraimovich, V. S. Transient cognitive dynamics, metastability, and decision making. PLOS Comput. Biol. 4, e1000072 (2008).

  100. 100.

    Merchant, H., Harrington, D. L. & Meck, W. H. Neural basis of the perception and estimation of time. Annu. Rev. Neurosci. 36, 313–336 (2013).

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Acknowledgements

I thank the many colleagues who provided insightful comments on earlier text drafts, including K. Berridge, P. Dayan, B. Knutson, J. Beeler, P. Redgrave, J. Lisman, and J. Goldberg. I regret that space limitations precluded discussion of many important prior studies. Essential support was provided by the National Institute on Neurological Disorders and Stroke, the National Institute of Mental Health, and the National Institute on Drug Abuse.

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  1. Departments of Neurology and Psychiatry, and Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA

    • Joshua D. Berke

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Correspondence to Joshua D. Berke.

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https://doi.org/10.1038/s41593-018-0152-y

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