Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neuron-type-specific signals for reward and punishment in the ventral tegmental area

Abstract

Dopamine has a central role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (that is, reward prediction error)1,2,3, but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neuron based on responses to odours and outcomes: approximately half of the neurons (type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with reward prediction error coding; the other half of neurons showed persistent activity during the delay between odour and outcome that was modulated positively (type II, 31%) or negatively (type III, 18%) by the value of outcomes. Whereas the activity of type I neurons was sensitive to actual outcomes (that is, when the reward was delivered as expected compared to when it was unexpectedly omitted), the activity of type II and type III neurons was determined predominantly by reward-predicting odours. We ‘tagged’ dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of type I and all GABAergic neurons were of type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate reward prediction error.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Odour-outcome association task in mice.
Figure 2: VTA neurons show three distinct response types.
Figure 3: Identifying dopaminergic and GABAergic neurons.
Figure 4: Response variability based on CS–US preference, reward omission and air puffs.

References

  1. Schultz, W., Dayan, P. & Montague, P. R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997)

    Article  CAS  Google Scholar 

  2. Bayer, H. M. & Glimcher, P. W. Midbrain dopamine neurons encode a quantitative reward prediction error signal. Neuron 47, 129–141 (2005)

    Article  CAS  Google Scholar 

  3. Schultz, W. Behavioral theories and the neurophysiology of reward. Annu. Rev. Psychol. 57, 87–115 (2006)

    Article  Google Scholar 

  4. Swanson, L. W. The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res. Bull. 9, 321–353 (1982)

    Article  CAS  Google Scholar 

  5. Margolis, E. B., Lock, H., Hjelmstad, G. O. & Fields, H. L. The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons? J. Physiol. 577, 907–924 (2006)

    Article  CAS  Google Scholar 

  6. Nair-Roberts, R. G. et al. Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat. Neuroscience 152, 1024–1031 (2008)

    Article  CAS  Google Scholar 

  7. Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006)

    Article  CAS  Google Scholar 

  8. Lüscher, C. & Malenka, R. C. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69, 650–663 (2011)

    Article  Google Scholar 

  9. Johnson, S. W. & North, R. A. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J. Neurosci. 12, 483–488 (1992)

    Article  CAS  Google Scholar 

  10. Mansvelder, H. D., Keath, J. R. & McGehee, D. S. Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33, 905–919 (2002)

    Article  CAS  Google Scholar 

  11. Szabo, B., Siemes, S. & Wallmichrath, I. Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Eur. J. Neurosci. 15, 2057–2061 (2002)

    Article  Google Scholar 

  12. Tan, K. R. et al. Neural bases for addictive properties of benzodiazepines. Nature 463, 769–774 (2010)

    Article  ADS  CAS  Google Scholar 

  13. Dobi, A., Margolis, E. B., Wang, H.-L., Harvey, B. K. & Morales, M. Glutamatergic and nonglutamatergic neurons of the ventral tegmental area establish local synaptic contacts with dopaminergic and nondopaminergic neurons. J. Neurosci. 30, 218–229 (2010)

    Article  CAS  Google Scholar 

  14. Steffensen, S. C., Svingos, A. L., Pickel, V. M. & Henriksen, S. J. Electrophysiological characterization of GABAergic neurons in the ventral tegmental area. J. Neurosci. 18, 8003–8015 (1998)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Nagel, G. et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc. Natl Acad. Sci. USA 100, 13940–13945 (2003)

    Article  ADS  CAS  Google Scholar 

  18. Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neurosci. 8, 1263–1268 (2005)

    Article  CAS  Google Scholar 

  19. Atasoy, D., Aponte, Y., Su, H. H. & Sternson, S. M. A. FLEX switch targets Channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping. J. Neurosci. 28, 7025–7030 (2008)

    Article  CAS  Google Scholar 

  20. Fiorillo, C. D., Newsome, W. T. & Schultz, W. The temporal precision of reward prediction in dopamine neurons. Nature Neurosci. 11, 966–973 (2008)

    Article  CAS  Google Scholar 

  21. Takikawa, Y., Kawagoe, R. & Hikosaka, O. A possible role of midbrain dopamine neurons in short- and long-term adaptation of saccades to position-reward mapping. J. Neurophysiol. 92, 2520–2529 (2004)

    Article  Google Scholar 

  22. Rescorla, R. A. & Wagner, A. R. in Classical Conditioning II: Current Research and Theory (eds Black, A. H. & Wagner, A. R. ) 64–99 (New York, 1972)

    Google Scholar 

  23. Houk, J. C., Adams, J. L. & Barto, A. G. in Models of Information Processing in the Basal Ganglia (eds Houk, J. C., Davis, J. L. & Beiser, D. G. ) 249–270 (MIT Press, 1995)

    Google Scholar 

  24. Carr, D. B. & Sesack, S. R. Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J. Neurosci. 20, 3864–3873 (2000)

    Article  CAS  Google Scholar 

  25. Okada, K., Toyama, K., Inoue, Y., Isa, T. & Kobayashi, Y. Different pedunculopontine tegmental neurons signal predicted and actual task rewards. J. Neurosci. 29, 4858–4870 (2009)

    Article  CAS  Google Scholar 

  26. Matsumoto, M. & Hikosaka, O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447, 1111–1115 (2007)

    Article  ADS  CAS  Google Scholar 

  27. Takahashi, Y. K. et al. Expectancy-related changes in firing of dopamine neurons depend on orbitofrontal cortex. Nature Neurosci. 14, 1590–1597 (2011)

    Article  CAS  Google Scholar 

  28. Omelchenko, N. & Sesack, S. R. Ultrastructural analysis of local collaterals of rat ventral tegmental area neurons: GABA phenotype and synapses onto dopamine and GABA cells. Synapse 63, 895–906 (2009)

    Article  CAS  Google Scholar 

  29. Jhou, T. C., Fields, H. L., Baxter, M. G., Saper, C. B. & Holland, P. C. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61, 786–800 (2009)

    Article  CAS  Google Scholar 

  30. Redish, A. D. Addiction as a computational process gone awry. Science 306, 1944–1947 (2004)

    Article  ADS  CAS  Google Scholar 

  31. Bäckman, C. M. et al. Characterization of a mouse strain expressing Cre recombinase from the 3′ untranslated region of the dopamine transporter locus. Genesis 44, 383–390 (2006)

    Article  Google Scholar 

  32. Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011)

    Article  CAS  Google Scholar 

  33. Tsai, H. C. et al. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 324, 1080–1084 (2009)

    Article  ADS  CAS  Google Scholar 

  34. Uchida, N. & Mainen, Z. F. Speed and accuracy of olfactory discrimination in the rat. Nature Neurosci. 6, 1224–1229 (2003)

    Article  CAS  Google Scholar 

  35. Lima, S. Q., Hromádka, T., Znamenskiy, P. & Zador, A. M. PINP: a new method of tagging neuronal populations for identification during in vivo electrophysiological recording. PLoS ONE 4, e6099 (2009)

    Article  ADS  Google Scholar 

  36. Zhao, S. et al. Cell-type specific channelrhodopsin-2 transgenic mice for optogenetic dissection of neural circuitry function. Nature Methods 8, 745–752 (2011)

    Article  CAS  Google Scholar 

  37. Thompson, K. G., Hanes, D. P., Bichot, N. P. & Schall, J. D. Perceptual and motor processing stages identified in the activity of macaque frontal eye field neurons during visual search. J. Neurophysiol. 76, 4040–4055 (1996)

    Article  CAS  Google Scholar 

  38. Schmitzer-Torbert, N. & Redish, A. D. Neuronal activity in the rodent dorsal striatum in sequential navigation: separation of spatial and reward responses on the Multiple T Task. J. Neurophysiol. 91, 2259–2272 (2004)

    Article  Google Scholar 

Download references

Acknowledgements

We thank M. Meister, V. N. Murthy, J. D. Schall and R. P. Heitz for comments, C. Dulac for sharing resources, C. I. Moore, J. Ritt and J. Siegle for advice about microdrives, K. Deisseroth for the AAV-FLEX-ChR2 construct, and E. Soucy and J. Greenwood for technical support. This work was supported by a Howard Hughes Medical Institute Fellowship from the Helen Hay Whitney Foundation (J.Y.C.); the Human Frontiers Science Program (S.H.); a Howard Hughes Medical Institute Collaborative Innovation Award, a Smith Family New Investigator Award, the Alfred Sloan Foundation, the Milton Fund (N.U.); F32 DK078478, P30 DK046200 (L.V.); and R01 DK075632, R01 DK089044, P30 DK046200, P30 DK057521 (B.B.L.).

Author information

Authors and Affiliations

Authors

Contributions

J.Y.C. and S.H. collected and analysed data. J.Y.C., S.H. and N.U. designed experiments and wrote the paper. L.V. and B.B.L. generated Vgat-Cre mice.

Corresponding author

Correspondence to Naoshige Uchida.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Notes 1-3 and Supplementary Figures 1-13 with legends. (PDF 8062 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cohen, J., Haesler, S., Vong, L. et al. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 482, 85–88 (2012). https://doi.org/10.1038/nature10754

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10754

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing