Skip to main content

Thank you for visiting 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.

  • Letter
  • Published:

Dopamine neurons modulate neural encoding and expression of depression-related behaviour


Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia1. Dopamine neurons involved in reward and motivation2,3,4,5,6,7,8,9 are among many neural populations that have been hypothesized to be relevant10, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.

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

Access options

Buy this article

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

Figure 1: Selective inhibition of VTA dopamine neurons induces a depression-like phenotype.
Figure 2: Temporally sparse phasic photoactivation of VTA dopamine neurons rescues stress-induced depression-like phenotype.
Figure 3: Phasic activation of VTA dopamine neurons modulates escape-related behaviour in TH::Cre rats.
Figure 4: Phasic activation of VTA dopamine neurons modulates NAc encoding of escape-related behaviour.

Similar content being viewed by others


  1. Kessler, R. C., Chiu, W. T., Demler, O. & Walters, E. E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication. Arch. Gen. Psychiatry 62, 617–627 (2005); erratum. 62, 709 (2005)

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Witten, I. B. et al. Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 72, 721–733 (2011)

    Article  CAS  Google Scholar 

  4. Willner, P., Muscat, R., Papp, M., Stamford, J. & Kruk, Z. Dopaminergic mechanisms in an animal model of anhedonia. Eur. Neuropsychopharmacol. 1, 295–296 (1991)

    Article  Google Scholar 

  5. Roitman, M. F., Wheeler, R. A., Wightman, R. M. & Carelli, R. M. Real-time chemical responses in the nucleus accumbens differentiate rewarding and aversive stimuli. Nature Neurosci. 11, 1376–1377 (2008)

    Article  CAS  Google Scholar 

  6. 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 

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

    Article  CAS  Google Scholar 

  8. Koob, G. Hedonic valence, dopamine and motivation. Mol. Psychiatry 1, 186 (1996)

    CAS  PubMed  Google Scholar 

  9. Ikemoto, S. & Panksepp, J. The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res. Brain Res. Rev. 31, 6–41 (1999)

    Article  CAS  Google Scholar 

  10. Nestler, E. J. & Carlezon, W. A., Jr The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151–1159 (2006)

    Article  CAS  Google Scholar 

  11. Lammel, S. et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature (2012)

  12. Porsolt, R. D., Le Pichon, M. & Jalfre, M. Depression: a new animal model sensitive to antidepressant treatments. Nature 266, 730–732 (1977)

    Article  ADS  CAS  Google Scholar 

  13. Willner, P., Muscat, R. & Papp, M. Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci. Biobehav. Rev. 16, 525–534 (1992)

    Article  CAS  Google Scholar 

  14. Strekalova, T., Spanagel, R., Bartsch, D., Henn, F. A. & Gass, P. Stress-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharmacology 29, 2007–2017 (2004)

    Article  Google Scholar 

  15. Cryan, J. F., Mombereau, C. & Vassout, A. The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neurosci. Biobehav. Rev. 29, 571–625 (2005)

    Article  CAS  Google Scholar 

  16. Fields, H. L., Hjelmstad, G. O., Margolis, E. B. & Nicola, S. M. Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement. Annu. Rev. Neurosci. 30, 289–316 (2007)

    Article  CAS  Google Scholar 

  17. Bewernick, B. H. et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol. Psychiatry 67, 110–116 (2010)

    Article  Google Scholar 

  18. Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354 (2000)

    Article  CAS  Google Scholar 

  19. Friedman, A., Friedman, Y., Dremencov, E. & Yadid, G. VTA dopamine neuron bursting is altered in an animal model of depression and corrected by desipramine. J. Mol. Neurosci. 34, 201–209 (2008)

    Article  CAS  Google Scholar 

  20. Tanaka, K. et al. Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice. J. Neurosci. 32, 4319–4329 (2012)

    Article  CAS  Google Scholar 

  21. Cao, J.-L. et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J. Neurosci. 30, 16453–16458 (2010)

    Article  CAS  Google Scholar 

  22. Krishnan, V. et al. molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007)

    Article  CAS  Google Scholar 

  23. Valenti, O., Gill, K. M. & Grace, A. A. Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress pre-exposure. Eur. J. Neurosci. 35, 1312–1321 (2012)

    Article  Google Scholar 

  24. Ikemoto, S. & Wise, R. A. Mapping of chemical trigger zones for reward. Neuropharmacology 47 (Suppl. 1). 190–201 (2004)

    Article  CAS  Google Scholar 

  25. 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)

    Article  ADS  CAS  Google Scholar 

  26. Tan, K. R. et al. GABA neurons of the VTA drive conditioned place aversion. Neuron 73, 1173–1183 (2012)

    Article  CAS  Google Scholar 

  27. van Zessen, R., Phillips, J. L., Budygin, E. A. & Stuber, G. D. Activation of VTA GABA neurons disrupts reward consumption. Neuron 73, 1184–1194 (2012)

    Article  CAS  Google Scholar 

  28. Lemos, J. C. et al. Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature (19 September 2012)

  29. Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005)

    Article  CAS  Google Scholar 

  30. Tye, K. M. & Deisseroth, K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nature Rev. Neurosci. 13, 251–266 (2012)

    Article  CAS  Google Scholar 

  31. Lemke, M. R., Wendorff, T., Mieth, B., Buhl, K. & Linnemann, M. Spatiotemporal gait patterns during over ground locomotion in major depression compared with healthy controls. J. Psychiatr. Res. 34, 277–283 (2000)

    Article  CAS  Google Scholar 

  32. Ungless, M. A., Magill, P. J. & Bolam, J. P. Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science 303, 2040–2042 (2004)

    Article  ADS  CAS  Google Scholar 

  33. Grace, A. A. & Bunney, B. S. The control of firing pattern in nigral dopamine neurons: burst firing. J. Neurosci. 4, 2877–2890 (1984)

    Article  CAS  Google Scholar 

  34. Freeman, A. S. & Bunney, B. S. Activity of A9 and A10 dopaminergic neurons in unrestrained rats: further characterization and effects of apomorphine and cholecystokinin. Brain Res. 405, 46–55 (1987)

    Article  CAS  Google Scholar 

Download references


We thank T. Davidson, S. Pak, C. Ramakrishnan, L. Grosenick, Z. Chen and the members of the Deisseroth Laboratory for support. I.B.W. was supported by the Helen Hay Whitney Foundation; K.M.T was supported by NRSA fellowship F32 MH880102 and the JPB Foundation; K.R.T., M.R.W. and K.D. are NARSAD grant awardees. K.D. was supported by the Wiegers Family Fund and by the NIMH, the NIDA, the DARPA REPAIR Program, the Keck Foundation, the McKnight Foundation, the Gatsby Charitable Foundation, the Snyder Foundation, the Woo Foundation and the Albert Yu and Mary Bechman Foundation. All tools and methods described are distributed and supported freely (

Author information

Authors and Affiliations



Author Contributions K.M.T., J.J.M., M.R.W., H.-C.T. and K.D. contributed to study design. K.M.T., J.J.M., M.R.W., H.-C.T., J.F., S-Y.K., E.A.F., A.A., K.R.T., L.A.G., I.B.W. and K.D. contributed to data collection or interpretation. K.M.T. coordinated all experiments, M.R.W. led development of the induction-coil FST and the FST electrophysiology; K.M.T., J.J.M., M.R.W. and A.S.A. contributed to data analysis, and K.D. supervised the project. K.M.T. and K.D. wrote the paper.

Corresponding authors

Correspondence to Kay M. Tye or Karl Deisseroth.

Ethics declarations

Competing interests

K.M.T., M.R.W. and K.D. have disclosed these findings to the Stanford Office of Technology Licensing, which has filed a patent application for the possible use of the findings and methods in identifying new treatments for depression. All materials, methods and reagents remain freely available for academic and non-profit research in perpetuity through the Deisseroth optogenetics website (

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-19 and additional references. (PDF 1528 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tye, K., Mirzabekov, J., Warden, M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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.


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