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Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons

Nature volume 493, pages 532–536 (2013)Cite this article

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Abstract

Ventral tegmental area (VTA) dopamine neurons in the brain’s reward circuit have a crucial role in mediating stress responses1,2,3,4, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities5. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing6,7,8. Phasic firing of the neurons, which is well known to encode reward signals6,7,9, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression5,8,10,11,12,13. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals5,8. However, direct evidence—in real time—linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA–NAc projection induced resilience, whereas inhibition of the VTA–mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.

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Figure 1: Phasic, but not tonic, optical stimulation of VTA dopamine neurons during a subthreshold social defeat induces a susceptible phenotype.
Figure 2: Phasic optical stimulation of VTA dopamine neurons during the social-interaction test instantly induces a susceptible phenotype in two social-defeat paradigms.
Figure 3: Bidirectional effect of modulating the VTA–NAc pathway on susceptibility to social defeat.
Figure 4: Effect of modulating the VTA–mPFC pathway on susceptibility to social defeat.

References

  1. Willner, P., Hale, A. S. & Argyropoulos, S. Dopaminergic mechanism of antidepressant action in depressed patients. J. Affect. Disord. 86, 37–45 (2005)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Berton, O. & Nestler, E. J. New approaches to antidepressant drug discovery: beyond monoamines. Nature Rev. Neurosci. 7, 137–151 (2006)

    Article  CAS  Google Scholar 

  4. Yadid, G. & Friedman, A. Dynamics of the dopaminergic system as a key component to the understanding of depression. Prog. Brain Res. 172, 265–286 (2008)

    Article  CAS  Google Scholar 

  5. 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 

  6. Grace, A. A., Floresco, S. B., Goto, Y. & Lodge, D. J. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci. 30, 220–227 (2007)

    Article  CAS  Google Scholar 

  7. 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 

  8. 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 

  9. Schultz, W. Dopamine signals for reward value and risk: basic and recent data. Behav. Brain Funct. 6, 24 (2010)

    Article  ADS  Google Scholar 

  10. Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006)

    Article  ADS  CAS  Google Scholar 

  11. Anstrom, K. K., Miczek, K. A. & Budygin, E. A. Increased phasic dopamine signaling in the mesolimbic pathway during social defeat in rats. Neuroscience 161, 3–12 (2009)

    Article  CAS  Google Scholar 

  12. Razzoli, M., Andreoli, M., Michielin, F., Quarta, D. & Sokal, D. M. Increased phasic activity of VTA dopamine neurons in mice 3 weeks after repeated social defeat. Behav. Brain Res. 218, 253–257 (2011)

    Article  CAS  Google Scholar 

  13. Krishnan, V., Berton, O. & Nestler, E. The use of animal models in psychiatric research and treatment. Am. J. Psychiatry 165, 1109 (2008)

    Article  Google Scholar 

  14. Lobo, M. K. et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 330, 385–390 (2010)

    Article  ADS  CAS  Google Scholar 

  15. Iñiguez, S. D. et al. Extracellular signal-regulated kinase-2 within the ventral tegmental area regulates responses to stress. J. Neurosci. 30, 7652–7663 (2010)

    Article  Google Scholar 

  16. 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 

  17. 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 

  18. Venzala, E., Garcia-Garcia, A. L., Elizalde, N. & Tordera, R. M. Social vs. environmental stress models of depression from a behavioural and neurochemical approach. Eur. Neuropsychopharmacol. advance online publication, http://dx.doi.org/10.1016/j.euroneuro.2012.05.010 (June 27, 2012)

    Google Scholar 

  19. Lammel, S., Ion, D. I., Roeper, J. & Malenka, R. C. Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 70, 855–862 (2011)

    Article  CAS  Google Scholar 

  20. Willner, P. The mesolimbic dopamine system as a target for rapid antidepressant action. Int. Clin. Psychopharmacol. 12 (Suppl. 3). S7–S14 (1997)

    Article  Google Scholar 

  21. Radulescu, A. R. Mechanisms explaining transitions between tonic and phasic firing in neuronal populations as predicted by a low dimensional firing rate model. PLoS ONE 5, e12695 (2010)

    Article  ADS  Google Scholar 

  22. Inyushin, M. U., Arencibia-Albite, F., Vazquez-Torres, R., Velez-Hernandez, M. E. & Jimenez-Rivera, C. A. Alpha-2 noradrenergic receptor activation inhibits the hyperpolarization-activated cation current (Ih) in neurons of the ventral tegmental area. Neuroscience 167, 287–297 (2010)

    Article  CAS  Google Scholar 

  23. Han, H. M. et al. Essential role of ventral tegmental area dopamine neurons in mediating the induction and rapid reversal of depression-like behaviours. Abstract, http://www.acnp.org/annualmeeting/programbooks.aspx (The 50th Anniversary Meeting of ACNP, 2011)

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

    CAS  Google Scholar 

  25. Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–964 (2010)

    Article  ADS  CAS  Google Scholar 

  26. Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011)

    Article  CAS  Google Scholar 

  27. Hemmeter, U. M., Hemmeter-Spernal, J. & Krieg, J. C. Sleep deprivation in depression. Expert Rev. Neurother. 10, 1101–1115 (2010)

    Article  Google Scholar 

  28. Giacobbe, P., Mayberg, H. S. & Lozano, A. M. Treatment resistant depression as a failure of brain homeostatic mechanisms: implications for deep brain stimulation. Exp. Neurol. 219, 44–52 (2009)

    Article  Google Scholar 

  29. Sartorius, A. et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol. Psychiatry 67, e9–e11 (2010)

    Article  Google Scholar 

  30. Li, B. et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470, 535–539 (2011)

    Article  ADS  CAS  Google Scholar 

  31. Lindeberg, J. et al. Transgenic expression of Cre recombinase from the tyrosine hydroxylase locus. Genesis 40, 67–73 (2004)

    Article  CAS  Google Scholar 

  32. Cardin, J. A. et al. Targeted optogenetic stimulation and recording of neurons in vivo using cell-type-specific expression of Channelrhodopsin-2. Nature Protocols 5, 247–254 (2010)

    Article  CAS  Google Scholar 

  33. Hommel, J. D., Sears, R. M., Georgescu, D., Simmons, D. L. & DiLeone, R. J. Local gene knockdown in the brain using viral-mediated RNA interference. Nature Med. 9, 1539–1544 (2003)

    Article  CAS  Google Scholar 

  34. Sparta, D. R. et al. Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits. Nature Protocols 7, 12–23 (2011)

    Article  Google Scholar 

  35. Gradinaru, V. et al. Targeting and readout strategies for fast optical neural control in vitro and in vivo. J. Neurosci. 27, 14231–14238 (2007)

    Article  CAS  Google Scholar 

  36. Golden, S. A., Covington, H. E., III, Berton, O. & Russo, S. J. A standardized protocol for repeated social defeat stress in mice. Nature Protocols 6, 1183–1191 (2011)

    Article  CAS  Google Scholar 

  37. Stuber, G. D. et al. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380 (2011)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institute of Mental Health (R01 MH092306 to D.C. and M.H.H.), Johnson & Johnson IMHRO Rising Star Translational Research Award (M.H.H.), the National Research Service Awards (F31 MH095425 to J.J.W. and F32 MH096464 to A.K.F) and the Mount Sinai PREP R25 GM064118 (B.J.). We would like to thank K. Roy for help with some of the schematics in the figures, and we thank R. Cachope and J. Cheer for help with chronic fibre implantation techniques.

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  1. Dipesh Chaudhury and Jessica J. Walsh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Dipesh Chaudhury, Jessica J. Walsh, Allyson K. Friedman, Barbara Juarez, Stacy M. Ku, Eric J. Nestler & Ming-Hu Han

  2. Fishberg Department of Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Jessica J. Walsh, Barbara Juarez, Stacy M. Ku, Ja Wook Koo, Deveroux Ferguson, Daniel J. Christoffel, Michelle S. Mazei-Robison, Ezekiell Mouzon, Mary Kay Lobo, Scott J. Russo, Eric J. Nestler & Ming-Hu Han

  3. Departments of Bioengineering and Psychiatry and Behavioural Sciences, Stanford University, Stanford, 94305, California, USA

    Hsing-Chen Tsai & Karl Deisseroth

  4. Laboratory of Molecular Genetics, Howard Hughes Medical Institute, Rockefeller University, New York, 10056, New York, USA

    Lisa Pomeranz, Alexander R. Nectow, Mats Ekstrand, Ana Domingos & Jeffrey M. Friedman

  5. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Rachael L. Neve

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Contributions

D.C., J.J.W., A.K.F., B.J., J.W.K., D.F., D.J.C., H.C.T., M.K.L., M.S.M.-R. and S.M.K. collected and analysed data. L.P., A.R.N. M.E., A.D., E.M., R.L.N., S.J.R., J.M.F., K.D. and E.J.N. generated and provided viral vectors and TH–Cre mice. D.C., J.J.W., E.J.N. and M.H.H. designed and wrote the paper.

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Correspondence to Ming-Hu Han.

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Chaudhury, D., Walsh, J., Friedman, A. et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532–536 (2013). https://doi.org/10.1038/nature11713

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