Original Article | Published:

The Protective Action Encoding of Serotonin Transients in the Human Brain

Neuropsychopharmacology volume 43, pages 14251435 (2018) | Download Citation

Abstract

The role of serotonin in human brain function remains elusive due, at least in part, to our inability to measure rapidly the local concentration of this neurotransmitter. We used fast-scan cyclic voltammetry to infer serotonergic signaling from the striatum of 14 brains of human patients with Parkinson’s disease. Here we report these novel measurements and show that they correlate with outcomes and decisions in a sequential investment game. We find that serotonergic concentrations transiently increase as a whole following negative reward prediction errors, while reversing when counterfactual losses predominate. This provides initial evidence that the serotonergic system acts as an opponent to dopamine signaling, as anticipated by theoretical models. Serotonin transients on one trial were also associated with actions on the next trial in a manner that correlated with decreased exposure to poor outcomes. Thus, the fluctuations observed for serotonin appear to correlate with the inhibition of over-reactions and promote persistence of ongoing strategies in the face of short-term environmental changes. Together these findings elucidate a role for serotonin in the striatum, suggesting it encodes a protective action strategy that mitigates risk and modulates choice selection particularly following negative environmental events.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. , , , , , et al (2010). Serotonin modulates sensitivity to reward and negative feedback in a probabilistic reversal learning task in rats. Neuropsychopharmacology 35: 1290–1301.

  2. , , , (2014). An extended reinforcement learning model of basal ganglia to understand the contributions of serotonin and dopamine in risk-based decision making, reward prediction, and punishment learning. Front Comput Neurosci 8: 47.

  3. , (2011). Opponency revisited: competition and cooperation between dopamine and serotonin. Neuropsychopharmacology 36: 74–97.

  4. , , (2008). Smokers' brains compute, but ignore, a fictive error signal in a sequential investment task. Nat Neurosci 11: 514–520.

  5. , , (2015). Serotonergic neurons signal reward and punishment on multiple timescales. Elife 4: e06346.

  6. , , (2008). Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci 12: 31–40.

  7. , , , , (2012). Serotonin modulates the effects of Pavlovian aversive predictions on response vigor. Neuropsychopharmacology 37: 2244–2252.

  8. , , (2009). Reconciling the role of serotonin in behavioral inhibition and aversion: acute tryptophan depletion abolishes punishment-induced inhibition in humans. J Neurosci 29: 11993–11999.

  9. , , (2002). Opponent interactions between serotonin and dopamine. Neural Netw 15: 603–616.

  10. , (2008). Serotonin, inhibition, and negative mood. PLoS Comput Biol 4: e4.

  11. , (2009). Serotonin in affective control. Annu Rev Neurosci 32: 95–126.

  12. (1983). Roles of serotonergic systems in escape, avoidance and other behaviours. Theory Psychopharmacol 2: 149–193.

  13. , , , , , et al (2009). Decision making under risk and under ambiguity in Parkinson’s disease. Neuropsychologia 47: 1901–1908.

  14. , , , , , et al (2013). Dissociable effects of dopamine and serotonin on reversal learning. Neuron 80: 1090–1100.

  15. , , (2008). Functional neuroimaging of reward processing and decision-making: a review of aberrant motivational and affective processing in addiction and mood disorders. Brain Res Rev 59: 164–184.

  16. , , , (2013). Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 501: 179–184.

  17. (2007). Reinforcement learning: computational theory and biological mechanisms. HFSP J 1: 30–40.

  18. , , , , , et al (2009). Dissociation of decision-making under ambiguity and decision-making under risk in patients with Parkinson's disease: a neuropsychological and psychophysiological study. Neuropsychologia 47: 2882–2890.

  19. , , , , , et al (2011). A selective role for dopamine in stimulus-reward learning. Nature 469: 53–57.

  20. , , (2015). Activation of dorsal raphe serotonergic neurons promotes waiting but is not reinforcing. Curr Biol 25: 306–315.

  21. , , (2004) By carrot or by stick: cognitive reinforcement learning in parkinsonism Science 306: 1940–1943.

  22. (2016). 5-HT receptors mediating pre-synaptic autoinhibition in central serotoninergic nerve. Serotonin 56.

  23. , (1991). 5-HT and mechanisms of defence. J Psychopharmacol 5: 305–315.

  24. , , , , (2011). In vivo electrochemical evidence for simultaneous 5‐HT and histamine release in the rat substantia nigra pars reticulata following medial forebrain bundle stimulation. J Neurochem 118: 749–759.

  25. , , , , , et al (2006). Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78: 815–826.

  26. (1994). Serotonin, motor activity and depression-related disorders. Am Sci 82: 456–463.

  27. , (2007) Fast scan cyclic voltammetry of dopamine and serotonin in mouse brain slices In: , (eds) Electrochemical Methods for Neuroscience. CRC Press/Taylor & Francis: Boca Raton, FL. Chapter 4.

  28. , (2007). Voltammetric characterization of the effect of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse caudate-putamen and substantia nigra slices. Neuropharmacology 52: 1596–1605.

  29. , , (1998). Serotonin neuronal function and selective serotonin reuptake inhibitor treatment in anorexia and bulimia nervosa. Biol Psychiatry 44: 825–838.

  30. , , , , , et al (2016). Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward. Proc Natl Acad Sci USA 113: 200–205.

  31. , , , , , et al (2011). Sub-second dopamine detection in human striatum. PLoS ONE 6: e23291.

  32. , (2005). Functional magnetic resonance imaging of reward prediction. Curr Opin Neurol 18: 411–417.

  33. , , , , , et al (2016). Serotonin neurons in the dorsal raphe nucleus encode reward signals. Nat Commun 7: 10503.

  34. , , , , , et al (2014). Dorsal raphe neurons signal reward through 5-HT and glutamate. Neuron 81: 1360–1374.

  35. , , , (2007). Neural signature of fictive learning signals in a sequential investment task. Proc Natl Acad Sci USA 104: 9493–9498.

  36. (2002). Functional subsets of serotonergic neurones: implications for control of the hypothalamic‐pituitary‐adrenal axis. J Neuroendocrinol 14: 911–923.

  37. , (2012). Serotonergic action on dorsal striatal function. Parkinsonism Relat Disord 18: S129–S131.

  38. , , (2012). The role of serotonin in the regulation of patience and impulsivity. Mol Neurobiol 45: 213–224.

  39. , , (2012). Activation of dorsal raphe serotonin neurons is necessary for waiting for delayed rewards. J Neurosci 32: 10451–10457.

  40. , , , , , et al (2014). Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards. Curr Biol 24: 2033–2040.

  41. , , , (2016). An efficiency framework for valence processing systems inspired by soft cross-wiring. Curr Opin Behav Sci 11: 121–129.

  42. , , , , , et al (2004). Dynamic gain control of dopamine delivery in freely moving animals. J Neurosci 24: 1754–1759.

  43. , , , , , (2007). Major depressive disorder, serotonin transporter, and personality traits: why patients use suboptimal decision-making strategies? J Affect Disord 103: 273–276.

  44. , , , (2002). Activity in human ventral striatum locked to errors of reward prediction. Nat Neurosci 5: 97–98.

  45. , , , , , et al (2014). Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients. J Clin Invest 124: 1340–1349.

  46. , , (2000). Serotonin and the sleep/wake cycle: special emphasis on microdialysis studies. Prog Neurobiol 60: 13–35.

  47. , , , , , et al (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301: 2462–2471.

  48. , , , , (2013). Canceling actions involves a race between basal ganglia pathways. Nat Neurosci 16: 1118–1124.

  49. , , (1997). A neural substrate of prediction and reward. Science 275: 1593–1599.

  50. , , , , , et al (2012). Dopamine and performance in a reinforcement learning task: evidence from Parkinson’s disease. Brain 135: 1871–1883.

  51. , , , , , (2009). Serotonin affects association of aversive outcomes to past actions. J Neurosci 29: 15669–15674.

  52. (1996). Regression shrinkage and selection via the lasso. J R Stat Soc Series B Methodol 58: 267–288.

  53. , , , (2009). Serotonin: modulator of a drive to withdraw. Brain Cogn 71: 427–436.

  54. , , , , , et al (2014). Measuring ‘waiting’ impulsivity in substance addictions and binge eating disorder in a novel analogue of rodent serial reaction time task. Biol Psychiatry 75: 148–155.

  55. , , , , , (2004). Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 363: 1341–1345.

  56. , , , , , et al (2016). Valence-dependent influence of serotonin depletion on model-based choice strategy. Mol Psychiatry 21: 624–629.

  57. , , , , (2014). Serotonin depletion induces ‘waiting impulsivity’on the human four-choice serial reaction time task: cross-species translational significance. Neuropsychopharmacology 39: 1519–1526.

  58. , , (2014). Optogenetic control of serotonin and dopamine release in Drosophila larvae. ACS Chem Neurosci 5: 666–673.

  59. , , , , , (2006). Dissociable systems for gain-and loss-related value predictions and errors of prediction in the human brain. J Neurosci 26: 9530–9537.

  60. , , , , , (2009). Selective oxidation of serotonin and norepinephrine over eriochrome cyanine R film modified glassy carbon electrode. Electrochim Acta 54: 4607–4612.

Download references

Acknowledgements

We thank the patients who took part in this study.

Author information

Author notes

    • Rosalyn J Moran
    • , Kenneth T Kishida
    •  & Terry Lohrenz

    These are joint first authors.

Affiliations

  1. Department of Engineering Mathematics, School of Computer Science, Electrical and Electronic Engineering, and Engineering Mathematics, University of Bristol, Bristol, UK

    • Rosalyn J Moran
  2. Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    • Kenneth T Kishida
  3. Department of Neurosurgery, Wake Forest School of Medicine, Winston-Salem, NC, USA

    • Kenneth T Kishida
    • , Adrian W Laxton
    • , Mark R Witcher
    • , Stephen B Tatter
    •  & Thomas L Ellis
  4. Virginia Tech Carilion Research Institute, Virginia Tech, Roanoke, VA, USA

    • Terry Lohrenz
    •  & P Read Montague
  5. Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA

    • Ignacio Saez
  6. Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, USA

    • Paul EM Phillips
  7. Department of Pharmacology, University of Washington, Seattle, WA, USA

    • Paul EM Phillips
  8. The Gatsby Computational Neuroscience Unit, University College London, London, UK

    • Peter Dayan
  9. Department of Physics, Virginia Tech, Blacksburg, VA, USA

    • P Read Montague
  10. Wellcome Trust Centre for Neuroimaging, University College London, London, UK

    • P Read Montague

Authors

  1. Search for Rosalyn J Moran in:

  2. Search for Kenneth T Kishida in:

  3. Search for Terry Lohrenz in:

  4. Search for Ignacio Saez in:

  5. Search for Adrian W Laxton in:

  6. Search for Mark R Witcher in:

  7. Search for Stephen B Tatter in:

  8. Search for Thomas L Ellis in:

  9. Search for Paul EM Phillips in:

  10. Search for Peter Dayan in:

  11. Search for P Read Montague in:

Corresponding author

Correspondence to P Read Montague.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/npp.2017.304

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)