A prospective code for value in the serotonin system

doi:10.1038/s41586-025-08731-7

. 2025 Mar 26.

doi: 10.1038/s41586-025-08731-7. Online ahead of print.

A prospective code for value in the serotonin system

Emerson F Harkin^{1

2

3

4}, Cooper D Grossman⁵, Jeremiah Y Cohen^{6

7}, Jean-Claude Béïque^{8

9

10}, Richard Naud^{11

12

13

14}

Affiliations

¹ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. emerson@efharkin.com.
² Centre for Neural Dynamics and AI, University of Ottawa, Ottawa, Ontario, Canada. emerson@efharkin.com.
³ University of Ottawa's Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada. emerson@efharkin.com.
⁴ Max Planck Institute for Biological Cybernetics, Tübingen, Germany. emerson@efharkin.com.
⁵ California Institute of Technology, Pasadena, CA, USA.
⁶ Allen Institute for Neural Dynamics, Seattle, WA, USA.
⁷ The Solomon H. Snyder Department of Neuroscience, Brain Science Institute, Kavli Neuroscience Discovery Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. jbeique@uottawa.ca.
⁹ Centre for Neural Dynamics and AI, University of Ottawa, Ottawa, Ontario, Canada. jbeique@uottawa.ca.
¹⁰ University of Ottawa's Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada. jbeique@uottawa.ca.
¹¹ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹² Centre for Neural Dynamics and AI, University of Ottawa, Ottawa, Ontario, Canada.
¹³ University of Ottawa's Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
¹⁴ Department of Physics, University of Ottawa, Ottawa, Ontario, Canada.

PMID: 40140568
DOI: 10.1038/s41586-025-08731-7

A prospective code for value in the serotonin system

Emerson F Harkin et al. Nature. 2025.

. 2025 Mar 26.

doi: 10.1038/s41586-025-08731-7. Online ahead of print.

Authors

Emerson F Harkin^{1

2

3

4}, Cooper D Grossman⁵, Jeremiah Y Cohen^{6

7}, Jean-Claude Béïque^{8

9

10}, Richard Naud^{11

12

13

14}

Affiliations

¹ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. emerson@efharkin.com.
² Centre for Neural Dynamics and AI, University of Ottawa, Ottawa, Ontario, Canada. emerson@efharkin.com.
³ University of Ottawa's Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada. emerson@efharkin.com.
⁴ Max Planck Institute for Biological Cybernetics, Tübingen, Germany. emerson@efharkin.com.
⁵ California Institute of Technology, Pasadena, CA, USA.
⁶ Allen Institute for Neural Dynamics, Seattle, WA, USA.
⁷ The Solomon H. Snyder Department of Neuroscience, Brain Science Institute, Kavli Neuroscience Discovery Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. jbeique@uottawa.ca.
⁹ Centre for Neural Dynamics and AI, University of Ottawa, Ottawa, Ontario, Canada. jbeique@uottawa.ca.
¹⁰ University of Ottawa's Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada. jbeique@uottawa.ca.
¹¹ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
¹² Centre for Neural Dynamics and AI, University of Ottawa, Ottawa, Ontario, Canada.
¹³ University of Ottawa's Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
¹⁴ Department of Physics, University of Ottawa, Ottawa, Ontario, Canada.

PMID: 40140568
DOI: 10.1038/s41586-025-08731-7

Abstract

The in vivo responses of dorsal raphe nucleus serotonin neurons to emotionally salient stimuli are a puzzle¹. Existing theories centring on reward², surprise³, salience⁴ and uncertainty⁵ individually account for some aspects of serotonergic activity but not others. Merging ideas from reinforcement learning theory⁶ with recent insights into the filtering properties of the dorsal raphe nucleus⁷, here we find a unifying perspective in a prospective code for value. This biological code for near-future reward explains why serotonin neurons are activated by both rewards and punishments^3,4,8-13, and why these neurons are more strongly activated by surprising rewards but have no such surprise preference for punishments^3,9-observations that previous theories have failed to reconcile. Finally, our model quantitatively predicts in vivo population activity better than previous theories. By reconciling previous theories and establishing a precise connection with reinforcement learning, our work represents an important step towards understanding the role of serotonin in learning and behaviour.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

1. Dayan, P. & Huys, Q. Serotonin’s many meanings elude simple theories. eLife 4, e07390 (2015). - PubMed - PMC - DOI
1. Liu, Z., Lin, R. & Luo, M. Reward contributions to serotonergic functions. Annu. Rev. Neurosci. 43, 141–162 (2020). - PubMed - DOI
1. Matias, S., Lottem, E., Dugué, G. P. & Mainen, Z. F. Activity patterns of serotonin neurons underlying cognitive flexibility. eLife 6, e20552 (2017). - PubMed - PMC - DOI
1. Paquelet, G. E. et al. Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors. Neuron 110, 2664–2679 (2022). - PubMed - PMC - DOI
1. Grossman, C. D., Bari, B. A. & Cohen, J. Y. Serotonin neurons modulate learning rate through uncertainty. Curr. Biol. 32, 586–599 (2022). - PubMed - DOI

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[1] Dayan, P. & Huys, Q. Serotonin’s many meanings elude simple theories. eLife 4, e07390 (2015). - PubMed - PMC - DOI

[2] Dayan, P. & Huys, Q. Serotonin’s many meanings elude simple theories. eLife 4, e07390 (2015). - PubMed - PMC - DOI

[3] Liu, Z., Lin, R. & Luo, M. Reward contributions to serotonergic functions. Annu. Rev. Neurosci. 43, 141–162 (2020). - PubMed - DOI

[4] Liu, Z., Lin, R. & Luo, M. Reward contributions to serotonergic functions. Annu. Rev. Neurosci. 43, 141–162 (2020). - PubMed - DOI

[5] Matias, S., Lottem, E., Dugué, G. P. & Mainen, Z. F. Activity patterns of serotonin neurons underlying cognitive flexibility. eLife 6, e20552 (2017). - PubMed - PMC - DOI

[6] Matias, S., Lottem, E., Dugué, G. P. & Mainen, Z. F. Activity patterns of serotonin neurons underlying cognitive flexibility. eLife 6, e20552 (2017). - PubMed - PMC - DOI

[7] Paquelet, G. E. et al. Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors. Neuron 110, 2664–2679 (2022). - PubMed - PMC - DOI

[8] Paquelet, G. E. et al. Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors. Neuron 110, 2664–2679 (2022). - PubMed - PMC - DOI

[9] Grossman, C. D., Bari, B. A. & Cohen, J. Y. Serotonin neurons modulate learning rate through uncertainty. Curr. Biol. 32, 586–599 (2022). - PubMed - DOI

[10] Grossman, C. D., Bari, B. A. & Cohen, J. Y. Serotonin neurons modulate learning rate through uncertainty. Curr. Biol. 32, 586–599 (2022). - PubMed - DOI

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A prospective code for value in the serotonin system

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A prospective code for value in the serotonin system

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