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Region-specific CREB function regulates distinct forms of regret associated with resilience versus susceptibility to chronic stress

View ORCID ProfileRomain Durand-de Cuttoli, View ORCID ProfileFreddyson J. Martínez-Rivera, Long Li, Angélica Minier-Toribio, Flurin Cathomas, View ORCID ProfileLeanne M. Holt, Farzana Yasmin, Salma O. Elhassa, Jasmine F. Shaikh, Sanjana Ahmed, Scott J. Russo, Eric J. Nestler, View ORCID ProfileBrian M. Sweis
doi: https://doi.org/10.1101/2022.01.17.476637
Romain Durand-de Cuttoli
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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  • ORCID record for Romain Durand-de Cuttoli
Freddyson J. Martínez-Rivera
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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  • ORCID record for Freddyson J. Martínez-Rivera
Long Li
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Angélica Minier-Toribio
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Flurin Cathomas
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Leanne M. Holt
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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  • ORCID record for Leanne M. Holt
Farzana Yasmin
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Salma O. Elhassa
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Jasmine F. Shaikh
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Sanjana Ahmed
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Scott J. Russo
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Eric J. Nestler
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Brian M. Sweis
1Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
2Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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  • ORCID record for Brian M. Sweis
  • For correspondence: brian.sweis@mountsinai.org
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Abstract

Regret describes recognizing that alternative actions could have led to better outcomes. This can transform into behavioral consequences, altering subsequent valuations, but remains unclear if regret derives from a generalized computation for mistake appraisal or instead is made up of dissociable action-specific processes. Using a novel neuroeconomic decision-making paradigm, we found mice were differentially sensitive to fundamentally distinct types of missed opportunities following exposure to chronic social defeat stress or manipulations of CREB, a key transcription factor implicated in chronic stress action. Bias to make compensatory decisions after rejecting high-value offers (regret type I) was unique to stress-susceptible mice. Bias following the converse operation, accepting low-value offers (regret type II), was enhanced in stress-resilient and absent in stress-susceptible mice. CREB function in either the medial prefrontal cortex or nucleus accumbens was required to suppress regret type I but differentially affected regret type II. We provide insight into how adaptive versus maladaptive stress-response traits may be related to fundamentally distinct forms of counterfactual thinking and could steer psychotherapy for mood disorders such as depression toward unveiling circuit-specific computations through a careful description of decision narrative.

Competing Interest Statement

The authors have declared no competing interest.

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Posted January 20, 2022.
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Region-specific CREB function regulates distinct forms of regret associated with resilience versus susceptibility to chronic stress
Romain Durand-de Cuttoli, Freddyson J. Martínez-Rivera, Long Li, Angélica Minier-Toribio, Flurin Cathomas, Leanne M. Holt, Farzana Yasmin, Salma O. Elhassa, Jasmine F. Shaikh, Sanjana Ahmed, Scott J. Russo, Eric J. Nestler, Brian M. Sweis
bioRxiv 2022.01.17.476637; doi: https://doi.org/10.1101/2022.01.17.476637
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Region-specific CREB function regulates distinct forms of regret associated with resilience versus susceptibility to chronic stress
Romain Durand-de Cuttoli, Freddyson J. Martínez-Rivera, Long Li, Angélica Minier-Toribio, Flurin Cathomas, Leanne M. Holt, Farzana Yasmin, Salma O. Elhassa, Jasmine F. Shaikh, Sanjana Ahmed, Scott J. Russo, Eric J. Nestler, Brian M. Sweis
bioRxiv 2022.01.17.476637; doi: https://doi.org/10.1101/2022.01.17.476637

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