TY - JOUR T1 - Region-specific CREB function regulates distinct forms of regret associated with resilience versus susceptibility to chronic stress JF - bioRxiv DO - 10.1101/2022.01.17.476637 SP - 2022.01.17.476637 AU - Romain Durand-de Cuttoli AU - Freddyson J. Martínez-Rivera AU - Long Li AU - Angélica Minier-Toribio AU - Flurin Cathomas AU - Leanne M. Holt AU - Farzana Yasmin AU - Salma O. Elhassa AU - Jasmine F. Shaikh AU - Sanjana Ahmed AU - Scott J. Russo AU - Eric J. Nestler AU - Brian M. Sweis Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/20/2022.01.17.476637.abstract N2 - 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 StatementThe authors have declared no competing interest. ER -