DEFICITS OF COGNITIVE FLEXIBILITY AND DYNAMIC ADJUSTMENT OF MOTIVATIONAL STATE SHAPE DECISIONAL PERFORMANCE UNDER DISTRESS

Adaptive decision-making (DM) relies on the balance between exploration of available options and exploitation of learned solutions. This process is strongly influenced by motivational state and cognitive flexibility, both of which are highly sensitive to stress. To investigate the neurobiological mechanisms underlying maladaptive DM under chronic distress, we used a murine model of chronic corticosterone (CORT) administration that mimics sustained activation of the hypothalamo–pituitary–adrenal axis. Using behavioral tasks and pharmacogenetic approaches with reinforcement learning paradigms, we assessed goal-directed behavior under chronic stress. Chronic distress induced impairments in instrumental learning, enhanced negatively valenced perception, and suboptimal management of uncertainty, collectively contributing to maladaptive decision strategies. Notably, motivational state and cognitive flexibility differentially contributed to decisional performance in male and female mice. At the neural level, post-mortem immunohistological analyses revealed the involvement of the basolateral amygdala and anterior insular cortex in distress-related motivational deficits. We further identified stress-induced plasticity of corticotropin-releasing factor (CRF) signaling in the prefrontal cortex, with elevated CRF levels correlating with poorer decisional performance under distress. Finally, in vivo modulation of prefrontal CRF signaling using DREADD technology induced deficits in reward and effort processing, altering motivational thresholds required to initiate goal-directed behavior in dynamic environments. Together, these findings highlight the interaction between stress, motivation and cognitive flexibility in shaping adaptive DM, and emphasize interindividual variability in behavioral responses to chronic distress.