Stress attenuates the flexible updating of aversive value

Abstract

In a dynamic environment, sources of threat or safety can unexpectedly change, requiring the flexible updating of stimulus-outcome associations that promote adaptive behavior. However, aversive contexts in which we are required to update predictions of threat are often marked by stress. Acute stress is thought to reduce behavioral flexibility, yet its influence on the modulation of aversive value has not been well characterized. Given that stress exposure is a prominent risk factor for anxiety and trauma-related disorders marked by persistent, inflexible responses to threat, here we examined how acute stress affects the flexible updating of threat responses. Participants completed an aversive learning task, in which one stimulus was probabilistically associated with an electric shock, while the other stimulus signaled safety. A day later, participants underwent an acute stress or control manipulation before completing a reversal learning task during which the original stimulus-outcome contingencies switched. Skin conductance and neuroendocrine responses provided indices of sympathetic arousal and stress responses, respectively. Despite equivalent initial learning, stressed participants showed marked impairments in reversal learning relative to controls. Additionally, reversal learning deficits across participants were related to heightened levels of alpha-amylase, a marker of noradrenergic activity. Finally, fitting arousal data to a computational reinforcement learning model revealed that stress-induced reversal learning deficits emerged from stress-specific changes in the weight assigned to prediction error signals, disrupting the adaptive adjustment of learning rates. Our findings provide insight into how stress renders individuals less sensitive to changes in aversive reinforcement and have implications for understanding clinical conditions marked by stress-related psychopathology.

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

“…Whilst the instrumental deficits on both the most salient (reward and punishment) and reward-only, but not punishment-only condition, as reported here, may at first seem surprising given the well-established role of serotonin in aversive processing (Cools et al 2008), this indeed aligns with the literature across species: the key marmoset studies on serotonin depletion and perseveration were conducted in the appetitive domain (Clarke et al 2004;Walker et al 2009 The deleterious effects of serotonin depletion and stress on reversal learning can be interpreted as a selective impairment in integrating new information about a change in reinforcement contingencies, needed to update the representation of aversive value appropriately (Raio et al 2017). These authors invoked the phenomenon of stress-induced dopamine release (Pruessner et al 2004), which may dampen negative prediction errors evoked by contingency reversal (Cools et al 2001).…”

“…Deficits in both domains were underscored by significant correlations showing that a greater extent of depletion, as assessed by plasma samples, was associated with more pronounced reversal impairments. Strikingly, the results align with data from neurotoxic serotonin depletion in experimental animals (Bari et al 2010;Clarke et al 2004Clarke et al , 2007Walker et al 2009), stress induction in humans (Raio et al 2017) That serotonin depletion impaired these fundamental learning processes pervasive in daily life highlights a failure mode that could lead to significant distress and impairment. The reversal deficits presented, furthermore, indicate how serotonergic dysfunction could impede the ability to engage in cognitive behavioural therapies (CBT).…”

“…), andSeymour et al (2012) found human ATD affected the appetitive but not aversive domain in a 4-choice probabilistic task on which computational modelling revealed enhanced perseveration.The Pavlovian reversal findings reported here resemble both the Pavlovian reversal learning impairment reported in OCD(Apergis-Schoute et al 2017) and what has been demonstrated in healthy volunteers under stress(Raio et al 2017). The reversal deficit in OCD, indexed by SCR on an identical paradigm, was explained by dysfunctional activity in the ventromedial prefrontal (vmPFC), which receives rich serotonergic innervation(Hornung 2010) Raio et al (2017),. meanwhile, used SCR and a similar design to that used here (but with neutral cues) and found that upon reversal, stress also attenuated the acquisition of threat responses to the newly threatening (previously safe) stimulus upon reversal, while leaving extinction learning to the previously threatening cue intact.…”

Constitutive differences in glucocorticoid responsiveness are related to divergent spatial information processing abilities

“…Therefore, it is plausible that superior performance in the High CORT line may involve AMPAR-dependent mechanisms and/or several of the other mechanisms mentioned above. Conversely, in agreement with the findings that stress affects reversal learning (Graybeal et al, 2011) and that glucocorticoids modulate mechanisms involved in reversal (Bryce and Howland, 2015; Myers et al, 2014; Raio et al, 2017), our data suggest that the Low CORT responding line may exhibit altered neural activity in key brain regions involved in flexible behaviors. In fact, our former analyses of these rats indicate that the Low line exhibits lower basal activity in the ventral orbitofrontal cortex (OFC), prefrontal cortex (mPFC) and hippocampus as compared to the High line (Walker and Sandi, 2018).…”

Role of Human Ventromedial Prefrontal Cortex in Learning and Recall of Enhanced Extinction

“…Computational modeling. In keeping with our prior computational model fitting approach (Raio et al, 2017), we fit and validated an associability model using individual subject SCRs. In the model, x n indicates the CS on trial n (CS ϩ or CS Ϫ ) and r n is the US (1 for US, 0 for no US).…”