Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making

Abstract

Dysregulation of the orbitofrontal and ventrolateral prefrontal cortices is implicated in anxiety and mood disorders, but the specific contributions of each region are unknown, including how they gate the impact of threat on decision making. To address this, the effects of GABAergic inactivation of these regions were studied in marmoset monkeys performing an instrumental approach–avoidance decision-making task that is sensitive to changes in anxiety. Inactivation of either region induced a negative bias away from punishment that could be ameliorated with anxiolytic treatment. However, whereas the effects of ventrolateral prefrontal cortex inactivation on punishment avoidance were seen immediately, those of orbitofrontal cortex inactivation were delayed and their expression was dependent upon an amygdala–anterior hippocampal circuit. We propose that these negative biases result from deficits in attentional control and punishment prediction, respectively, and that they provide the basis for understanding how distinct regional prefrontal dysregulation contributes to the heterogeneity of anxiety disorders with implications for cognitive-behavioral treatment strategies.

Lateral, not medial, prefrontal cortex contributes to punishment and aversive instrumental learning

“…( * ) P , 0.05. Cold Spring Harbor Laboratory Press on June 7, 2019 -Published by learnmem.cshlp.org Downloaded from was otherwise unable to affect behavior (Clarke et al 2015). This pattern of results is inconsistent with OFC simply encoding outcome value in aversive decision-making tasks.…”

Why we need nonhuman primates to study the role of ventromedial prefrontal cortex in the regulation of threat- and reward-elicited responses

“…One informative and translational approach to investigating such affective decision making in rats, monkeys, and humans is the use of instrumental approach-avoidance paradigms that simultaneously pit rewards and punishments against each other to influence decisions (77)(78)(79)(80). However, even within such paradigms, there is significant task variation, which makes comparison both between-and within-species difficult (reviewed in ref.…”

A dimensional approach to modeling symptoms of neuropsychiatric disorders in the marmoset monkey

“…Hence, the cost‐benefit balance of responding for reward in the face of punishment is switched from a positive approach response to a negative avoidance response. In contrast, inactivation of antOFC has no effect on the day of receiving punishment, but it acts to bias responding away from the punished side the following day, presumably as a consequence of its effects on memory consolidation (Clarke et al, ).…”

“…For instance, anxiety may be the result of poor learning of predictive cues signaling negative consequences, causing uncertainty, a known contributor to anxious behavior. Alternatively, impaired attentional flexibility may promote anxiety by making it more likely that subjects stay focused on salient negative stimuli, unable to switch their attention toward more positive events in the environment (Clarke et al, ; Shiba et al, ). Fourth, even when treatments are successful there is poor understanding of the underlying psychological and neurobiological mechanisms, making it difficult to match specific treatments to specific symptoms in individual patients.…”