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.

Keywords: anxiety; negative bias; orbitofrontal cortex; ventrolateral prefrontal cortex.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Behavioral task and prefrontal cannulae placements. (A) Responding to either of two identical visual stimuli presented to the left and right of a touch-sensitive computer screen gained the reward (5-s banana juice) according to independent but identical VI schedules. In occasional test sessions (average one per week), responding to one of the stimuli also resulted in a punishment (0.3-s, 117-dB loud noise) on a leaner independent VI schedule, whereas the reward schedule was unchanged. (B) Under control conditions, marmosets responded relatively equally to both stimuli, with only a slight preference for one side. Accordingly, that side received the punishment on punishment sessions, and thus, overall, there is more responding to the “punished” or “to be” punished (P) side than the nonpunished or “to be” nonpunished (NP) side (F1,7 = 26.08, P = 0.001). This remained the same regardless of whether punishment was present or not (F1,7 = 0.16, P = 0.698; see Results for a detailed explanation of why animals in control conditions did not avoid punishment). (C) Sagittal marmoset MRI section illustrating the rostro-caudal locations of the vlPFC and OFC for target infusions. (D) Schematics showing the single and double intracerebral cannulae targeting, respectively, area 11/antOFC and area 12/vlPFC, together with the actual cannulae locations for each animal and representative histological sections with arrows marking the position of the cannulae. All cannulae were located within the range of AP 15.8–16.6, plotted here on a single coronal section for each target area. (Scale bar, 5 mm.) Cytoarchitectonic parcellation was performed according to Burman and Rosa, 2009 (44), and the circles represent the estimated maximal spread of the muscimol/baclofen or saline infusions (15).

Fig. 2.

Inactivation of either the vlPFC (n = 4) or antOFC (n = 4) induces a negative decision bias but on different time scales. (A) Inactivation of either the vlPFC or OFC did not affect responding when only the reward was present (left two pairs of bars) but produced differential effects on responding when punishment was introduced (right two pairs of bars). vlPFC inactivation (green bars) caused a bias away from punishment on the day of punishment (“infusion” day), whereas OFC inactivation (blue bars) caused a bias away from punishment the day after (“next” day). (B) The overall number of responses was not affected by either inactivation. The region of inactivation (vlPFC or OFC), the day of inactivation (infusion day or the next day), and the presence of reward (blue droplet) and/or punishment (bell) are all indicated in the grid below the bars. A response bias of 100% indicates that an inactivation was identical to that of saline treatment. See Materials and Methods for details of bias calculation.*P < 0.05 on square root-transformed data. Data are represented as mean ± SEM.

Fig. 3.

The negative decision biases were abolished by anxiolytic treatment. (A) The bias away from the punished side that is seen after vlPFC inactivation on a punished day (left dark green bar) was abolished by the concomitant presence of diazepam (left light green bar). Next day performance was unaffected (right green bars). (B) The bias away from the punished side that is seen on the next day after OFC inactivation on a punished day (right dark blue bar) was completely abolished when diazepam was administered on the infusion day (right midblue bar) and partially abolished when diazepam was administered on the next day (right pale blue bar). P < 0.05 on square root-transformed data. The region of inactivation (vlPFC or OFC), the day of inactivation (infusion day or the next day), and the presence of diazepam (D), reward (blue droplet), and punishment (bell) are all indicated in the grid below the bars. Data are represented as mean ± SEM.

Fig. 4.

antOFC inactivation modulates a punishment memory within an amygdala–hippocampal circuit. (A) Sagittal marmoset MRI section illustrating the rostro-caudal coordinates of the antOFC, amygdala, and anterior hippocampus for cannula placements (n = 3). (B) The effects of amygdala and anterior hippocampal inactivation or their crossed disconnection on the next day, after antOFC inactivation on a punished day, were compared with the effects of amygdala/hippocampal manipulations on the next day, after punishment in the absence of antOFC inactivation. The bias away from the punished side that is seen on the next day after OFC inactivation on a punished day (right dark blue bar compared with left dark blue bar) was completely abolished if the anterior hippocampus (right red bar), amygdala (right khaki bar), or a unilateral crossed disconnection of both (right purple bar) were also inactivated the next day. *P < 0.05 on square root-transformed data. The region of inactivation (amygdala, Amyg; antOFC, OFC; hippocampal/amygdala disconnection, H/A; or hippocampus, Hipp), the day of inactivation (infusion day or the next day), and the presence of reward (blue droplet) and punishment (bell) are all indicated in the grid below the bars. Data are represented as mean ± SEM. (C and D) Schematics illustrating the location of the amygdala and anterior hippocampal cannulae in a coronal section for each animal, alongside representative histological sections with arrows marking the position of the cannulae tracts.