Behavioral flexibility is associated with changes in structure and function distributed across a frontal cortical network in macaques.

One of the most influential accounts of central orbitofrontal cortex-that it mediates behavioral flexibility-has been challenged by the finding that discrimination reversal in macaques, the classic test of behavioral flexibility, is unaffected when lesions are made by excitotoxin injection rather than aspiration. This suggests that the critical brain circuit mediating behavioral flexibility in reversal tasks lies beyond the central orbitofrontal cortex. To determine its identity, a group of nine macaques were taught discrimination reversal learning tasks, and its impact on gray matter was measured. Magnetic resonance imaging scans were taken before and after learning and compared with scans from two control groups, each comprising 10 animals. One control group learned discrimination tasks that were similar but lacked any reversal component, and the other control group engaged in no learning. Gray matter changes were prominent in posterior orbitofrontal cortex/anterior insula but were also found in three other frontal cortical regions: lateral orbitofrontal cortex (orbital part of area 12 [12o]), cingulate cortex, and lateral prefrontal cortex. In a second analysis, neural activity in posterior orbitofrontal cortex/anterior insula was measured at rest, and its pattern of coupling with the other frontal cortical regions was assessed. Activity coupling increased significantly in the reversal learning group in comparison with controls. In a final set of experiments, we used similar structural imaging procedures and analyses to demonstrate that aspiration lesion of central orbitofrontal cortex, of the type known to affect discrimination learning, affected structure and activity in the same frontal cortical circuit. The results identify a distributed frontal cortical circuit associated with behavioral flexibility.

Microstimulation of primate neocortex targeting striosomes induces negative decision-making.

Here, we combined MRI-guided electrical microstimulation and viral tracing to examine the function of a corticostriatal circuit implicated by previous cortical microstimulation as modulating affective judgment and decision-making. Local microstimulation of a small part of the pregenual anterior cingulate cortex (pACC) was found to increase avoidance decisions in a cost-benefit decision-making task (Ap-Av task) in which differing amounts of "good" and "bad" options were given simultaneously. No effect of such stimulation was found when the monkeys performed a task in which both offers were rewarding, but given in different amounts. We asked whether we could identify the targets of such corticostriatal circuits when the cortical microstimulation sites were explicitly identified as affecting approach or avoidance in the Ap-Av task. We explored the pACC and caudal orbitofrontal cortex (cOFC) to look for such sites. For each cortical region, we found sites at which microstimulation induced increased avoidance behavior. After identifying these sites, we injected viral tracers carrying constructs allowing subsequent track-tracing post-mortem. For each site identified behaviorally as increasing avoidance choices, we found strong fiber projections to the anterior striatum with large parts of these targeting striosomes subsequently identified by serial section immunohistochemistry. With fMRI, we demonstrated that microstimulation in an anesthetized monkey at sites pre-identified as affecting Ap-Av choices induced blood oxygen level dependent activation of the anterior striatum, confirming that the microstimulation method that we applied was effective in activating the striatum. These findings outline circuits leading from pACC/cOFC to striosomes and causally modulating decision-making under emotional conflict.

The macaque anterior cingulate cortex translates counterfactual choice value into actual behavioral change.

The neural mechanisms mediating sensory-guided decision-making have received considerable attention, but animals often pursue behaviors for which there is currently no sensory evidence. Such behaviors are guided by internal representations of choice values that have to be maintained even when these choices are unavailable. We investigated how four macaque monkeys maintained representations of the value of counterfactual choices-choices that could not be taken at the current moment but which could be taken in the future. Using functional magnetic resonance imaging, we found two different patterns of activity co-varying with values of counterfactual choices in a circuit spanning the hippocampus, the anterior lateral prefrontal cortex and the anterior cingulate cortex. Anterior cingulate cortex activity also reflected whether the internal value representations would be translated into actual behavioral change. To establish the causal importance of the anterior cingulate cortex for this translation process, we used a novel technique, transcranial focused ultrasound stimulation, to reversibly disrupt anterior cingulate cortex activity.

Inverted activity patterns in ventromedial prefrontal cortex during value-guided decision-making in a less-is-more task.

Ventromedial prefrontal cortex has been linked to choice evaluation and decision-making in humans but understanding the role it plays is complicated by the fact that little is known about the corresponding area of the macaque brain. We recorded activity in macaques using functional magnetic resonance imaging during two very different value-guided decision-making tasks. In both cases ventromedial prefrontal cortex activity reflected subjective choice values during decision-making just as in humans but the relationship between the blood oxygen level-dependent signal and both decision-making and choice value was inverted and opposite to the relationship seen in humans. In order to test whether the ventromedial prefrontal cortex activity related to choice values is important for decision-making we conducted an additional lesion experiment; lesions that included the same ventromedial prefrontal cortex region disrupted normal subjective evaluation of choices during decision-making.

Mesolimbic Dopamine Encodes Prediction Errors in a State-Dependent Manner.

Mesolimbic dopamine encodes the benefits of a course of action. However, the value of an appetitive reward depends strongly on an animal's current state. To investigate the relationship between dopamine, value, and physiological state, we monitored sub-second dopamine release in the nucleus accumbens core while rats made choices between food and sucrose solution following selective satiation on one of these reinforcers. Dopamine signals reflected preference for the reinforcers in the new state, decreasing to the devalued reward and, after satiation on food, increasing for the valued sucrose solution. These changes were rapid and selective, with dopamine release returning to pre-satiation patterns when the animals were re-tested in a standard food-restricted state. Such rapid and selective adaptation of dopamine-associated value signals could provide an important signal to promote efficient foraging for a varied diet.

Contrasting Roles for Orbitofrontal Cortex and Amygdala in Credit Assignment and Learning in Macaques.

Recent studies have challenged the view that orbitofrontal cortex (OFC) and amygdala mediate flexible reward-guided behavior. We trained macaques to perform an object discrimination reversal task during fMRI sessions and identified a lateral OFC (lOFC) region in which activity predicted adaptive win-stay/lose-shift behavior. Amygdala and lOFC activity was more strongly coupled on lose-shift trials. However, lOFC-amygdala coupling was also modulated by the relevance of reward information in a manner consistent with a role in establishing how credit for reward should be assigned. Day-to-day fluctuations in signals and signal coupling were correlated with day-to-day fluctuation in performance. A second experiment confirmed the existence of signals for adaptive stay/shift behavior in lOFC and reflecting irrelevant reward in the amygdala in a probabilistic learning task. Our data demonstrate that OFC and amygdala each make unique contributions to flexible behavior and credit assignment.