Several investigators have suggested that a single functional circuit underlies emotion and reward processing. The circuit is thought to include the amygdala and PFo; the amygdala and PFo are anatomically related and the behavioral profiles that follow damage to each region are similar. For example, tests of stimulus-reward association such as object reversal learning and instrumental extinction are disrupted by damage to either the amygdala or PFo. ? ? Because aspirative lesions often cause inadvertent damage to projections to and from the inferotemporal cortex, which pass near the amygdala, conclusions about amygdala function based on effects of aspirative (or radiofrequency) lesions need to be reevaluated. MR-based stereotaxic surgical approaches combined with the injection of excitotoxins can now be used to selectively damage subcortical structures such as the amygdala. We therefore evaluated the effects of selective, excitotoxic lesions of the amygdala on a battery of tasks, including object reversal learning. Insofar as this task requires subjects to link objects with the occurrence of food reward in a flexible manner, it is thought to measure stimulus-reward association. Contrary to earlier reports based on aspirative lesions, there was no effect of the selective amygdala lesions on initial learning of the discrimination problem, nor was there an effect on object reversal learning. Thus, excitotoxic amygdala lesions, in contrast to aspiration or radiofrequency lesions of this structure, fail to disrupt stimulus-reward association, at least that based on the occurrence of food reward. These results overturn dogma regarding the neural basis of stimulus-reward learning, and argue for a new view of amygdala contributions to reward processing. Other findings from this Section have shown that the amygdala is essential for linking objects with the current value of food rewards. Taken together, the data indicate a narrower and more specific role for the amygdala in stimulus-reward association than previously appreciated. Moreover, because PFo lesions severely disrupt reversal learning, this is one task in which the roles of PFo and amygdala may be dissociated. ? ? In tests like object reversal learning and extinction, when a previously rewarded response no longer produces reward, subjects with PFo lesions continue to choose according to the previous reward contingency. This behavior has been regarded as a failure of behavioral inhibition. In addition, unlike control subjects, subjects with PFo damage fail to inhibit responding to food reward in the presence of a fake snake. This example, too, links PFo damage to impaired inhibitory control. To assess the role of PFo in inhibitory control in a setting involving food values, we examined the ability of subjects to inhibit a response bias in the reversed-reward contingency (RRC) task. In RRC, subjects are presented with two amounts of food simultaneously, and are allowed to choose between them. Selection of the smaller amount (e.g. 1 half peanut) yields receipt of the larger amount (e.g. 4 half peanuts) and vice versa. Accordingly, RRC provides a stringent measure of inhibitory control in the affective domain: subjects must suppress the prepotent choice of selecting larger food quantities. We found that PFo damage had no effect on the acquisition of the RRC task. Thus, PFo cannot be said to be essential for all types of inhibitory control. ? ? Earlier work from this Section has shown that the amygdala and PFo work together in marshaling responses to fear-evoking objects and in responding appropriately to objects based on their current biological value, processes typically considered to lie in the affective domain. The recent work shows that their functions diverge in responding appropriately to changes in reward contingency. Major accomplishments of the past year include reconfirming a role for the amygdala in positive emotions, and overturning dogma that identifies a role for the amygdala in all kinds of flexible stimulus-reward learning. Contrary to the commonly held notions regarding amygdala function, we found that the amygdala contributes little, if anything, to visual learning for food reward when object choices are guided by the occurrence (or not) of the underlying food reward. These and related findings suggest an important role for the inferotemporal visual cortex, rather than the amygdala, in signaling the expected value of familiar objects and foodstuffs.? ? The neurotransmitter serotonin plays a central role in emotion, as evidenced by brain serotonergic abnormalities in emotional disorders and the therapeutic efficacy of drugs targeting this system. At the same time, serotonergic manipulations appear to affect cognitive functions mediated specifically by the PFo. For example, subjects with 5-HT depletion within the prefrontal cortex exhibit impaired performance on reversal learning. Accordingly, to advance our understanding of the neurotransmitter systems contributing to reward processing, we made use of the naturally-occurring differences in the structure of the gene encoding the serotonin transporter (5-HTT), which regulates serotonergic turnover via extracellular clearance. In vitro functional analyses of the 5-HTT gene-linked polymorphic regions (5-HTTLPR) demonstrate lowered transcriptional activity associated with short (S) compared to long (L) alleles. We found that subjects homozygous for the short allele (SS) scored more errors on a test of object reversal learning than subjects homozygous for the long allele. The relationship of 5-HTT genotype to cognitive processing, and the way in which it modulates frontal cortex function is a goal for future research.
