Neural substrates of reward processing and emotion

该项目对杏仁核和眼窝额叶皮层在学习刺激-奖励关联中的不同作用有了深入的了解（Rudebeck和Murray， 2008）。我们比以前更详细地研究了客体逆转任务中，当刺激-奖励随变发生变化时，受试者是如何适应的。在刺激-奖励偶发事件发生变化后，受试者几乎总是会选择先前获得奖励的对象，而未能获得奖励会导致消极的情绪反应。最终，当受试者停止选择那个物体并探索另一个选择时，它会产生一种不被强烈期望的奖励，而这一事件会引发积极的情绪反应。眼窝额叶皮层受损的受试者对这些变化的刺激-奖励偶然性的选择适应缓慢。基于对奖励和非奖励选择的试验分析，我们发现眼窝额叶皮层受损的受试者在选择先前奖励的物体导致没有奖励时，使用负面反馈没有问题。相反，这些被试从正面反馈中获得的好处要少于完整的被试。因此，他们的损害是由于在学习一个给定的选择将产生积极的结果方面效率低下。杏仁核受损的受试者表现出相反的结果模式：他们比完整的受试者从每次正确执行错误后的试验中受益更多。这些发现表明，眼窝额叶皮层和杏仁核在客体逆转学习中有不同的贡献，因此对学习刺激-奖励关联有不同的贡献。眼窝额叶皮质损伤的受试者在表示先前低值刺激的更新值方面存在缺陷。他们并不像传统的说法那样，在客体逆转任务中表现不佳，因为他们的毅力在这些科目中是温和的。认识到这一点很重要，因为毅力与重度抑郁症等疾病关系不大。另一方面，对眼窝额叶皮质功能的理解是利用正反馈来提升（对物体或自我）低评价的能力，这与这种疾病有明显的相关性。这些患者对自己的评价很低，认为生活中只会发生低价值的事件（或未来可能发生的事件）。

This project has produced insights into the differential contributions of the amygdala and orbitofrontal cortex in learning stimulus-reward associations (Rudebeck and Murray, 2008). We studied, in much more detail than previously attempted, how subjects adapt when stimulus-reward contingencies change in the object-reversal task. After a change in stimulus-reward contingencies, the subject will nearly always choose the previously rewarded object, and the failure to obtain a reward causes a negative emotional reaction. Eventually, when the subject stops choosing that object and explores the alternative choice, it produces a reward that is not strongly expected, and this event triggers a positive emotional reaction. Subjects with orbitofrontal cortex lesions are slow to adapt their choices to these changing stimulus-reward contingencies. Based on trial-by-trial analyses of rewarded and unrewarded choices, we have found that subjects with orbitofrontal cortex lesions did not have a problem with using the negative feedback that resulted when the choice of a previously rewarded object led to no reward. Instead, these subjects benefited less than intact subjects from the positive feedback that followed each correctly performed trial after an error. Accordingly, their impairment resulted from an inefficiency in learning that a given choice would yield a positive outcome. Subjects with amygdala lesions showed the opposite pattern of results: they benefited more than intact subjects from each correctly performed trial that followed an error. These findings demonstrate that the orbitofrontal cortex and amygdala make different contributions to object-reversal learning and therefore to learning stimulus-reward associations. Subjects with orbitofrontal cortex lesions have a deficit in representing the updated value of a stimulus that has previously been of low value. They do not, as the traditional account has it, perform poorly on the object-reversal task because of perseveration, which is mild in these subjects. This realization is important because perseveration is of little relevance to diseases like major depressive disorder. An understanding of orbitofrontal cortex function in terms of an ability to use positive feedback to upgrade low valuations (of objects or self), on the other hand, has an obvious relevance to this disease. These patients have a low valuation of themselves and believe that only low-value events occur in their lives (or are likely to occur in the future). Our previous work has also shown that amygdala lesions, like lesions of the orbitofrontal cortex, cause a disruption of satiety-specific devaluation effects. But the previous experimental design left open whether the instrumental (response-reward) associations or Pavlovian (stimulus-reward) associations were guiding performance. To investigate the specificity of amygdala function along these lines, we designed a task in which responding relied on instrumental control of behavior and could not be explained via Pavlovian mechanisms. Subjects were trained to perform two different instrumental responses (tap and hold) on a touch-sensitive screen for two different food rewards. One of the foods was then devalued by selective satiation. As in our previous studies, control subjects showed a reduction in responses associated with a devalued outcome, but subjects with amygdala lesions failed to show this effect. This finding supports the idea that the amygdala is required for updating reward value and therefore plays a crucial role in guiding goal-directed behavior based on response-reward associations. This project has also made progress in understanding the role of distinct parts of orbitofrontal cortex in reward-guided behavior and emotion. Marked changes in reward-guided behavior and emotion are hallmarks of damage or dysfunction within the orbitofrontal cortex, but it is not a homogeneous structure. A lateral region broadly encompasses Walkers areas 11 and 13 and is heavily interconnected with sensory areas of cortex. A medial region, which includes Walkers area 14, is more densely interconnected with medial frontal cortex and autonomic structures. There has been speculation that these two regions play distinct roles in regulating emotion and reward-guided behavior, but direct evidence to this effect has been elusive. The current project used the selective satiation procedure to examine the ability of subjects to update their valuations of particular objects based on reward expectation. We found that lateral but not medial orbitofrontal cortex is essential for choosing objects based on their updated value. By contrast, medial orbitofrontal cortex but not lateral orbitofrontal cortex is important for the ability to stop responding to an object when it is no longer rewarded (i.e., in extinction). These results provide clear evidence for functional dissociations within the orbitofrontal cortex, and we are currently testing hypotheses about the contributions of medial vs. lateral orbitofrontal cortex in signaling expected outcomes. These results agree well with those described above for the object-reversal task: in both cases they point to a role for the lateral orbitofrontal cortex in updating reward expectations based on object-reward associations. In a further examination of extinction, which entails the abolition of a previously established object-reward association, we examined frontal areas medial to the orbitofrontal cortex. Evidence from one animal model had suggested that a part of the medial frontal cortex, the infralimbic cortex, plays an important role in mediating extinction. Lesions of this region in rats results in an increased expression of the older, original learning through the spontaneous recovery of responding. In the present project, however, we showed that this finding does not generalize to all animal models. In our animal model, lesions of infralimbic cortex performed no differently than controls; there was no spontaneous recovery of the previously extinguished behavior. (Lesions of another medial frontal area, the prelimbic cortex, also had no effect.) This finding shows that infralimbic cortex plays different roles in the two animal models studied to date.