Neural substrates of reward processing and emotion

奖励处理和情绪的神经基质

• 批准号: 7969449
• 负责人: ELISABETH A MURRAY
• 金额: $ 148.57万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969449
• 关键词: Accounting; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Area; Arousal; Back; Behavior; Behavior Control; Blood flow; Cerebrovascular Disorders; Charge; Clinical; Clinical Research; Controlled Study; Desire for food; Disease; Dissociation; Electric Stimulation; Emotions; Event; Experimental Designs; Exposure to; Extinction (Psychology); Failure; Feedback; Food; Fright; Functional disorder; Future; Goals; Hand; Hydrocortisone; Impairment; Lateral; Learning; Left; Lesion; Life; Light; Link; Major Depressive Disorder; Medial; Mediating; Mental disorders; Metabolism; Moods; Neurosecretory Systems; Onset of illness; Outcome; Panic Attack; Parkinson Disease; Patients; Pattern; Performance; Phobic anxiety disorder; Play; Procedures; Rattus; Recovery; Regional Blood Flow; Research; Reversal Learning; Rewards; Risk; Role; Satiation; Sensory; Signal Transduction; Sleep; Specificity; Stimulus; Structure; Symptoms; Testing; Thick; Touch sensation; Training; Update; Visceral; Walkers; Weight; Work; base; depressed; depression; design; dysphoria; emotional reaction; expectation; frontal lobe; information processing; insight; neuroimaging; neuromechanism; relating to nervous system; research study; response; reward processing

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.

该项目深入了解了杏仁核和眶额皮质在学习刺激-奖励关联中的不同贡献（Rudebeck 和 Murray，2008）。 我们比以前尝试更详细地研究了当客体逆转任务中刺激奖励意外事件发生变化时，受试者如何适应。 在刺激奖励偶然事件发生变化后，主体几乎总是会选择之前的奖励对象，而未能获得奖励会导致负面情绪反应。 最终，当受试者停止选择该对象并探索替代选择时，它会产生并非强烈预期的奖励，并且此事件会引发积极的情绪反应。 患有眶额皮层损伤的受试者很难适应这些不断变化的刺激奖励突发事件的选择。 基于对奖励和无奖励选择的逐项分析，我们发现，眶额皮质损伤的受试者在使用先前奖励对象的选择导致没有奖励时产生的负面反馈方面没有问题。 相反，这些受试者从错误后每次正确执行的试验所获得的积极反馈中获得的好处少于完整受试者。 因此，他们的缺陷是由于无法有效地了解给定的选择会产生积极的结果。 患有杏仁核损伤的受试者显示出相反的结果模式：他们比完整的受试者从每次错误后正确执行的试验中受益更多。 这些发现表明，眶额皮层和杏仁核对物体反转学习以及学习刺激奖励关联做出不同的贡献。 患有眶额皮层损伤的受试者在表示先前价值较低的刺激的更新值方面存在缺陷。 他们并不像传统的说法那样，因为坚持不懈而在客体反转任务中表现不佳，而在这些受试者中，坚持是温和的。 这种认识很重要，因为坚持与重度抑郁症等疾病关系不大。 另一方面，对眶额皮层功能的理解，即利用正反馈来提升（物体或自我）的低评价的能力，与这种疾病有明显的相关性。 这些患者对自己的评价很低，认为自己的生活中只会发生低价值的事件（或者将来很可能发生）。 我们之前的工作还表明，杏仁核病变，就像眶额皮层的病变一样，会导致饱腹感特异性贬值效应的破坏。 但之前的实验设计并未明确是工具性（反应-奖励）关联还是巴甫洛夫（刺激-奖励）关联在指导表现。 为了沿着这些思路研究杏仁核功能的特异性，我们设计了一项任务，其中响应依赖于行为的工具控制，并且无法通过巴甫洛夫机制来解释。 受试者接受训练，在触摸屏上执行两种不同的仪器反应（点击并按住）以获得两种不同的食物奖励。 然后，其中一种食物因选择性饱足而贬值。 正如我们之前的研究一样，对照受试者表现出与贬值结果相关的反应减少，但杏仁核病变的受试者未能表现出这种效果。 这一发现支持这样的观点：杏仁核是更新奖励值所必需的，因此在指导基于反应-奖励关联的目标导向行为方面发挥着至关重要的作用。 该项目在理解眶额皮层不同部分在奖励引导行为和情绪中的作用方面也取得了进展。 奖励引导的行为和情绪的显着变化是眶额皮层损伤或功能障碍的标志，但它不是一个均质的结构。 外侧区域广泛包含 Walkers 区域 11 和 13，并且与皮层的感觉区域紧密相连。 包括 Walkers 区域 14 在内的内侧区域与内侧额叶皮层和自主结构的互连更加紧密。 有人猜测这两个区域在调节情绪和奖励引导行为方面发挥着不同的作用，但这种作用的直接证据一直难以捉摸。 当前的项目使用选择性满足程序来检查受试者根据奖励期望更新其对特定对象的评估的能力。 我们发现，外侧眶额皮层对于根据更新值选择对象至关重要，而内侧眶额皮层则不然。 相比之下，内侧眶额皮层（而不是外侧眶额皮层）对于当不再获得奖励（即灭绝）时停止对物体做出反应的能力很重要。 这些结果为眶额皮质内的功能分离提供了明确的证据，我们目前正在测试有关内侧与外侧眶额皮质在发出预期结果信号方面的贡献的假设。 这些结果与上述对象反转任务的结果非常吻合：在这两种情况下，它们都指出了外侧眶额皮层在根据对象奖励关联更新奖励期望方面的作用。 在对灭绝的进一步研究中，这需要废除先前建立的物体-奖励关联，我们检查了眶额皮质内侧的额叶区域。 来自一种动物模型的证据表明，内侧额叶皮层的一部分，即下边缘皮层，在介导灭绝中发挥着重要作用。 大鼠中该区域的损伤会通过反应的自发恢复而导致旧的、原始学习的表达增加。 然而，在本项目中，我们表明这一发现并不能推广到所有动物模型。 在我们的动物模型中，边缘下皮质损伤的表现与对照组没有什么不同。先前消失的行为没有自发恢复。 （另一个内侧额叶区域，即前边缘皮层的损伤也没有影响。）这一发现表明，边缘下皮层在迄今为止研究的两种动物模型中发挥着不同的作用。