Neural Substrates of Reward Processing and Emotion

病变研究表明内侧前额叶皮层（MFC）和眶额皮层（OFC）的功能是分离的，MFC对社会认知至关重要，OFC对基于价值的决策至关重要。一个令人困惑的发现是，动物双侧眶额皮层损伤的吸入，直接删除皮层，表现出一套不同的行为障碍比动物兴奋性毒性病变的同一区域。具体地，具有双侧OFC吸入去除的动物在认知灵活性和情绪调节测试中受损，而具有双侧OFC兴奋性毒性损伤的动物则没有（Rudebeck等人，Nat. Neurosci.，2013年）的报告。这种差异归因于吸入性病变而非兴奋性毒性病变对通道纤维的无意破坏。潜在的问题是：当受损时，哪些通道纤维负责认知灵活性和情绪调节的损伤？一个候选者是胆碱能纤维，其起源于基底核大细胞（NBM），并且在它们到达其他额叶皮质区域的途中经过OFC附近或通过OFC（Kitt等人，Brain Res. 1987）。为了研究这种可能性，我们给了三只动物的OFC单侧抽吸病变，然后我们比较了胆碱能神经支配的前扣带皮层（ACC），MFC的一部分，半球和没有OFC之间。我们的依赖措施是乙酰胆碱酯酶的表达。评估显示，减少AChE的表达在ACC的半球OFC病变，特别是在第I和III/V层。这种差异是更明显的吻侧ACC和更少的尾侧区域。纹状体中的胆碱能染色没有观察到差异，纹状体接受来自局部中间神经元的胆碱能神经支配。这些研究结果表明，吸入性病变的OFC破坏胆碱能纤维的通道，可能解释的认知灵活性和情绪调节的显着损害相比，兴奋性毒性病变。进一步的研究是必要的，以证明额叶皮层胆碱能神经支配的中断和其对行为的影响之间的因果关系。 如上所述，MFC与杏仁核和颞顶交界处附近的皮质一起参与社会认知。这个大脑区域网络专门用于处理社会信息。例如，MFC中的神经元不仅编码奖励值，还编码同种和自身的特征。 我们之前的研究已经证明，MFC损伤会削弱亲社会偏好的学习。然而，很难理清MFC对社会注意力、社会偏好和社会奖励的贡献，如通过替代强化（即，愿为他人奉献自己）。此外，MFC，包括ACC，有助于非社会奖励处理。为了进一步研究MFC在非社会性奖励处理中的作用，这将作为与我们的社会（替代强化）措施的比较，我们评估了ACC的因果贡献，通过自主措施的奖励预期的表达。三只动物接受双侧ACC. THEORY神经毒性病变与四个未操作的控制（CON），他们提出了一个巴甫洛夫程序，即视觉刺激在监视器屏幕上预测奖励交付，独立的动物的行动。在每次试验中，动物看到两个蓝色圆圈慢慢地向对方移动15秒，直到它们接触，消失，并提供液体奖励。随后是15秒的试验间隔，在此期间屏幕是空白的。用体积描记传感器采集心率（HR）并离线提取。我们发现，在预期奖励的人力资源组的差异。 而CON动物表现出逐渐增加的HR，而圆圈移动靠近在一起，动物与ACC病变没有。 这意味着反映奖励期望的自主输出由于ACC损伤而丢失。 相比之下，我们观察到一个显着的HR变化后，奖励交付在所有动物，对照组和动物与ACC病变一样，表明自主反应收到奖励后ACC病变是完整的。两者合计，结果支持ACC特别是在产生自主反应奖励预期的重要作用。因此，前扣带回可能通过在预期积极情绪事件时产生唤醒来促进积极情绪。

Lesion studies suggest dissociable functions of medial prefrontal cortex (MFC) and orbitofrontal cortex (OFC), with MFC being essential for social cognition and OFC being essential for value-based decision making. One puzzling finding is that animals with bilateral damage to the OFC made by aspiration, which directly removes the cortex, exhibit a different set of behavioral impairments than animals with excitotoxic lesions of the same region. Specifically, animals with bilateral aspiration removals of OFC are impaired on tests of cognitive flexibility and emotion regulation, whereas those with bilateral excitotoxic lesions of OFC are not (Rudebeck et al., Nat. Neurosci., 2013). This discrepancy is attributed to the inadvertent disruption of fibers of passage by aspiration lesions but not by excitotoxic lesions. The underlying question is: Which fibers of passage are responsible for impairments in cognitive flexibility and emotion regulation when compromised? One candidate is the cholinergic fibers originating in the nucleus basalis magnocellularis (NBM) and passing nearby or through OFC on their way to other frontal cortex regions (Kitt et al., Brain Res. 1987). To investigate this possibility, we gave three animals unilateral aspiration lesions of the OFC, and then we compared cholinergic innervation of the anterior cingulate cortex (ACC), a part of the MFC, between hemispheres with and without OFC. Our dependent measure was AChE expression. The assessment revealed diminished AChE expression in the ACC of hemispheres with OFC lesions, particularly in layers I and III/V. This disparity was more pronounced in the rostral ACC and less so in the more caudal regions. No difference was observed in cholinergic staining in the striatum, which receives cholinergic innervation from local interneurons. These findings suggest that aspiration lesions of the OFC disrupt cholinergic fibers of passage, potentially explaining the significant impairments in cognitive flexibility and emotion regulation observed in comparison to excitotoxic lesions. Further research is necessary to demonstrate a causal relationship between the interruption of cholinergic innervation in the frontal cortex and its effects on behavior. As indicated above, the MFC, together with the amygdala and cortex near the temporal-parietal junction is implicated in social cognition. This network of brain regions is specialized for processing social information. For example, neurons in the MFC encode not only reward value but also features of conspecifics and of oneself. Our previous research has demonstrated that MFC damage blunts learning of prosocial preferences. It has been difficult, however, to disentangle MFC contributions to social attention, social preference, and social reward, as measured by vicarious reinforcement (i.e., the willingness to give reward to others). In addition, MFC, including the ACC, contributes to nonsocial reward processing. To further investigate the role of the MFC in nonsocial reward processing, which would serve as a comparison with our social (vicarious reinforcement) measures, we assessed the ACCs causal contribution to the expression of reward expectancy via an autonomic measure. Three animals received bilateral neurotoxic lesions of ACC. Together with four unoperated controls (CON), they were presented with a Pavlovian procedure whereby visual stimuli on a monitor screen predicted reward delivery, independent of the animals actions. In each trial, animals saw two blue circles slowly move towards each other for 15 seconds until they touched, disappeared, and fluid reward was delivered. A 15-s intertrial interval ensued, during which the screen was blank. Heart rate (HR) was acquired with a plethysmography sensor and was extracted off-line. We found a group difference in HR in anticipation of reward. Whereas CON animals exhibited a gradual HR increase while the circles moved closer together, animals with ACC lesions did not. This implies that the autonomic output that reflects reward expectancy was lost as a result of the ACC lesion. In contrast, we observed a significant HR change after reward delivery in all animals, controls and animals with ACC lesions alike, indicating that the autonomic response to receipt of reward was intact after ACC lesions. Taken together, the results support an essential role for the ACC specifically in generating autonomic responses to reward expectancy. Thus, the ACC may contribute to positive affect by generating arousal in anticipation of positive emotional events.