Role of orbitofrontal signaling of expected outcomes in Pavolvian blocking

描述（由申请人提供）：许多人脑疾病的关键组成部分可能是联想学习功能的变化。例如，许多作为药物成瘾特征的异常行为是由环境线索驱动的，成瘾者已经学会将其与他们选择的药物联系起来。了解控制这种联想学习的过程和大脑回路可以产生治疗成瘾这些方面的新方法。联想学习是由识别预期结果和实际结果之间的错误的能力支持的。有证据表明，腹侧被盖区（VTA）的多巴胺能神经元通过阶段性活动的波动发出这些预测错误的信号。腹侧被盖区神经元的活动增加表明了不可预测的奖励，而活动减少则表明了预测奖励的缺失。然而，产生这样的预测误差大概需要将实际结果与对奖励的先验期望进行比较。也许产生这种结果预期的最佳应用程序是眶额叶皮层（OFC）。眶额皮层不仅向腹侧被盖区发送投射，而且在预期结果和预期结果发生时，眶额皮层神经元也会放电。这种活动随着学习而发展，反映了动物对不同结果的偏好。这种期望信号在眶额皮层中的作用也得到了损伤研究的支持，这些研究表明，眶额皮层对结果期望指导的行为和面对意外结果的新学习至关重要。这一证据表明，OFC信号提供的关键信息，导致产生或抑制VTA的时间预测误差信号，以促进学习的模型。本提案将测试这一假设，使用失活和单单位记录，询问OFC是如何参与学习和多巴胺能腹侧被盖区神经元预测误差的计算。为此，我们将使用一个巴甫洛夫阻断任务，其中一个新的线索的联想学习是防止同时提出的第二个先前条件的线索。基于我们的假设，我们预测1）OFC信号将与阻断的有效性相关，2）OFC失活将损害阻断，3）阻断期间VTA信号的抑制（先前在灵长类动物中观察到的）将被OFC失活损害，以及4）断开OFC和VTA的对侧病变将损害阻断的有效性。这些结果，无论是证实还是拒绝我们的假设，都将极大地增强我们对眶额皮层和腹侧被盖区在正常和病理学习的基础上的简单联想过程中所起作用的理解。

DESCRIPTION (provided by applicant): A critical component of many human brain diseases may be changes to associative learning functions. For example, much of the aberrant behavior that characterizes drug addiction is driven by environmental cues, which the addict has learned to associate with their drug of choice. Understanding the processes and brain circuits governing such associative learning could generate novel approaches for treating these aspects of addiction. Associative learning is supported by the ability to recognize errors between expected and actual outcomes. Evidence suggests that dopaminergic neurons in ventral tegmental area (VTA) signal these prediction errors through fluctuations in phasic activity. Elevated activity in VTA neurons has been shown to signal unpredicted reward while a decline in activity signals the omission of a predicted reward. However, generating such prediction errors presumably requires comparison of the actual outcome to an a priori expectation for reward. Perhaps the best applicant for generating such outcome expectancies is the orbito frontal cortex (OFC). Not only does OFC send projections to VTA, OFC neurons also fire in anticipation of and during expected outcomes. This activity develops with learning and reflects animals' preferences for different outcomes. This role of expectancy signaling in OFC is also supported by lesion studies, which demonstrate that OFC is critical to behavior guided by outcome expectancies and for new learning in the face of unexpected outcomes. This evidence suggests a model in which OFC signaling provides critical information that leads to the generation or suppression of temporal prediction error signals in VTA to facilitate learning. This proposal will test this hypothesis, using inactivation and single-unit recording to ask how OFC is involved in learning and in the calculation of prediction errors in dopaminergic VTA neurons. For this, we will use a Pavlovian blocking task, in which associative learning for a novel cue is prevented by the simultaneous presentation of a second previously-conditioned cue. Based on our hypothesis, we predict 1) that OFC signaling will correlate with the effectiveness of blocking, 2) that OFC inactivation will impair blocking, 3) that suppression of VTA signaling during blocking (previously observed in primates) will be impaired by OFC inactivation, and 4) that contralateral lesions, which disconnect OFC and VTA, will impair the effectiveness of blocking. The results, whether they confirm or reject our hypothesis, will greatly enhance our understanding of the role OFC and VTA play in simple associative processes that underlie normal and pathological learning.