Role of orbitofrontal signaling of expected outcomes in Pavolvian blocking

描述（由申请人提供）：许多人类大脑疾病的一个关键组成部分可能是联想学习功能的改变。例如，许多以吸毒成瘾为特征的异常行为是由环境因素驱动的，成瘾者已经学会了将环境因素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为治疗成瘾的这些方面提供新的方法。联想学习是由识别预期结果和实际结果之间错误的能力所支持的。有证据表明，腹侧被盖区（VTA）的多巴胺能神经元通过相活动的波动来发出这些预测误差的信号。VTA神经元活动的升高预示着未预料到的奖励，而活动的下降则预示着未预料到的奖励。然而，产生这种预测错误可能需要将实际结果与先验的奖励期望进行比较。也许产生这种结果预期的最佳申请人是眶额叶皮质（OFC）。OFC不仅向VTA发送投射，OFC神经元也会在预期结果和预期结果期间发出信号。这种活动随着学习而发展，反映了动物对不同结果的偏好。预期信号在OFC中的作用也得到了病变研究的支持，这些研究表明，OFC对结果预期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，在该模型中，OFC信号提供关键信息，导致VTA中时间预测误差信号的产生或抑制，以促进学习。本研究将通过失活和单单元记录来验证这一假设，探讨OFC如何参与多巴胺能VTA神经元的学习和预测误差的计算。为此，我们将使用巴甫洛夫阻塞任务，在该任务中，对新线索的联想学习被同时呈现的第二个先前条件提示所阻止。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)阻断过程中VTA信号的抑制（先前在灵长类动物中观察到）将因OFC失活而受损，4)断开OFC和VTA的对侧病变将损害阻断的有效性。无论结果是证实还是否定我们的假设，都将极大地增强我们对OFC和VTA在正常和病理学习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.