Role of orbitofrontal signaling of expected outcomes in Pavolvian blocking

描述(申请人提供)：许多人类大脑疾病的一个重要组成部分可能是联想学习功能的改变。例如，毒瘾的许多异常行为都是由环境线索驱动的，吸毒者已经学会将环境线索与他们选择的毒品联系在一起。了解支配这种联想学习的过程和大脑回路可能会产生治疗成瘾的这些方面的新方法。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时相活动的波动向这些预测误差发出信号。VTA神经元活动的增加被证明是意外奖赏的信号，而活动的下降则是预知奖赏的遗漏。然而，产生这样的预测误差大概需要将实际结果与对回报的先验预期进行比较。也许产生这种结果预期的最好应用是眼眶额叶皮质(OFC)。OFC不仅向VTA发送投射，OFC神经元也在预期结果和预期结果期间放电。这种活动是随着学习而发展的，反映了动物对不同结果的偏好。预期信号在OFC中的这种作用也得到了病变研究的支持，这些研究表明，OFC对于由结果预期指导的行为和面对意外结果的新学习至关重要。这一证据表明了一种模型，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。这项提议将验证这一假设，使用失活和单单位记录来询问OFC如何参与学习和计算多巴胺能VTA神经元的预测误差。为此，我们将使用巴甫洛夫阻塞任务，在该任务中，通过同时呈现第二个预先条件的线索来阻止对新线索的联想学习。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的失活将削弱阻断的效果，3)OFC失活将削弱阻断过程中VTA信号的抑制(以前在灵长类动物中观察到的)，以及4)OFC与VTA的对侧损害将削弱阻断的有效性。这些结果，无论是证实还是否定我们的假设，都将极大地增强我们对FC和VTA在作为正常和病理性学习基础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.