Role of orbitofrontal cortex and outcome expectancies in associative learning

描述（由申请人提供）：眼窝额叶功能障碍与许多人类神经精神疾病有关，包括抑郁症、躁狂、强迫症、注意缺陷多动障碍、自闭症和成瘾。在大多数这些疾病状态中，眼窝前额皮质的作用才刚刚开始被理解。现有的理论依赖于动物研究，表明眼窝前额皮质对决策至关重要，因为它在促进联想学习和抑制不适当反应方面发挥着重要作用。然而，最近在动物身上的研究表明，眼窝额叶对联想学习的贡献的概念化是不正确的。相反，眼窝额叶皮层可能有助于联想学习和决策，因为它在对未来结果的可能性产生动态的、前瞻性的预测方面发挥作用。这样outcome-expectancies ?在面对意想不到的结果时，既能指导适当的决定，也能促进大脑其他区域的联想学习。这种概念化将从根本上不同于当前的理论，即视眶额皮质为静态的，回顾性的？关联查找表？本提案中的实验将为这一假设提供一个关键的测试，在两种不同的环境中操纵老鼠对奖励结果的期望，以证明眶额叶皮层会发出这些期望的信号。此外，我们将证明这些信号在面对意外结果时促进了灵活的行为，因为它们有能力改变储存在下游大脑区域的联想表征。这些结果将促进我们对眶额皮质基本功能的理解，超越目前对该区域的常见概念。因此，他们将阐明这一区域在上述神经精神疾病中所起的作用，以及如何操纵这一作用可能促进这些疾病的治疗。

DESCRIPTION (provided by applicant): Orbitofrontal dysfunction is implicated in a host of human neuropsychiatric disease, including depression, mania, obsessive-compulsive disorder, attention deficit hyperactivity disorder, autism, and addiction. In most of these disease states, the role of orbitofrontal cortex is only beginning to be understood. Existing theories rely on animal research showing that orbitofrontal cortex is critical to decision-making because of the role it plays in promoting associative learning and the inhibition of inappropriate responses. However recent work in animals now suggests that the conceptualization of orbitofrontal contributions to associative learning is incorrect. Instead orbitofrontal cortex may contribute to associative learning and decision-making due to its role in generating dynamic, prospective predictions regarding the likelihood of future outcomes. Such ?outcome-expectancies? would both guide appropriate decisions and also facilitate associative learning in other brain regions in the face of unexpected outcomes. Such a conceptualization would be fundamentally different from current theories that view orbitofrontal cortex as a static, retrospective ?associative look-up table?. The experiments in this proposal will provide a critical test of this hypothesis, manipulating rats' expectations for rewarding outcomes in two different settings, in order to demonstrate orbitofrontal cortex signals these expectations. Further we will show that these signals facilitate flexible behavior in the face of unexpected outcomes due to their ability to their ability to alter associative representations stored in downstream brain regions. These results will advance our understanding of the fundamental function of orbitofrontal cortex, beyond the current common conceptualization of this area. As such, they will clarify the role this area plays in the neuropsychiatric diseases described above and how manipulation of that role may facilitate treatment of these diseases.