Investigating the Neural Processing of Negative Feedback across Rats and Humans

描述（由申请人提供）：有药物滥用障碍的个人经常继续寻求和使用非法药物，尽管这种行为可能产生负面后果。为了理解面对负面后果时这种行为不灵活性的神经基础，有必要了解健康的大脑是如何处理负面反馈的。决策模型表明，反馈提供了将我们行动的实际结果与预期结果进行比较的信息，在这种情况下，不愉快结果的呈现和有价值结果的遗漏都可以被认为是负面反馈的形式。然而，这两种形式的负反馈会导致不同的行为：当结果失去其价值时，反应率会下降，而忽略预期的高价值结果时，反应率会上升。这些不同形式的负反馈的影响背后的神经系统还没有被清楚地描绘出来。我们假设单独的皮质边缘纹状体回路介导不同形式的负反馈，这取决于这种反馈是否表明结果概率的变化或结果值的变化。为了检验这一假设，我们将进行一套涉及啮齿动物和人类研究的跨学科实验。在两个平行的实验中，老鼠和人类将采取不同的行动来获得两种有益的食物结果。在获得此任务后，我们将通过偶尔省略预期结果来操纵结果概率。此外，我们将通过允许受试者吃到饱来选择性地降低一种食物的价值，从而操纵结果值。在实验1.1中，大鼠将经历一个神经断开过程，以去除基底外侧杏仁核（BLA）或前额叶皮层（PFC）对纹状体的输入，通过结果省略和贬值测试来确定这些回路在负反馈处理中的重要性。在实验1.2中，我们将使用功能磁共振成像（fMRI）评估贬值过程后的人脑活动，当受试者收到贬值或有价值的结果，或这些结果的预期交付被遗漏时。实验2.1将这项工作扩展到更抽象的行为结果，更典型的人类实验工作。在概率学习任务中，指示响应是否正确的正反馈和负反馈将被提供，这种反馈偶尔会意外地被省略。这将使我们能够确定负反馈是被大脑解释为贬值的结果还是缺乏积极的结果。这些实验的跨学科性质将为本科生和研究生提供独特的训练经验。此外，这一建议将有助于弥合行为和认知神经科学研究之间的差距，并最终将有助于转化方法来理解神经系统潜在的负反馈处理如何在药物成瘾中受到损害。

DESCRIPTION (provided by applicant): Individuals with substance abuse disorders often continue to seek and use illicit drugs despite the negative consequences that can arise from this behavior. In order to understand the neural basis of this behavioral inflexibility in the face of negative consequences, it is necessary to understand how negative feedback is processed in the healthy brain. Models of decision making have shown that feedback provides information to compare actual to expected outcomes of our actions, and, in this context, presentations of unpleasant outcomes and omissions of valued outcomes can both be thought of as forms of negative feedback. However, these two forms of negative feedback result in different behaviors: response rates decrease when an outcome loses its value, whereas response rates increase for omission of an expected high-value outcome. The neural systems which underlie the effects of these different forms of negative feedback have not been clearly delineated. We hypothesize that separate cortico-limbic-striatal circuits mediate different forms of negative feedback, depending on whether this feedback indicates a change in outcome probability or a change in outcome value. To examine this hypothesis, we will perform an interdisciplinary set of experiments involving research on rodents and humans. In two parallel experiments, rats and humans will perform distinct actions to obtain two types of rewarding food outcomes. Following acquisition of this task, we will manipulate outcome probability by occasionally omitting expected outcomes. In addition, we will manipulate outcome value by selectively devaluing one food outcome by allowing subjects to eat it to satiety. In Experiment 1.1, rats will undergo a neural disconnection procedure to remove basolateral amygdala (BLA) or pre-frontal cortex (PFC) inputs to the striatum, to determine the importance of these circuits in negative feedback processing using the outcome omission and devaluation tests. In Experiment 1.2, we will assess human brain activity using fMRI following the devaluation procedure, as subjects receive the devalued or the valued outcome, or an omission of the expected delivery of these outcomes. Experiment 2.1 extends this work to more abstract behavioral outcomes more typical of experimental work in humans. Positive and negative feedback indicating whether a response is correct or incorrect will be provided in a probabilistic learning task, with this feedback occasionally omitted unexpectedly. This will allow us to determine whether the negative feedback is interpreted by the brain as a devalued outcome or as the lack of a positive outcome. The interdisciplinary nature of these experiments will provide a unique training experience for undergraduate and graduate students. Furthermore, this proposal will help to bridge the gap between behavioral and cognitive neuroscience research and ultimately will aid translational approaches to understanding how neural systems underlying negative feedback processing may be compromised in drug addiction. PUBLIC HEALTH RELEVANCE: Understanding how negative feedback processing operates in the normal brain using natural outcomes will be useful in deciphering how impairments in these processes arise in individuals with substance abuse disorders. Furthermore, such knowledge will aid in developing therapeutic strategies to facilitate recovery from addiction.