The role of the orbitofrontal cortex in goal-directed behavior

描述（由申请人提供）：动物根据环境变化而改变行为的能力被称为灵活的目标导向行为。患有神经精神疾病（如成瘾、多动症和自闭症）的患者通常难以做出这种行为。在实验室中，一种用于测量灵活目标导向行为的任务是条件强化物贬值任务。在这个任务中，动物形成刺激物（如物体）和特定强化物（如各种食物奖励）之间的联系。强化物随后通过选择性饱足（随意喂食其中一种食物）而“贬值”。在贬值之后，正常被试调整了自己的反应，反映了强化者的新“价值”。眶额皮质（OFC）与其他大脑结构（如杏仁核、纹状体）一起是参与条件强化物贬值任务的重要神经基质。然而，目前尚不清楚OFC是否需要将食物的下降值与预测它的刺激联系起来，或者在测试过程中指导选择。这一建议的目的是阐明参与不同阶段的强化物贬值的神经回路。具体来说，拟议的实验计划确定OFC在强化物贬值中的作用，并比较和对比啮齿动物和非人类灵长类动物的作用。我建议在猕猴中使用可逆的药理学操作来研究OFC在强化物贬值的不同阶段（形成联想，记录强化物值的变化，更新刺激的强化物值，指导选择以反映值的变化）中的作用。可逆的药理学操作提供了一个机会来描述OFC在任务的各个阶段的作用。此外，我计划比较OFC在不同物种间条件强化物贬值中的作用。为了实现这一目标，我开发了一种新的啮齿动物（老鼠）强化器-贬值任务，进一步调和了迄今为止猴子和老鼠任务之间的差异。我还提出在新的大鼠强化物贬值任务中研究损伤对大鼠的影响，以便与以往使用各种形式的大鼠强化物贬值任务的工作进行直接比较。进一步了解灵活的目标导向行为背后的神经回路将有助于阐明神经精神障碍患者损伤的机制。这将为奖励处理不良的个体提供新的、更具选择性的治疗干预靶点系统。以下目标将用于实现我的目标：具体目标1-确定OFC在猕猴强化物贬值的不同阶段的作用。具体目标2-确定OFC在大鼠强化物贬值中的作用。直接比较不同物种在特定强化物贬值任务中的OFC将增强我们对柔性目标导向行为中涉及的神经回路的理解。

DESCRIPTION (provided by applicant): The ability of an animal to alter behavior in response to changes in their environment is known as flexible goal-directed behavior. Patients with neuropsychiatric disorders (e.g., addiction, ADHD, and autism) often have difficulty with this type of behavior. In the laboratory one type of task used to measure flexible goal directed behavior is a conditioned reinforcer devaluation task. In this task, animals form associations between stimuli (e.g. objects) and specific reinforcer(s) (e.g. various food rewards). The reinforcer is subsequently "devalued" by selective satiation (feeding one of the foods ad libitum). Following devaluation, normal subjects adjust their responding which reflects the new "value" of the reinforcer. The orbitofrontal cortex (OFC) in conjunction with several other brain structures (e.g., amygdala, striatum) is an important neural substrate involved in the conditioned reinforcer devaluation task. However, it is unknown if OFC is necessary for linking the decreased value of the food to the stimuli that predicts it, or guiding choices during testing. The goal of this proposal is to elucidate the neural circuitry involved in different stages of reinforcer devaluation. Specifically, the proposed experiments plan to determine the role of the OFC in reinforcer devaluation and compare and contrast the roles in rodents and non human primates. I propose to use reversible pharmacological manipulations in macaque monkeys to study the role of OFC during different stages of reinforcer devaluation (forming associations, registering a change in reinforcer value, updating reinforcer value to the stimuli, guiding choices to reflect the change in value). Reversible pharmacological manipulations provide an opportunity to delineate the role of OFC involved in individual phases of the task. In addition I plan to compare the role of the OFC in conditioned reinforcer devaluation across species. To achieve this, I developed a new rodent (rat) reinforcer- devaluation task that further reconciles the differences between the monkey and the rat tasks used to date. I also propose to study the effects of lesion in rats in the new rat reinforcer devaluation task to compare directly with previous work using various forms of reinforcer devaluation tasks in rats. Further understanding of the neural circuitry underlying flexible goal- directed behavior will help elucidate mechanisms for impairments in patients with neuropsychiatric disorders. This will provide new and more selective target systems for therapeutic intervention for individuals with maladaptive reward processing. The following aims will be used to reach my goals: specific aim 1-Determine the role of OFC in different phases of reinforcer devaluation in macaque monkeys. Specific aim 2- Determine the role of OFC in reinforcer devaluation in rats. A direct comparison OFC across species in a specific reinforcer devaluation task will enhance our understanding of the neural circuitry involved in flexible goal directed behavior. PUBLIC HEALTH RELEVANCE: Patients with addiction, autism, or attention deficit hyperactivity disorder are impaired in adjusting responding based on consequences. These types of deficits are studied by measuring the ability of a subject to alter behavior based on changing outcomes. The goal of this proposal is to further understand the role of a specific brain structure (orbitofrontal cortex) using a task which measures changing behavior.