Department of Functional Brain Imaging, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
Laboratory of Neuropsychology, National Institute of Mental Health, Bethesda, Maryland 20892.
J Neurosci. 2022 Aug 10;42(32):6267-6275. doi: 10.1523/JNEUROSCI.0229-22.2022. Epub 2022 Jul 6.
The orbitofrontal cortex (OFC) and its major downstream target within the basal ganglia-the rostromedial caudate nucleus (rmCD)-are involved in reward-value processing and goal-directed behavior. However, a causal contribution of the pathway linking these two structures to goal-directed behavior has not been established. Using the chemogenetic technology of designer receptors exclusively activated by designer drugs with a crossed inactivation design, we functionally and reversibly disrupted interactions between the OFC and rmCD in two male macaque monkeys. We injected an adeno-associated virus vector expressing an inhibitory designer receptor, hM4Di, into the OFC and contralateral rmCD, the expression of which was visualized by positron emission tomography and confirmed by postmortem immunohistochemistry. Functional disconnection of the OFC and rmCD resulted in a significant and reproducible loss of sensitivity to the cued reward value for goal-directed action. This decreased sensitivity was most prominent when monkeys had accumulated a certain amount of reward. These results provide causal evidence that the interaction between the OFC and the rmCD is needed for motivational control of action on the basis of the relative reward value and internal drive. This finding extends the current understanding of the physiological basis of psychiatric disorders in which goal-directed behavior is affected, such as obsessive-compulsive disorder. In daily life, we routinely adjust the speed and accuracy of our actions on the basis of the value of expected reward. Abnormalities in these kinds of motivational adjustments might be related to behaviors seen in psychiatric disorders such as obsessive-compulsive disorder. In the current study, we show that the connection from the orbitofrontal cortex to the rostromedial caudate nucleus is essential for motivational control of action in monkeys. This finding expands our knowledge about how the primate brain controls motivation and behavior and provides a particular insight into disorders like obsessive-compulsive disorder in which altered connectivity between the orbitofrontal cortex and the striatum has been implicated.
额眶部皮层（OFC）及其在基底神经节中的主要下游靶点——尾状核头部腹侧（rmCD）——参与奖赏价值处理和目标导向行为。然而，尚未确定连接这两个结构的通路对目标导向行为的因果贡献。我们使用化学遗传技术，通过交叉失活设计，用专门被设计药物激活的设计受体，在两只雄性猕猴中，功能上和可逆地破坏了 OFC 和 rmCD 之间的通路相互作用。我们将表达抑制性设计受体 hM4Di 的腺相关病毒载体注入 OFC 和对侧 rmCD，通过正电子发射断层扫描观察到其表达，并通过死后免疫组织化学证实。OFC 和 rmCD 的功能连接中断导致对目标导向行为的提示奖励价值的敏感性显著且可重现地丧失。当猴子积累了一定数量的奖励时，这种敏感性下降最为明显。这些结果提供了因果证据，表明 OFC 和 rmCD 之间的相互作用对于基于相对奖励价值和内部驱动力来控制行动的动机是必要的。这一发现扩展了当前对目标导向行为受到影响的精神障碍的生理基础的理解，例如强迫症。在日常生活中，我们会根据预期奖励的价值来调整我们的行动速度和准确性。这些动机调整的异常可能与强迫症等精神障碍中观察到的行为有关。在当前的研究中，我们表明，从额眶部皮层到尾状核头部腹侧的连接对于猴子的动机控制行动是必不可少的。这一发现扩展了我们对灵长类动物大脑如何控制动机和行为的认识，并为强迫症等涉及额眶部皮层和纹状体之间连接改变的疾病提供了特定的见解。
