Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou, Zhejiang, 325027, China.
The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang, 325027, China.
Neuropharmacology. 2020 May 15;168:108010. doi: 10.1016/j.neuropharm.2020.108010. Epub 2020 Feb 13.
The ability to learn the reward-value and action-outcome contingencies in dynamic environment is critical for flexible adaptive behavior and development of effective pharmacological control of goal-directed behaviors represents an important challenge for improving the deficits in goal-directed behavior which may underlie seemingly disparate symptoms across psychiatric disorders. Adenosine A receptor (AR) is emerging as a novel neuromodulatory target for controlling goal-directed behavior for its unique neuromodulatory features: the ability to integrate dopamine and glutamate signaling, the "brake" constraint of various cognitive processes and the balanced control of goal-directed and habit actions. However, the contribution and circuit mechanisms of the striatopallidal ARs in nucleus accumbens (NAc) to control of goal-directed behavior remain to be determined. Here, we employed newly developed opto-AR and the focal AR knockdown strategies to demonstrate the causal role of NAc AR in control of goal-directed behavior. Furthermore, we dissected out multiple distinct behavioral mechanisms underlying which NAc ARs control goal-directed behavior: (i) NAc ARs preferentially control goal-directed behavior at the expense of habit formation. (ii) NAc ARs modify the animals' sensitivity to the value of the reward without affecting the action-outcome contingency. (iii) AR antagonist KW6002 promotes instrumental actions by invigorating motivation. (iv) NAc ARs facilitate Pavlovian incentive value transferring to instrumental action. (v) NAc ARs control goal-directed behavior probably not through NAc-VP pathway. These insights into the behavioral and circuit mechanisms for NAc AR control of goal-directed behavior facilitate translational potential for AR antagonists in reversal of deficits in goal-directed decision-making associated with multiple neuropsychiatric disorders.
在动态环境中学习奖励价值和行为结果关联的能力对于灵活适应行为至关重要，而开发有效的药物控制目标导向行为的方法代表了改善目标导向行为缺陷的重要挑战，这些缺陷可能是各种精神障碍中看似不同症状的基础。腺苷 A 受体 (AR) 作为一种新的神经调制靶点，因其独特的神经调制特征而成为控制目标导向行为的候选靶点：整合多巴胺和谷氨酸信号的能力、对各种认知过程的“制动”约束以及对目标导向和习惯行为的平衡控制。然而，纹状体苍白球 AR 在伏隔核 (NAc) 中对控制目标导向行为的贡献和回路机制仍有待确定。在这里，我们采用了新开发的光 AR 和焦点 AR 敲低策略，以证明 NAc AR 在控制目标导向行为中的因果作用。此外，我们还剖析了 NAc AR 控制目标导向行为的多个不同行为机制：(i) NAc AR 优先控制目标导向行为，而牺牲习惯形成。(ii) NAc AR 改变动物对奖励价值的敏感性，而不影响行为结果关联。(iii) AR 拮抗剂 KW6002 通过增强动机促进工具性动作。(iv) NAc AR 促进了条件性奖励价值向工具性动作的转移。(v) NAc AR 可能不是通过 NAc-VP 通路来控制目标导向行为。这些关于 NAc AR 控制目标导向行为的行为和回路机制的见解，为 AR 拮抗剂在逆转与多种神经精神障碍相关的目标导向决策缺陷方面的转化潜力提供了便利。
