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 A2A receptor (A2AR) 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 A2ARs in nucleus accumbens (NAc) to control of goal-directed behavior remain to be determined. Here, we employed newly developed opto-A2AR and the focal A2AR knockdown strategies to demonstrate the causal role of NAc A2AR in control of goal-directed behavior. Furthermore, we dissected out multiple distinct behavioral mechanisms underlying which NAc A2ARs control goal-directed behavior: (i) NAc A2ARs preferentially control goal-directed behavior at the expense of habit formation. (ii) NAc A2ARs modify the animals' sensitivity to the value of the reward without affecting the action-outcome contingency. (iii) A2AR antagonist KW6002 promotes instrumental actions by invigorating motivation. (iv) NAc A2ARs facilitate Pavlovian incentive value transferring to instrumental action. (v) NAc A2ARs control goal-directed behavior probably not through NAc-VP pathway. These insights into the behavioral and circuit mechanisms for NAc A2AR control of goal-directed behavior facilitate translational potential for A2AR antagonists in reversal of deficits in goal-directed decision-making associated with multiple neuropsychiatric disorders.

中文翻译：

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伏隔核中的纹状体最高血脂腺苷A2A受体赋予目标定向行为的动机控制。

在动态环境中学习奖励价值和行动结果的意外事件的能力对于灵活的适应行为至关重要，开发有效的药理控制目标导向行为代表着改善目标导向行为缺陷的重要挑战，这种缺陷可能是潜在的。精神病患者的症状完全不同。腺苷A2A受体（A2AR）由于其独特的神经调节功能而成为控制目标行为的新型神经调节靶标：整合多巴胺和谷氨酸信号的能力，各种认知过程的“制动”约束以及对目标-指导和习惯行动。然而，伏隔核（NAc）中的纹状体的A2ARs对控制目标行为的贡献和电路机制尚待确定。在这里，我们采用了新开发的光电A2AR和焦点A2AR组合式策略来证明NAc A2AR在控制目标定向行为中的因果作用。此外，我们剖析了NAc A2ARs控制目标定向行为的多种不同行为机制：（i）NAc A2ARs以习惯形成为代价优先控制目标定向行为。（ii）NAc A2ARs改变了动物对奖励价值的敏感性，而不会影响行动结果的偶然性。（iii）A2AR拮抗剂KW6002通过激发动力来促进工具性行为。（iv）NAc A2AR促进巴甫洛夫的激励价值转移到工具性行动。（v）NAc A2ARs可能不通过NAc-VP途径控制目标导向的行为。这些对NAc A2AR控制目标行为的行为和电路机制的见解促进了A2AR拮抗剂逆转与多种神经精神疾病相关的目标决策中的缺陷的转化潜力。