Groman Stephanie M, Smith Nathaniel J, Petrullli J Ryan, Massi Bart, Chen Lihui, Ropchan Jim, Huang Yiyun, Lee Daeyeol, Morris Evan D, Taylor Jane R
Departments of Psychiatry.
Biomedical Engineering, and Department of Diagnostic Radiology.
J Neurosci. 2016 Jun 22;36(25):6732-41. doi: 10.1523/JNEUROSCI.3253-15.2016.
Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [(11)C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel three-choice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [(11)C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [(11)C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders.
Flexible decision-making behavior is dependent upon dopamine D2/3 signaling in corticostriatal brain regions. However, the role of D3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D3-preferring radioligand [(11)C]-(+)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [(11)C]-(+)-PHNO receptor availability relates to specific aspects of flexible decision making. We confirm these relationships using a D3-preferring agonist, thus identifying a unique role of midbrain D3 receptors in decision-making processes.
多巴胺D2/3受体信号传导对于灵活的适应性行为至关重要；然而，尚不清楚是D2受体亚型、D3受体亚型还是两者共同调节构成最佳决策基础的反馈和奖励历史的精确信号。在这里，使用放射性配体[(11)C]-(+)-PHNO进行正电子发射断层扫描（PET），以量化在具有概率强化的新型三选空间获取和逆向学习任务中训练的啮齿动物中假定的D3受体可用性的个体差异。[(11)C]-(+)-PHNO在中脑的结合与大鼠适应奖励位置变化的能力呈负相关，但与初始学习无关。逆向阶段选择行为的计算模型表明，[(11)C]-(+)-PHNO在中脑的结合与学习率以及对正向而非负向反馈的敏感性有关。给予优先作用于D3的激动剂同样会通过降低学习率和对正向反馈的敏感性来损害逆向学习表现。这些结果证明了D3受体在强化学习的特定方面具有先前未被认识到的作用，并表明中脑D3受体的个体差异会影响灵活行为。我们结合神经影像学、行为学、药理学和计算方法，表明多巴胺D3受体参与了在精神疾病中发生改变的决策过程。
灵活的决策行为依赖于皮质纹状体脑区中的多巴胺D2/3信号传导。然而，D3受体在适应性目标导向行为中的作用尚未得到充分研究。通过将PET成像与优先作用于D3的放射性配体[(11)C]-(+)-PHNO、药理学、一种新型三选概率辨别和逆向任务以及大鼠行为的计算模型相结合，我们报告[(11)C]-(+)-PHNO受体可用性的自然变化与灵活决策的特定方面相关。我们使用优先作用于D3的激动剂证实了这些关系，从而确定了中脑D3受体在决策过程中的独特作用。
