Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239.
Department of Neuroscience, University of Pittsburgh, Pittsburg, Pennsylvania 15260.
J Neurosci. 2021 Nov 10;41(45):9419-9430. doi: 10.1523/JNEUROSCI.1321-21.2021. Epub 2021 Oct 5.
Neuronal underpinning of learning cause-and-effect associations in the adolescent brain remains poorly understood. Two fundamental forms of associative learning are Pavlovian (classical) conditioning, where a stimulus is followed by an outcome, and operant (instrumental) conditioning, where outcome is contingent on action execution. Both forms of learning, when associated with a rewarding outcome, rely on midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra (SN). We find that, in adolescent male rats, reward-guided associative learning is encoded differently by midbrain dopamine neurons in each conditioning paradigm. Whereas simultaneously recorded VTA and SN adult neurons have a similar phasic response to reward delivery during both forms of conditioning, adolescent neurons display a muted reward response during operant but a profoundly larger reward response during Pavlovian conditioning. These results suggest that adolescent neurons assign a different value to reward when it is not gated by action. The learning rate of adolescents and adults during both forms of conditioning was similar, supporting the notion that differences in reward response in each paradigm may be because of differences in motivation and independent of state versus action value learning. Static characteristics of dopamine neurons, such as dopamine cell number and size, were similar in the VTA and SN of both ages, but there were age-related differences in stimulated dopamine release and correlated spike activity, suggesting that differences in reward responsiveness by adolescent dopamine neurons are not because of differences in intrinsic properties of these neurons but engagement of different dopaminergic networks. Reckless behavior and impulsive decision-making by adolescents suggest that motivated behavioral states are encoded differently by the adolescent brain. Motivated behavior, which is dependent on the function of the dopamine system, follows learning of cause-and-effect associations in the environment. We find that dopamine neurons in adolescents encode reward differently depending on the cause-and-effect relationship of the means to receive that reward. Compared with adults, reward contingent on action led to a muted response, whereas reward that followed a cue but was not gated by action produced an augmented phasic response. These data demonstrate an age-related difference in dopamine neuron response to reward that is not uniform and is guided by processes that differentiate between state and action values.
青少年大脑中学习因果关系的神经基础仍知之甚少。两种基本形式的联想学习是巴甫洛夫（经典）条件作用，其中刺激后跟随结果，以及操作性（工具性）条件作用，其中结果取决于行动执行。当与奖励结果相关联时，这两种形式的学习都依赖于腹侧被盖区（VTA）和黑质（SN）中的中脑多巴胺神经元。我们发现，在青春期雄性大鼠中，奖励指导的联想学习在每种条件作用范式中都由中脑多巴胺神经元以不同的方式编码。虽然同时记录的 VTA 和 SN 成年神经元在两种形式的条件作用过程中对奖励传递有类似的相位反应，但青春期神经元在操作性条件作用过程中显示出对奖励的反应减弱，而在巴甫洛夫条件作用过程中则显示出强烈的更大的奖励反应。这些结果表明，当奖励不受行动控制时，青春期神经元会赋予其不同的价值。青少年和成年人在两种形式的条件作用中的学习率相似，支持这样一种观点，即每个范式中的奖励反应差异可能是由于动机的差异，而与状态与动作价值学习无关。多巴胺神经元的静态特征，如多巴胺细胞数量和大小，在 VTA 和 SN 中在两个年龄段都相似，但在刺激多巴胺释放和相关尖峰活动方面存在年龄相关差异，这表明青春期多巴胺神经元对奖励反应的差异不是由于这些神经元的内在特性不同，而是由于不同的多巴胺能网络的参与。青少年的鲁莽行为和冲动决策表明，动机行为状态由青少年大脑以不同的方式编码。受动机驱动的行为取决于多巴胺系统的功能，它遵循环境中因果关系的学习。我们发现，多巴胺神经元根据获得该奖励的手段的因果关系以不同的方式编码奖励。与成年人相比，与行动相关的奖励导致反应减弱，而紧随提示但不受行动控制的奖励则产生增强的相位反应。这些数据表明，多巴胺神经元对奖励的反应存在与年龄相关的差异，这种差异不是统一的，而是由区分状态和动作值的过程指导的。
