Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility
Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility
复制标题
多巴胺清除机制在调节行为灵活性中的独特作用
DOI：
10.1101/823401
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Korn C
中科院分区：
文献类型：
--
作者：
Korn C
调节多巴胺传递的机制对于其对行为的影响至关重要，并因地区而异。通过多巴胺转运蛋白（DAT）的再循环在纹状体占主导地位，而儿茶酚-O-甲基转移酶（COMT）的降解在皮质占主导地位。然而，问题仍然存在，每种机制是否以及如何影响这些区域多巴胺传递的快速波动并影响行为。为了解决这个问题，我们使用药物阻断每种清除机制，以评估它们在奖励引导决策和调节纹状体和皮质中的亚秒多巴胺传递中的作用。我们发现，DAT和COMT选择性地影响奖励值更新在相反的方向，与DAT封锁损害和COMT抑制提高学习的多步决策任务，需要小鼠监测最佳反应策略和奖励概率的变化。相比之下，两种药物都不会影响作用状态转换概率变化后的逆转速度。此外，在决策任务和累进比率范式中，DAT而不是COMT影响任务参与和奖励工作动机。在麻醉小鼠中诱发多巴胺释放的快速扫描循环伏安法记录显示，DAT而不是COMT阻断增强了延髓核中的多巴胺瞬变。出乎意料的是，这两种操作对内侧额叶皮层的诱发释放都没有影响。总之，这些数据完善了我们的理解，多巴胺清除机制如何在不同的区域和不同的时间尺度运作，以塑造奖励引导的决策方面。然而，尽管我们对多巴胺神经元的活动如何与奖励导向行为相关了解很多，但对不同清除机制在塑造这些过程中的确切作用却知之甚少。这一点很重要，因为功能障碍的清除机制与许多神经精神疾病有关。在这里，我们展示了两种清除机制-多巴胺转运蛋白和儿茶酚-O-甲基转移酶-在奖励值中的具体和不同的作用，但不是动作状态概率，在多步决策过程中的更新，以及在调节纹状体和皮质多巴胺瞬变。我们的研究结果表明，在不同的时间尺度和不同的大脑区域，多巴胺传输的调节如何影响奖励导向行为的多个方面。
Mechanisms for regulation of dopamine transmission are critical to its effects on behavior and vary by region. Recycling via the dopamine transporter (DAT) predominates in striatum, while degradation by catechol-O-methyltransferase (COMT) predominates in cortex. However, questions remain about whether and how each mechanism affects fast fluctuations in dopamine transmission in these regions and influences behavior. To address this issue, we used pharmacological blockade of each clearance mechanism to assess their roles in reward-guided decision making and in regulating sub-second dopamine transmission in striatum and cortex. We found that DAT and COMT selectively influence reward value updating in opposite directions, with DAT blockade impairing and COMT inhibition improving learning in a multi-step decision making task that requires mice to monitor changes in both optimal response strategy and reward probabilities. By contrast, neither drug influenced the speed of reversals following a change in action-state transition probabilities. In addition, DAT but not COMT influenced task engagement and motivation to work for reward in both the decision making task and a progressive ratio paradigm. Fast scan cyclic voltammetry recordings of evoked dopamine release in anesthetized mice revealed that DAT but not COMT blockade enhanced dopamine transients in nucleus accumbens. Unexpectedly, neither manipulation had an effect on evoked release in medial frontal cortex. Together, these data refine our understanding of how dopamine clearance mechanisms operate in different regions and at distinct timescales to shape aspects of reward-guided decision making.Significance StatementDopamine transmission is tightly regulated by clearance mechanisms and these clearance mechanisms exhibit regional specificity. However, while we know a lot about how the activity of dopamine neurons relates to reward-guided behavior, the precise role of different clearance mechanisms in shaping these processes is much less understood. This is important, as dysfunctional clearance mechanisms have been implicated in many neuropsychiatric disorders. Here, we show specific and distinct roles for two clearance mechanisms – the dopamine transporter and catechol-O-methyltransferase – in reward value, but not action-state probability, updating during multi-step decision making, and in regulating striatal and cortical dopamine transients. Our findings demonstrate how regulation of dopamine transmission, over distinct timescales and in different brain regions, can influence multiple aspects of reward-guided behavior.
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影响因子：
5
作者：
Keithley, Richard B.;Wightman, R. Mark
通讯作者：
Wightman, R. Mark
DOI：
10.1016/j.baga.2016.02.001
发表时间：
2016-08
期刊：
Basal ganglia
影响因子：
--
作者：
Sulzer D;Cragg SJ;Rice ME
通讯作者：
Rice ME
影响因子：
16.6
作者：
Verharen JPH;de Jong JW;Roelofs TJM;Huffels CFM;van Zessen R;Luijendijk MCM;Hamelink R;Willuhn I;den Ouden HEM;van der Plasse G;Adan RAH;Vanderschuren LJMJ
通讯作者：
Vanderschuren LJMJ
影响因子：
2.6
作者：
Swainson, R;Rogers, RD;Robbins, TW
通讯作者：
Robbins, TW
DOI：
10.1523/jneurosci.14-05-02531.1994
发表时间：
1994-05
期刊：
--
影响因子：
--
作者：
AC Roberts;M. D. De Salvia;L. Wilkinson;P. Collins;J. Muir;B. Everitt;T. Robbins
通讯作者：
AC Roberts;M. D. De Salvia;L. Wilkinson;P. Collins;J. Muir;B. Everitt;T. Robbins