Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility.
Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility.
复制标题
DOI：
10.1038/s41380-021-01194-y
复制
发表时间：
2021-12
影响因子：
11
通讯作者：
Walton ME
中科院分区：
文献类型：
--
作者：
Korn C;Akam T;Jensen KHR;Vagnoni C;Huber A;Tunbridge EM;Walton ME
多巴胺在适应行为中起着至关重要的作用，功能失调的多巴胺与多种以不灵活或不一致的选择为特征的精神疾病有关。然而，多巴胺与灵活决策之间的确切关系仍不清楚。原因之一是，虽然许多研究都集中在多巴胺神经元的活动上，但有效的多巴胺信号传导也依赖于清除机制，特别是纹状体中占主导地位的多巴胺转运蛋白（DAT）和皮质中占主导地位的儿茶酚-O-甲基转移酶（COMT）。 DAT 和 COMT 影响的确切地点、范围和时间尺度尚不确定。此外，关于任一机制的严重破坏如何影响皮质纹状体网络介导的灵活决策策略的数据有限。为了解决这些问题，我们将 DAT 和 COMT 的药理学调节与小鼠的电化学和行为相结合。 DAT 阻断（而非 COMT 抑制）调节了伏隔核核心的亚秒多巴胺释放，但令人惊讶的是，两种清除机制都不影响前边缘皮层的诱发释放。这并不是由于缺乏敏感性，因为安非他明和托莫西汀都改变了亚秒释放的动力学。在一项多步骤决策任务中，小鼠必须对奖励概率或选择序列的逆转做出反应才能达到目标，奖励逆转后，DAT 阻断选择性受损，COMT 抑制改善，但两种操作都不影响行动状态转换逆转后的选择适应。总之，我们的数据表明，DAT 和 COMT 分别通过调节纹状体和皮质多巴胺动力学的不同方面来塑造行为灵活性的特定方面。
Dopamine plays a crucial role in adaptive behavior, and dysfunctional dopamine is implicated in multiple psychiatric conditions characterized by inflexible or inconsistent choices. However, the precise relationship between dopamine and flexible decision making remains unclear. One reason is that, while many studies have focused on the activity of dopamine neurons, efficient dopamine signaling also relies on clearance mechanisms, notably the dopamine transporter (DAT), which predominates in striatum, and catechol-O-methyltransferase (COMT), which predominates in cortex. The exact locus, extent, and timescale of the effects of DAT and COMT are uncertain. Moreover, there is limited data on how acute disruption of either mechanism affects flexible decision making strategies mediated by cortico-striatal networks. To address these issues, we combined pharmacological modulation of DAT and COMT with electrochemistry and behavior in mice. DAT blockade, but not COMT inhibition, regulated sub-second dopamine release in the nucleus accumbens core, but surprisingly neither clearance mechanism affected evoked release in prelimbic cortex. This was not due to a lack of sensitivity, as both amphetamine and atomoxetine changed the kinetics of sub-second release. In a multi-step decision making task where mice had to respond to reversals in either reward probabilities or the choice sequence to reach the goal, DAT blockade selectively impaired, and COMT inhibition improved, performance after reward reversals, but neither manipulation affected the adaptation of choices after action-state transition reversals. Together, our data suggest that DAT and COMT shape specific aspects of behavioral flexibility by regulating different aspects of the kinetics of striatal and cortical dopamine, respectively.
登录
查看更多内容
影响因子：
64.8
作者：
Flagel SB;Clark JJ;Robinson TE;Mayo L;Czuj A;Willuhn I;Akers CA;Clinton SM;Phillips PE;Akil H
通讯作者：
Akil H
影响因子：
10.6
作者：
Cools, Roshan;D'Esposito, Mark
通讯作者：
D'Esposito, Mark
影响因子：
16.2
作者：
Akam T;Rodrigues-Vaz I;Marcelo I;Zhang X;Pereira M;Oliveira RF;Dayan P;Costa RM
通讯作者：
Costa RM
影响因子：
16.2
作者：
Cagniard, Barbara;Beeler, Jeff A.;Zhuang, Xiaoxi
通讯作者：
Zhuang, Xiaoxi
影响因子：
16.2
作者：
Daw ND;Gershman SJ;Seymour B;Dayan P;Dolan RJ
通讯作者：
Dolan RJ