美国斯坦福大学Robert C. Malenka研究小组揭示纹状体多巴胺和血清素对强化的对立控制。相关论文于2024年11月25日在线发表于国际学术期刊《自然》。

研究人员建立了一个小鼠模型，能够同时进行大脑中多巴胺（DA）和血清素（5-羟色胺；5HT）神经元的遗传学接入。顺行示踪揭示，伏隔核（NAc）是整合收敛的DA和5HT信号的潜在热点。通过同时记录DA和5HT轴突活动，以及遗传编码的DA和5HT传感器信号，研究人员发现奖励会增加NAc中的DA信号并减少5HT信号。

单独光遗传学抑制DA或5HT的奖励反应，在一种奖励条件反射任务中产生了适度的行为缺陷，而同时抑制这两种信号则显著干扰了学习和强化过程。光遗传学共同再现DA和5HT的奖励反应，足以驱动新联结的学习，并比单独操控其中任何一种信号更有效地支持强化。

综上，这些结果表明，纹状体中的DA和5HT信号通过对强化施加对立控制来共同塑造了学习过程。

研究人员表示，神经调节物DA和5HT在联结学习中起着强大的调控作用。由于这些神经调节系统在活动和连接性上的相似性，激发了关于DA和5HT如何相互作用以推动新联结形成的竞争性模型。然而，这些假设尚未得到直接检验，因为此前无法在单一实验对象中同时探讨和操控多个神经调节系统。

附：英文原文

Title: Opponent control of reinforcement by striatal dopamine and serotonin

Author: Cardozo Pinto, Daniel F., Pomrenze, Matthew B., Guo, Michaela Y., Touponse, Gavin C., Chen, Allen P. F., Bentzley, Brandon S., Eshel, Neir, Malenka, Robert C.

Issue&Volume: 2024-11-25

Abstract: The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) powerfully regulate associative learning1–8. Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations9–14. However, these hypotheses have not been tested directly because it has not been possible to interrogate and manipulate multiple neuromodulatory systems in a single subject. Here, we establish a mouse model enabling simultaneous genetic access to the brain’s DA and 5HT neurons. Anterograde tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recording of DA and 5HT axon activity, together with genetically encoded DA and 5HT sensor recordings, revealed that rewards increase DA signaling and decrease 5HT signaling in the NAc. Optogenetically dampening DA or 5HT reward responses individually produced modest behavioral deficits in an appetitive conditioning task, while blunting both signals together profoundly disrupted learning and reinforcement. Optogenetically reproducing DA and 5HT reward responses together was sufficient to drive acquisition of new associations and supported reinforcement more potently than either manipulation alone. Together, these results demonstrate that striatal DA and 5HT signals shape learning by exerting opponent control of reinforcement.

DOI: 10.1038/s41586-024-08412-x

Source: https://www.nature.com/articles/s41586-024-08412-x