Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels.
Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels.
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DOI：
10.7554/elife.76111
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发表时间：
2022-07-20
期刊：
影响因子：
7.7
通讯作者：
Kellendonk, Christoph
中科院分区：
文献类型：
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作者：
Martyniuk, Kelly M.;Torres-Herraez, Arturo;Lowes, Daniel C.;Rubinstein, Marcelo;Labouesse, Marie A.;Kellendonk, Christoph
在纹状体中，乙酰胆碱（ACh）神经元的活动与多巴胺（DA）的释放同时受到调制，以响应不可预测的奖励和奖励预测线索，并且这两种神经调质被认为是相互调节的。虽然已经使用刺激研究来研究这种共调节，但是在自然行为期间这种相互调节在体内的存在仍然在很大程度上未被探索。一个长期存在的争议是纹状体DA是否负责胆碱能暂停的诱导或DA D2受体（D2Rs）是否调节由其他机制诱导的暂停。在这里，我们使用基因编码的传感器结合药理学和遗传失活的D2Rs从胆碱能中间神经元（CINS），同时测量ACh和DA水平后，CIN D2R失活小鼠。我们发现，CIN D2Rs是不必要的线索诱导的ACh水平下降的启动。相反，它们延长了减少的持续时间并抑制ACh反弹水平。值得注意的是，线索诱发的乙酰胆碱水平的变化与线索诱发的DA释放的改变无关。此外，D2R失活强烈降低DA和ACh信号之间的时间相关性，不仅在提示介绍，但也在审讯间隔指向一个一般的机制，D2Rs协调这两个信号。在行为水平，D2R拮抗作用增加了杠杆按压的潜伏期，这在CIN选择性D2R敲除小鼠中没有观察到。按压潜伏期与ACh水平的线索诱发的降低相关，并且人工抑制CINs显示，与较短的抑制相比，较长的抑制缩短了按压潜伏期。这支持了ACh信号的作用，以及D2R在启动行动的动机中的调节作用。
In the striatum, acetylcholine (ACh) neuron activity is modulated co-incident with dopamine (DA) release in response to unpredicted rewards and reward-predicting cues and both neuromodulators are thought to regulate each other. While this co-regulation has been studied using stimulation studies, the existence of this mutual regulation in vivo during natural behavior is still largely unexplored. One long-standing controversy has been whether striatal DA is responsible for the induction of the cholinergic pause or whether DA D2 receptors (D2Rs) modulate a pause that is induced by other mechanisms. Here, we used genetically encoded sensors in combination with pharmacological and genetic inactivation of D2Rs from cholinergic interneurons (CINs) to simultaneously measure ACh and DA levels after CIN D2R inactivation in mice. We found that CIN D2Rs are not necessary for the initiation of cue-induced decrease in ACh levels. Rather, they prolong the duration of the decrease and inhibit ACh rebound levels. Notably, the change in cue-evoked ACh levels is not associated with altered cue-evoked DA release. Moreover, D2R inactivation strongly decreased the temporal correlation between DA and ACh signals not only at cue presentation but also during the intertrial interval pointing to a general mechanism by which D2Rs coordinate both signals. At the behavioral level D2R antagonism increased the latency to lever press, which was not observed in CIN-selective D2R knock out mice. Press latency correlated with the cue-evoked decrease in ACh levels and artificial inhibition of CINs revealed that longer inhibition shortens the latency to press compared to shorter inhibition. This supports a role of the ACh signal and it’s regulation by D2Rs in the motivation to initiate actions.