Department of Neuroscience, Columbia University, New York, United States.
Department of Psychiatry, Columbia University, New York, United States.
Elife. 2022 Jul 20;11:e76111. doi: 10.7554/eLife.76111.
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.
在纹状体中，乙酰胆碱（ACh）神经元的活动与多巴胺（DA）的释放同时被调节，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相互调节。虽然这种共调节已经通过刺激研究进行了研究，但在自然行为过程中，这种相互调节的存在在很大程度上仍未得到探索。一个长期存在的争议是，纹状体 DA 是否负责诱导胆碱能暂停，或者 DA D2 受体（D2R）是否调节由其他机制诱导的暂停。在这里，我们使用遗传编码传感器结合药理学和胆碱能中间神经元（CIN）中 D2R 的基因失活，以在 CIN D2R 失活后在小鼠中同时测量 ACh 和 DA 水平。我们发现 CIN D2R 对于诱导的 ACh 水平降低的起始不是必需的。相反，它们延长了降低的持续时间并抑制了 ACh 的反弹水平。值得注意的是，线索诱发的 ACh 水平的变化与改变的线索诱发的 DA 释放无关。此外，D2R 失活不仅在线索呈现时，而且在试验间间隔期间强烈降低了 DA 和 ACh 信号之间的时间相关性，这表明 D2R 以一般机制协调两个信号。在行为水平上，D2R 拮抗作用增加了按压杠杆的潜伏期，而在 CIN 选择性 D2R 敲除小鼠中则没有观察到这种情况。潜伏期与线索诱发的 ACh 水平降低相关，并且 CIN 的人工抑制表明，与较短的抑制相比，较长的抑制会缩短按压的潜伏期。这支持了 ACh 信号及其 D2R 调节在启动动作动机中的作用。
