Co-Regulation of Striatal Dopamine and Acetylcholine During Flexible Learning

项目摘要 神经调节剂乙酰胆碱(ACh)和多巴胺(DA)在学习中起着重要作用。在纹状体中 胆碱能中间神经元(CINs)与DA的释放同时被调制，以响应不可预知的 奖励和奖励预测提示，这两个信号都与编码预测误差信号有关。 虽然DA神经元大多被这些显著事件激活，但CIN通常表现出多相反应 活动中明显的停顿。这两个信号的时间锁定表明它们是协调的，但 目前尚不清楚它们是相互独立监管，还是相互监管 彼此之间。此外，它们在时间上的共同出现对学习是否重要仍有待确定。 对相互协同调节的支持来自刺激和损伤研究。在片段中，DA从 DA终末通过激活D2受体抑制CINs的活性。引人注目的是，经典的6-OHDA损伤 对非人类灵长类动物的研究表明，灵长类动物强直活动神经元(TANS)中的停顿 CINS的对应者，完全依赖DA；尽管这一假设受到了数据的挑战 停顿一代的丘脑或其他投射。切片生理学和体内刺激研究 进一步表明，CINS局部释放ACh可诱导DA的释放。刺激研究的一个局限性是 他们不会测量自然诱发的ACh或DA水平。因此，这种相互协调的监管的重要性 在学习过程中必须在自然条件下确定。实现这一目标的理想方法是同时 测量同一动物体内行为诱发的DA和ACh水平的变化。自从纹状体ACh一直是 当需要调整行为以适应应用程序将关注的新任务规则时，发现这一点很重要 了解DA和ACh相互协同调节对认知灵活性的重要性。为此，我们 建议在小鼠两次灵活学习期间同时记录任务诱发的DA和ACh瞬变 行为、去/不去和反转学习。我们的初步数据显示，这两种行为都受到纹状体的影响 CIN功能。然后，我们将通过增强或取消来分离ACh信号中依赖于DA的分量 DA抑制CINs的能力。相反，我们将取消CIN释放ACh或抑制CIN的能力 具有高时间分辨率的活动。确定这些操作如何影响 ACh/DA水平和性能将确定DA和ACh信号相互协同调节的重要性 灵活学习。我们的研究将为纹状体中DA和ACh的共同调节提供机械性的见解。 这具有临床意义，因为两种神经递质在脑病患者的纹状体内调节失调。 包括精神分裂症和帕金森障碍在内的疾病，这两种神经调节系统都是 目前的治疗方法。

Project Summary The neuromodulators acetylcholine (ACh) and dopamine (DA) play important roles in learning. In the striatum cholinergic interneurons (CINs) are modulated co-incident with the release of DA in response to unpredicted rewards and reward predicting cues and both signals have been implicated in coding prediction error signals. Whereas DA neurons are mostly activated by these salient events, CINs often show a multiphasic response with a prominent pause in activity. The time locked occurrence of both signals suggest that they are coordinated but it is still unclear whether they are regulated independently from each other or whether they mutually regulate each other. Moreover, whether their temporal co-incidence is important for learning still needs to be determined. Support for a mutual co-regulation comes from both stimulation and lesion studies. In the slice, DA released from DA terminals inhibits the activity of CINs via activation of D2 receptors. Strikingly, classical 6-OHDA lesion studies in non-human primates suggest that the pause in Tonically Active Neurons (TANs), the primate counterparts of CINs, is fully dependent on DA; although this hypothesis has been challenged by data implicating thalamic or other projections in the pause generation. Slice physiology and in vivo stimulations studies have further shown that ACh released from CINs locally induces DA release. One limitation of stimulation studies is that they do not measure naturally evoked ACh or DA levels. Thus, the importance of this mutual co-regulation during learning must be determined under natural conditions. An ideal way to achieve this is to simultaneously measure behaviorally-evoked changes in DA and ACh levels in the same animal. Since striatal ACh has been found to be important when behavior needs to be adapted to new task rules the application will focus on understanding the importance of the mutual co-regulation of DA and ACh for cognitive flexibility. To this end, we propose to simultaneously record task-evoked DA and ACh transients in the mouse during two flexible learning behaviors, Go/NoGo and reversal learning. Our preliminary data show that both behaviors are affected by striatal CIN function. We then will isolate the DA-dependent component of the ACh signal by enhancing or abolishing the ability of DA to inhibit CINs. Conversely, we will abolish the ability of CINs to release ACh or inhibit CIN activity with high temporal resolution. Determining how these manipulations affect task-evoked changes in ACh/DA levels and performance will establish the importance of mutual co-regulation of DA and ACh signals for flexible learning. Our studies will provide mechanistic insights into DA and ACh co-regulation in the striatum. This has clinical relevance as both neurotransmitters are dysregulated in the striatum of patients with brain disorders including schizophrenia and Parkinson disorder, where both neuromodulator systems are targeted by current therapeutic treatments.