Control of Glutamatergic Transmission by Acetylcholine Release in Striatum

描述（由申请人提供）：纹状体是基底神经节的主要输入，基底神经节是一系列涉及自发运动和运动学习的结构。这种结构与许多运动和认知障碍有关。纹状体的主要输出是gaba能介质棘神经元（MSNs）。纹状体的胆碱能中间神经元（CINs）为纹状体提供神经调节剂乙酰胆碱（Ach）的唯一来源。在体外，Ach突触前抑制皮质纹状体EPSCs。这为MSN活动的管理提供了一个强有力的机会。然而，很难评估CIN在这种抑制中的作用。此外，CINs被认为与体内报道的强直活性神经元（TANs）相对应。这些细胞短暂地停止对奖励刺激和预测奖励的刺激的反应，这表明这种暂停可能会减少乙酰胆碱，从而缓解这种抑制。在这个项目中，我们试图在体外和体内将CINs的活性与MSN发射和皮质纹状体EPSCs的变化联系起来。我们使用病毒传递的光激活膜蛋白、通道视紫红质（ChR2）和盐视紫红质（HR）选择性地控制CINs的发射。我们已经证实，我们可以在体内和体外控制CINs的发射。我们现在可以研究CIN动作电位的时间和它们的放电速率如何影响急性切片的msn中的EPSCs。有了HR，我们现在有能力暂时暂停纹状体中的CINs。我们将观察皮质纹状体EPSCs的任何变化，使我们能够预测TAN暂停的功能。此外，利用植入的光纤和体内记录设备，我们可以激活和暂停体内的CINs。通过比较可调用的CINs和明显的tins，我们可以确定CINs是否实际上是tins。通过记录周围msn的活动，我们可以确定CIN活动或暂停对自发和皮层驱动活动的净影响。这种方法使我们第一次有机会观察到胆碱能中间神经元活动的影响，并首次深入了解在TAN放电中具有重要行为意义的暂停的功能。

DESCRIPTION (provided by applicant): The striatum is the primary input to the basal ganglia, a collection of structures involved in initiation of voluntary movements and motor learning. This structure is involved in many movement and cognitive disorders. The principle output of striatum is through the GABAergic medium spiny neurons (MSNs). Cholinergic interneurons (CINs) of the striatum fire tonically and provide the sole source of the neuromodulator acetylcholine (Ach) to the striatum. In vitro, Ach presynaptically inhibits corticostriatal EPSCs in MSNs. This provides a powerful opportunity for regulation of MSN activity. However, it has been difficult to assess the role of CIN firing on this inhibition. Furthermore, CINs are thought to correspond to tonically active neurons (TANs) reported in vivo. These cells briefly cease firing to rewarding stimuli and stimuli that predict reward, suggesting the possibility that this pause reduces Ach relieving this inhibition. In this project we seek to link the activity of CINs to changes in MSN firing and corticostriatal EPSCs both in vitro and in vivo. We selectively control the firing of CINs using virally delivered light activated membrane proteins, channelrhodopsin (ChR2) and halorhodopsin (HR). We have validated that we can control the firing of CINs in vivo and in vitro. We can now investigate how both the timing of CIN action potential and their firing rate affects EPSCs in MSNs in the acute slice. And, with HR we now have the ability to briefly pause CINs in striatum. We will observe any changes to corticostriatal EPSCs, allowing us to make predictions on the function of TAN pauses. Additionally, using implanted fiberoptics and in vivo recording devices we can activate and pause CINs in vivo. By comparing evocable CINs to apparent TANs we can identify if CINs are in fact TANs. And by recording the activity of the surrounding MSNs we can identify the net effect of CIN activity or pause on spontaneous and cortically driven activity. This approach allows the first opportunity to observe the effects of cholinergic interneuron activity, and provides the first insight to a function of the behaviorally important pause in TAN firing.