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，基底神经节是参与自主运动和运动学习启动的结构集合。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通过GABA能中型棘神经元（MSN）。纹状体的胆碱能中间神经元（CINs）紧张性地放电，并向纹状体提供神经调节剂乙酰胆碱（Ach）的唯一来源。在体外，乙酰胆碱突触前抑制皮质纹状体EPSC的MSN。这为规范MSN活动提供了一个强有力的机会。然而，很难评估CIN放电对这种抑制的作用。此外，CIN被认为对应于体内报告的紧张性活性神经元（TAN）。这些细胞短暂地停止了对奖励刺激和预测奖励的刺激的放电，这表明这种暂停减少Ach缓解这种抑制的可能性。在这个项目中，我们试图在体外和体内将CIN的活性与MSN放电和皮质纹状体EPSC的变化联系起来。我们选择性地控制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）的CINs的发射。我们已经证实，我们可以控制在体内和体外的CIN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频率如何影响急性切片中MSN中的EPSC。而且，有了HR，我们现在有能力短暂暂停纹状体中的CIN。我们将观察皮质纹状体EPSC的任何变化，使我们能够预测TAN暂停的功能。此外，使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CIN。通过比较可诱发的CINs和明显的TAN，我们可以确定CINs是否实际上是TAN。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质驱动活动的净效应。这种方法允许第一次有机会观察胆碱能中间神经元活动的影响，并提供了第一个洞察力的功能的行为上重要的暂停TAN发射。

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.