The role of glutamate receptors in compulsive and perseverative behavior

背外侧纹状体整合会聚性皮质和丘脑输入以控制动作的启动和终止 多种障碍包括强迫症（OCD）、自闭症谱系障碍（ASD）、 和抽动秽语综合征改变了功能或适应不良的三端电路重排， 异常的持续和重复行为。多刺投射神经元（spiny projection neurons，SPN）约占 纹状体中90%的所有神经元，并严格按照它们的结合和贡献进行划分 直接途径（对动作起始很重要）和间接途径（参与动作终止 特别地，两种谷氨酸受体类型，第1组代谢型谷氨酸受体（mGluR）和 红藻氨酸受体（KAR）在调节直接途径SPNs（dSPNs）和间接途径SPNs（dSPNs）的活性中是重要的。 通路神经元（iSPNs）。这些受体中的每一种都有多种重叠的细胞功能，但它仍然存在于 目前尚不清楚每种受体类型如何精确地建立和调节突触，并影响 背外侧纹状体中SPNs的兴奋性。我们已经培育出了一种新的小鼠， 受体在dSPN或iSPN中被有条件地消融。这些老鼠表现出有趣的行为 表型表明纹状体中每种谷氨酸受体类型的作用是不同的和二分的。 在这项提案中，我们将采取全面的方法来映射mGluRs的细胞电路功能 和KARs，并确定它们中的每一个如何在调节纹状体输出中发挥不同的作用。目标是 确定每种受体类型如何调节SPN的突触和内在特性，以及如何 有助于该电路的平衡输出，这对适当的行为动作至关重要。因此，在第一次 我们将确定mGluRs和KAR在每种SPN类型中的细胞作用。在第二个目标中， 将决定每种谷氨酸受体类型如何对纹状体回路的平衡活动做出贡献。 最后，在第三个目标中，我们将在运动和习惯性运动的启动期间使用SPN活动的体内成像。 确定在异常和适应不良行为期间SPN功能是否明显失衡的措施 当谷氨酸受体在SPN中被消融时。这些研究将共同采取全面和 谷氨酸受体在纹状体神经元调节中的细胞和回路作用的综合研究 电路，并将告诉我们这些受体如何有助于适应不良和强迫症的障碍 行为。

The dorsolateral striatum integrates convergent cortical and thalamic input to control action initiation and termination Multiple disorders including obsessive compulsive disorder (OCD), autism spectrum disorders (ASDs), and Tourette syndrome have altered function or maladaptive rearrangements of triatal circuits, resulting in aberrant perseverative and repetitive behaviors. The spiny projection neurons (SPNs) make up approximately 90% of all the neurons in the striatum and are strictly divided by their incorporation and contribution to the direct pathway (important for action initiation) and the indirect pathway (involved in action termination In particular, two glutamate receptor types, Group 1 metabotropic glutamate receptors (mGluRs) and kainate receptors (KARs) are important in regulating activity of both the direct pathway SPNs (dSPNs) and indirect pathway neurons (iSPNs). Each of these receptors have multiple overlapping cellular functions, yet it remains unclear how each receptor type contributes precisely to establishing and modulating synapses, and affecting excitability of SPNs in the dorsolateral striatum. We have developed novel mice in which each of these receptors are ablated conditionally in either dSPN or iSPNs. These mice demonstrate interesting behavioral phenotypes that suggest divergent and dichotomous roles for each glutamate receptor type in the striatum. In this proposal we will take a comprehensive approach to map the cellular to circuit function of mGluRs and KARs, and determine how each of them has distinct roles in regulating striatal output. The goal is to determine how each of the receptor types regulates synaptic and intrinsic properties of the SPNs, and how contribute to the balanced output of this circuit that is vital to appropriate behavioral actions. Thus, in the first aim we will determine the cellular roles of mGluRs and KARs in each of the SPN types. In the second aim we will determine how each of the glutamate receptor types contributes to the balanced activity of the striatal circuit. Finally, in the third aim we will use in vivo imaging of SPN activity during the initiation of motor and habitual actions to determine whether imbalanced SPN function is evident during aberrant and maladaptive behaviors when glutamate receptors are ablated in SPNs. Together these studies will take a comprehensive and integrative approach to determine the cellular and circuit roles played by glutamate receptors in regulating striatal circuits, and will inform us about how these receptors contribute to disorders with maladaptive and compulsive behaviors.