The role of glutamate receptors in compulsive and perseverative behavior

背外侧纹状体整合了皮质和丘脑的汇聚输入来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(ASDS)、 和Tourette综合征改变了三房回路的功能或不适应的重排，导致 在反常、坚持不懈和重复的行为中。棘突投射神经元大致由 纹状体中所有神经元的90%，并严格按照它们的结合和贡献进行划分 直接通路(对动作启动很重要)和间接通路(参与动作终止) 特别是，两种谷氨酸受体类型，第1组代谢性谷氨酸受体(MGluRs)和 海人藻酸受体(KARs)在调节直接途径SPN和间接途径SPN的活性中起重要作用 通路神经元(ISPN)。这些受体中的每一个都有多种重叠的细胞功能，但它仍然 不清楚每种受体类型如何准确地作用于建立和调节突触，以及影响 背外侧纹状体SPN的兴奋性。我们已经开发出新的小鼠，在这些小鼠中， 在dSPN或iSPN中，受体被有条件地消融。这些小鼠表现出有趣的行为 表明纹状体中每种谷氨酸受体类型的不同和二分作用的表型。 在这项提案中，我们将采用一种全面的方法来映射mGluRs的细胞与电路功能 和KARS，并确定它们如何在调节纹状体输出中扮演不同的角色。我们的目标是 确定每种受体类型如何调节SPN的突触和固有属性，以及如何 有助于该电路的平衡输出，这对适当的行为行为至关重要。因此，在第一个 目的探讨mGluRs和KARs在不同类型SPN中的细胞作用。在第二个目标中，我们 将决定每种类型的谷氨酸受体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，我们将使用SPN在启动运动和习惯性过程中的活体成像 在异常和适应不良行为中确定SPN功能失衡是否明显的行动 当SPN中的谷氨酸受体被消融时。总而言之，这些研究将采取全面和 确定谷氨酸受体在调节纹状体中的细胞和回路作用的综合方法 并将告诉我们这些受体是如何在适应不良和强迫症的障碍中起作用的 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.