Glutamate transporter control of excitation and inhibition in the striatum

动物有能力学习新的运动技能，并将其转化为运动习惯。纹状体是大脑中称为基底神经节的关键运动系统的主要部分，已知在控制习惯性动作的执行方面发挥基本作用。纹状体究竟如何协调其神经元的活动，以确保正确执行习惯性动作，这一点尚不清楚。最近的研究结果表明，一种特殊的神经递质转运蛋白，神经元谷氨酸转运蛋白EAAT 3，可能是控制大脑多个区域（包括纹状体）兴奋性传递时程的关键参与者。该研究项目将确定EAAT 3如何控制两种不同类型的纹状体神经元的突触整合和突触能信号。为了实现这一目标，研究人员使用了一个全面的多学科工具箱，其中包括电生理学，光学成像和计算机建模方法，以及表达D1或D2型多巴胺神经元的基因工程小鼠。该项目包括在科学，技术，工程和数学（STEM）学科的研究生和本科生的培训，同时推进和改造我们的纹状体回路的知识。将代表性不足的少数民族和公众参与活动纳入其中是该项目不可或缺的一部分，以扩大其对公众的影响。我们执行运动的能力依赖于被称为皮质-纹状体-丘脑-皮质（CSTC）通路的神经元回路的活动。CSTC通路中的信息中继依赖于纹状体中神经元的协调激活，纹状体是CSTC通路的主要节点。纹状体主要由表达D1或D2多巴胺受体的两种类型的长投射神经元组成。谷氨酸转运体在纹状体中大量表达，但它们在控制纹状体神经元协调活动中的作用仍然是个谜。本项目的第一个目标是确定神经元谷氨酸转运蛋白如何调节D1和D2表达神经元的兴奋性传递。第二个目标是确定这些转运蛋白如何塑造这些细胞从传入兴奋性输入中传递信息的时间准确性。实验策略需要基于电生理学，光遗传学，成像和计算机建模的创新多学科方法。拟议的研究将产生新的知识谷氨酸转运蛋白的功能作用的活动模式和动力学的电路牵连在习惯性运动执行。

Animals have the ability to learn new motor skills and convert them into motor habits. The striatum, a major part of a key motor system in the brain called basal ganglia, is known to exert a fundamental role in controlling the execution of habitual actions. What is not known is exactly how the striatum coordinates the activity of its neurons to ensure proper execution of habitual actions. Recent findings suggest that a particular neurotransmitter transporter, the neuronal glutamate transporter EAAT3, might act as a key player in controlling the time course of excitatory transmission in multiple regions of the brain, including in the striatum. This research project will determine how EAAT3 controls glutamatergic signaling and synaptic integration onto two distinct types of striatal neurons. To accomplish this goal, the investigators use a comprehensive and multidisciplinary toolbox that includes electrophysiological, optical imaging, and computer modeling approaches, as well as mice genetically-engineered that express either D1- or D2-type dopamine neurons.. The project includes training of graduate and undergraduate students in Science, Technology, Engineering, and Mathematics (STEM) disciplines while advancing and transforming our knowledge of striatal circuits. Inclusion of underrepresented minorities and public engagement activities are an integral part of the project, to broaden its impact with the general public.Our ability to perform movements relies on the activity of a neuronal circuit known as the cortico-striatal-thalamo-cortical (CSTC) pathway. Relay of information in the CSTC pathway relies on the coordinated activation of neurons in the striatum, a major node of the CSTC pathway. The striatum is largely composed of two types of long-projection neurons that express either D1 or D2 dopamine receptors. Glutamate transporters are abundantly expressed in the striatum but their role in controlling the coordinated activity of striatal neurons remains enigmatic. The first goal of this project is to determine how neuronal glutamate transporters regulate excitatory transmission in D1- and D2-expressing neurons. The second goal is to determine how these transporters shape the temporal accuracy with which these cells relay information from incoming excitatory inputs. The experimental strategies entail innovative multi-disciplinary approaches based on electrophysiology, optogenetics, imaging and computer modeling. The proposed research will generate new knowledge on the functional role of glutamate transporters in the activity patterns and dynamics of circuits implicated in habitual movement execution.