The Function of Striatal Microcircuits in Health and Disease

描述(申请人提供)：基底节是一个高度保守的神经系统，在运动、学习和认知中发挥作用。基底神经节的输出由两条神经通路控制，这两条通路要么促进运动(直接通路)，要么抑制运动(间接通路)。在肌张力障碍、帕金森氏病、多发性抽动症和亨廷顿氏症等神经系统疾病中，这两条通路的平衡失调是运动障碍的基础。因此，了解直接和间接通路在细胞水平上是如何协调的具有非常重要的意义和潜在的治疗价值。在过去的十年里，研究网络功能的细胞组织的研究已经集中在一类被称为抑制性中间神经元的高度专业化的神经元上。这些神经元在基底节功能中的重要性体现在它们在纹状体的丢失，纹状体是基底节的输入核，严重损害运动功能。尽管它们很重要，但中间神经元在纹状体加工中的基本作用仍然知之甚少，因为它们历来很难作为电生理研究的目标。这项建议描述了我们使用一种新的方法来研究纹状体中抑制性中间神经元的作用，通过使用转基因小鼠品系来荧光标记纹状体回路中不同类型的细胞。这项新技术首次能够直接测试抑制信号如何影响直接和间接基底节通路中的神经元。 使用这种方法，我们将检验关于纹状体抑制中间神经元功能的三个假说：(1)不同类别的中间神经元在纹状体加工中扮演不同的角色；(2)纹状体中间神经元接收调节纹状体输出的重要反馈信号；以及(3)中间神经元参与帕金森病期间观察到的纹状体输出的失衡(间接通路的过度激活)。验证这些假说的实验将利用全细胞记录技术来研究急性脑片中中间神经元的兴奋性和突触信号。这些切片将由转基因小鼠制成，纹状体回路中不同类型的细胞被荧光标记，从而能够将关于突触属性和连接性的发现置于回路功能的系统级背景下。这些结果将深入了解突触可塑性或重组如何改变帕金森病的纹状体输出，以及这可能如何导致帕金森病和其他基底节疾病的回路功能障碍。

DESCRIPTION (provided by applicant): The basal ganglia are a highly conserved neural system that play a role in movement, learning, and cognition. The output of the basal ganglia is controlled by two neural pathways that either facilitate movement (direct pathway) or inhibit movement (indirect pathway). Dissruption in the balance of these two pathways underlies motor defecits observed in neurological diseases such as dystonia, Parkinson's disease, Tourette's syndrome, and Huntington's disease. Understanding how direct- and indirect-pathway circuits are coordinated at the cellular level is therefore of great importance and potential therapeutic value. Over the past decade, studies investigating the cellular organization of network function have converged upon classes of highly specialized neurons called inhibitory interneurons. The importance of these neurons in basal ganglia function is demonstrated by the fact that their loss in the striatum, the input nucleus of the basal ganglia, severely impairs motor function. Despite their importance, the basic role of interneurons in striatal processing remains poorly understood because they have been historically difficult to target for electrophysiological study. This proposal describes our use of a novel approach to study the role of inhibitory interneurons in the striatum, by using transgenic mouse lines to fluorescently label distinct cell types in the striatal circuit. This new technology enables direct testing of how inhibitory signaling affects neurons in the direct and indirect basal ganglia pathways for the first time. Using this approach, we will tests three hypotheses about inhibitory interneuron function in the striatum: (1) That different classes of interneurons play distinct roles in striatal processing (2) that striatal interneurons receive an important feedback signal that tunes striatal output and (3) that interneurons contribute to imbalances in striatal output (hyperactivation of the indirect-pathway) observed during Parkinson's disease. The experiments to test these hypotheses will utilize whole-cell recording techniques to study excitability and synaptic signaling of interneurons in acute brain slices. The slices will be made from transgenic mice where distinct cell types in the striatal circuit are fluorescently labeled, enabling discoveries about synaptic properties and connectivity to be placed in a systems-level context of circuit function. These results will yield insights into how synaptic plasticity or reorganization changes striatal output in PD and how this might contribute to circuit dysfunction in PD and other diseases of the basal ganglia.