The Function of Striatal Microcircuits in Health and Disease

描述（申请人提供）：基底神经节是一个高度保守的神经系统，在运动、学习和认知中起作用。基底神经节的输出受两种神经通路控制，即促进运动（直接通路）或抑制运动（间接通路）。这两种通路的平衡被破坏是神经系统疾病（如肌张力障碍、帕金森氏病、图雷特氏综合征和亨廷顿氏病）中观察到的运动缺陷的基础。因此，了解直接和间接通路回路在细胞水平上是如何协调的具有重要意义和潜在的治疗价值。在过去的十年中，研究网络功能的细胞组织已经集中在被称为抑制性中间神经元的高度特化的神经元上。这些神经元在基底神经节的输入核纹状体中的缺失严重损害了运动功能，这一事实证明了这些神经元在基底神经节功能中的重要性。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，因为它们在电生理研究中一直难以定位。该提案描述了我们使用一种新的方法来研究抑制性中间神经元在纹状体中的作用，通过转基因小鼠系荧光标记纹状体回路中的不同细胞类型。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神经节通路中的神经元。使用这种方法，我们将测试纹状体中抑制性中间神经元功能的三个假设：(1)不同类别的中间神经元在纹状体加工中发挥不同的作用(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(3)在帕金森病中观察到的纹状体输出失衡（间接通路的过度激活）。验证这些假设的实验将利用全细胞记录技术来研究急性脑切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，其中纹状体回路中的不同细胞类型被荧光标记，使突触特性和连通性的发现能够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神经节疾病的电路功能障碍。

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. PUBLIC HEALTH RELEVANCE: Parkinson's Disease is a devestating neurological disorder that affects 1% of people over 65. Its well-known motor symptoms, including loss of voluntary movement and limb tremors, result from widespread dysfunction of the brain's motor control center, the basal ganglia. In this grant, I will test hypotheses that local inhibition of activity by specialized brain cells in the input nucleus to the basal ganglia, play a critical role in controling motor function in both health and disease. This research will advance our understanding of the neural circuitry that underlies motor control and potentially identify new targets for disease therapy.