Dissecting the inhibitory architecture governing basal ganglia output

剖析控制基底神经节输出的抑制结构

• 批准号: 10536523
• 负责人: Rebekah Coleman Evans
• 金额: $ 5.92万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536523
• 关键词: Affect; Architecture; Axon; Basal Ganglia; Cell Nucleus; Cells; Deep Brain Stimulation; Degenerative Disorder; Equilibrium; Fiber; Globus Pallidus; Implant; Label; Locomotion; Motion; Motor output; Mus; Neurons; Output; Parkinson Disease; Play; Role; STN stimulation; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; Testing; base; behavior test; in vivo; insight; motor behavior; motor control; motor disorder; motor learning; motor skill learning; motor symptom; optogenetics; therapeutic target

Abstract. The subthalamic nucleus (STN) is part of the basal ganglia. It plays a role in motor behavior through its connections with the globus pallidus, substantia nigra, and possibly through direct connections with the pedunculopontine nucleus (PPN). Retrograde labeling shows that the STN synapses onto PPN neurons, but it is unclear whether this connection has a functional role in motor output. Because both the STN and PPN are targeted in deep brain stimulation to alleviate motor symptoms in degenerative disorders, understanding their connectivity will yield deeper insights into the circuit mechanisms of motor control. Using in vivo optogenetic stimulation, we will directly test the behavioral effects of activating this connection. Specifically, we will infect STN neurons with channelrhodopsin and activate STN axons via a fiber implanted above the PPN. We will activate this circuit in freely-moving mice, during motor skill learning, and during a challenging balance task. While stimulating the STN input onto the substantia nigra inhibits motion, we hypothesize that stimulating the STN-PPN connection will modulate locomotion, balance, and motor learning. This hypothesis is based on previous findings that the STN sends excitatory inputs to the PPN and that direct stimulation of STN cell bodies affects motion and motor skill learning. This project will yield a better understanding of the functional relationship between the STN and the PPN and is the first step toward developing more specific deep brain stimulation treatments.

抽象。丘脑底核（subthalamic nucleus，简称丘脑底核）是基底神经节（basal ganglia）的一部分。它在运动中起作用 行为通过其与苍白球，黑质，并可能通过 与脑桥脚核（pedunculopontine nucleus，PPN）的直接联系。逆行标记显示， 突触连接到PPN神经元上，但尚不清楚这种连接是否具有功能作用 在电机输出中。因为在脑深部电刺激中，脑脊膜和PPN都是靶向的， 退行性疾病的运动症状，了解它们的连接将产生更深的 深入了解电机控制的电路机制。使用体内光遗传学刺激，我们 将直接测试激活这种连接的行为效果。具体来说，我们将感染 神经元与通道视紫红质和激活轴突通过纤维植入以上PPN。我们 在运动技能学习过程中，以及在一个具有挑战性的过程中， 平衡任务。虽然刺激黑质的神经元输入会抑制运动， 假设刺激STN-PPN连接将调节运动，平衡， 运动学习这一假设是基于先前的发现，即大脑皮层发送兴奋性输入， PPN的直接刺激，并认为直接刺激神经细胞体会影响运动和运动技能 学习该项目将使人们更好地了解 这是开发更特异性脑深部电刺激的第一步 治疗。