Cholinergic Modulation of Motor Preparation in the Midbrain

描述(由申请人提供)：拟议研究的长期目标是了解在正常和病理条件下控制运动输出的神经机制。中心假设是，脑干胆碱能系统对运动准备的贡献与它们被认为对感觉注意的贡献大致相同：通过调节运动结构中的活动，使最符合行为目标的动作更有可能被执行。我们在一个有利的动物模型系统的强劲解剖学投影中检验了这一假说：从小鼠脑干桥脑脚被盖核(PPT)到上丘(SC)中间灰层的胆碱能输入。该项目的目标将通过记录和操纵(使用药理学和光遗传学)自由移动的野生型和转基因小鼠的神经活动来实现，这些小鼠执行需要准备和产生定向运动的行为任务。目标1将研究胆碱能输入如何调节SC的活动和SC依赖的行为输出。目标2将直接关注行为过程中胆碱能PPT神经元的活动。如果成功，我们的提议将在一个遗传可及的小鼠模型中阐明运动控制的关键神经底物。除了测试这里提出的具体假设外，我们开发的模型还将使未来研究其他遗传定义的神经元网络如何影响运动输出成为可能。最终，了解正常的运动输出有助于改进运动障碍的治疗方法，如帕金森氏症。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to understand the neural mechanisms underlying the control of motor output under normal and pathological conditions. The central hypothesis is that brainstem cholinergic systems contribute to motor preparation in much the same way that they are thought to contribute to sensory attention: by modulating activity in motor structures such that the movements most in line with behavioral goals are more likely to be executed. We examine this hypothesis in a robust anatomical projection of an advantageous animal model system: The cholinergic input from the brainstem pedunculopontine tegmental nucleus (PPT) to the intermediate gray layer of the superior colliculus (SC) in the mouse. The project goals will be achieved by recording and manipulating (using pharmacology and optogenetics) neural activity in freely-moving wild-type and transgenic mice performing behavioral tasks that require preparing and generating orienting movements. Aim 1 will examine how cholinergic input modulates SC activity and SC-dependent behavioral output. Aim 2 will focus directly on the activity of cholinergic PPT neurons during behavior. If successful, our proposal will elucidate, in a genetically accessible mouse model, key neural substrates underlying motor control. In addition to testing the specific hypotheses proposed here, the model we develop will make possible future research into how other genetically-defined networks of neurons contribute to motor output. Ultimately, understanding normal motor output can contribute to improving therapies for movement disorders, such as Parkinson's disease.