An optogenetic investigation of cholinergic mechanisms modulating midbrain motor

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最有可能得到执行。我在一个有利的动物模型系统的强大解剖学投影中检验了这一假设：从脑干脚桥脑被盖核(PPT)到中脑区域(小鼠上丘(SC)的中间灰层)的胆碱能输入。该项目的目标将通过操纵(使用光遗传学)并记录自由移动的转基因小鼠的神经活动来实现，以确定这种胆碱能输入如何调节SC神经元的活动。在另一组单独的实验中，行为实验将直接报告PPT信号如何调节运动准备。目标1将研究胆碱能输入如何在体内调节中间层SC的活动。目标2将通过直接关注这种胆碱能输入如何改变定向运动，将目标1中的发现转化为行为正常的小鼠。如果成功，我们的建议将在一个遗传可及的小鼠模型中阐明运动准备的关键神经底物。除了测试这里提出的特定假设外，我还将结合这两个目的，直接检查行为正常的小鼠在胆碱能PPT的光遗传操作过程中的运动准备活动。所有这些实验都为未来研究其他基因定义的神经元网络如何影响运动输出提供了可能。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 most likely to be executed. I 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 a midbrain area, the intermediate gray layer of the superior colliculus (SC) in the mouse. The project goals will be achieved by manipulating (using optogenetics) and recording neural activity in freely-moving transgenic mice to establish how this cholinergic input modulates the activity SC neurons. In a separate set of experiments, behavioral experiments will directly report how PPT signaling modulates motor preparation. Aim 1 will examine how cholinergic input modulates intermediate layer SC activity in vivo. Aim 2 will serve to translate findings in Aim 1 into the behaving mouse by focusing directly on how this cholinergic input alters directional movements. If successful, our proposal will elucidate, in a genetically accessible mouse model, key neural substrates underlying motor preparation. In addition to testing the specific hypotheses proposed here, I will then combine both Aims and directly examine motor-preparatory activity in the behaving mouse during optogenetic manipulation of the cholinergic PPT. All of these experiments 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.