Identifying pathways for motor variability in the mammalian brain

识别哺乳动物大脑运动变异的途径

基本信息

批准号：
8955334
负责人：
Jesse Heymann Goldberg
金额：
$ 241.5万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Deficits in movement initiation, control and variability constitute the core dysfunctions of neurological disease, but we still don't know how these processes are implemented in the brain. The main obstacle is the sheer complexity of brain pathways for movement. The mammalian motor system is a distributed group of neural circuits, which are in turn comprised of complex microcircuits and specific cell types. Because we don't know how these small circuit elements influence behavior, current treatments lack effectiveness and specificity. To address this problem, we developed a panel of new technologies that will allow us to define how previously inaccessible microcircuits control motor behavior. First, we invented a touch-sensing joystick that quantifies mouse forelimb trajectories with unprecedented (micron-millisecond) spatiotemporal resolution. Second, we incorporate this joystick into automated, computer-controlled homecages that perform real-time behavioral analysis and high-throughput behavioral training. Third, we devise a new way of doing high-throughput optogenetics in untethered mice using newly available red-shifted opsins. Finally, we demonstrate for the first time that mice can learn complex center-out forelimb tasks similar to ones long used in primates. By establishing a new, sophisticated motor learning paradigm in mice - a tractable model system with powerful genetic tools - we are now poised to selectively manipulate neural activity in large batches of behaving animals. First, we will perform projection-specific optogenetic silencing to determine how each of fourteen pathways converging on mouse forelimb motor cortex controls movement initiation and variability in the joystick trajectories. Next, we will use Cre-transgenic mouse lines to test how distinct layers inside forelimb cortex differentially control these processes. For both of these experiments, real-time behavioral analysis will enable optogenetic manipulations to be time-locked to specific task events and animal postures, as well as at distinct stages of skill learning. In summary, the proposed work combines unprecedented readout of motor output with unprecedented tools for manipulating previously inaccessible parts of the mammalian motor system. Our new behavioral and experimental paradigm will identify yet-to-be discovered circuits controlling movement initiation, variability and learning. If successful, it will no longer be so mysterious where tremos, dystonias, akinesias and choreas come from. We will be able to point to specific pathways and cell types positioned to cause specific deficits, which in turn will provide a roadmap towards the next generation of more targeted therapies.

描述（由适用提供）：运动计划，控制和可变性的缺陷构成神经疾病的核心功能障碍，但我们仍然不知道在大脑中如何实现这些过程。主要的障碍是运动通路的纯粹复杂性。哺乳动物运动系统是一组分布式的神经元电路，而复杂的微电路和特定的细胞类型又完成了。因为我们不知道这些小电路元素如何影响行为，所以当前的治疗方法缺乏有效性和特异性。为了解决这个问题，我们开发了一组新技术，使我们能够定义以前无法访问的微电路控制运动行为。首先，我们发明了一个接触式操纵杆，该操纵杆用前所未有的（微米）时空分辨率量化了小鼠前肢轨迹。其次，我们将此操纵杆纳入了自动化的，计算机控制的家庭，这些家庭进行了实时行为分析和高通量行为训练。第三，我们设计了一种使用新近可用的红移OPSIN的无束缚小鼠进行高通量光遗传学的新方法。最后，我们首次证明了小鼠可以学习与私人长期使用的任务相似的复杂中心前肢任务。通过在小鼠中建立一种新的，复杂的运动学习范式（一种具有强大遗传工具的可拖动模型系统），我们现在被毒死，可以选择性地操纵大批行为动物的神经活动。首先，我们将执行针对特定的光遗传学沉默，以确定在小鼠前肢运动皮层上收敛的14个途径如何控制操纵杆轨迹的运动和可变性。接下来，我们将使用CRE-转基因小鼠系来测试前肢皮质内部的不同层如何不同地控制这些过程。对于这两个实验，实时行为分析将使光学遗传操作能够延伸到特定的任务事件和动物姿势以及技能学习的不同阶段。总而言之，拟议的工作将电机输出的前所未有的读数与前所未有的工具结合在一起，用于操纵哺乳动物运动系统的先前无法接近的部分。我们的新行为和实验范式将确定尚未发现的电路控制运动计划，可变性和学习。如果成功的话，那将不再是如此神秘，而颤音，肌张力障碍，阿肯西亚和唱片来自。我们将能够指出定位以引起特定定义的特定途径和细胞类型，这反过来将为下一代提供更多目标疗法提供路线图。