Vestibular control of axial motor circuitry

描述(由申请者提供)：当动物在环境中移动或导航时，良好的姿势和方向控制是至关重要的。脊椎动物依靠前庭脊髓系统将来自内耳的重力感觉转化为适当的代偿性躯干(轴向)和肢体运动，以稳定和定位自己。虽然这个系统存在于所有脊椎动物中，对生存至关重要，但对它的研究一直停滞不前，因为记录前庭和脊髓神经元的技术难度很大，特别是在动物运动时。我的长期目标是定义前庭和小脑通路影响脊髓回路活动模式以微调行为输出的方法。这项建议的目的是通过定义前庭神经元控制脊髓运动神经元和中间神经元活动的突触回路，确定前庭信号如何转化为适当的代偿性姿势调整。为了克服限制先前努力的技术困难，我提议使用斑马鱼幼体。斑马鱼是这一研究领域的优秀系统，因为它们的脑干和脊柱很容易接触，而且斑马鱼和哺乳动物的脊髓回路之间有很强的同源性。因此，脑干和脊髓之间的电路映射可以比在哺乳动物系统中更容易地进行，并且结果可能适用于脊椎动物。由于斑马鱼的身体规划相对简单，微电路活动随后可以转化为行为输出，从而产生这一重要的感觉运动转换的完整图景。在目标1中，结合体内钙信号和电生理学将被用来检查背侧和腹侧肌肉的不同招募，同时动物试图从侧卧到直立。对前庭信号的要求将是 在缺失耳石(重力传感器)的突变动物身上进行了测试。这些实验将确定运动池是如何被前庭信号激活以驱动自我恢复的。在目标2中，前庭神经元将在活体记录已识别的脊髓运动神经元的过程中被刺激，以测试前庭脊髓驱动如何分配到适当的运动神经元池以进行自我扶正。最后，目标3将把这项研究扩展到脊髓中间神经元，以确定下行输入如何调节神经元间回路，以实现高度特异性的运动调制。前庭脊髓信号的障碍会导致眩晕和跌倒，这是老年人的主要健康威胁。因此，对前庭脊髓信号从感觉到运动的完整分析将促进我们对行为下行控制的理解，并有可能确定改善人类姿势控制的策略。

DESCRIPTION (provided by applicant): Good control of posture and orientation is vital for animals as they make movements or navigate the environment. Vertebrates rely on the vestibulospinal system to translate gravity sensations from the inner ear into appropriate compensatory trunk (axial) and limb movements to stabilize and orient themselves. Although this system exists in all vertebrates and is crucial for survival, research on it has languished du to the technical difficulties in recording from vestibular and spinal neurons, especially during animal motion. My long-term goal is to define the means by which vestibular and cerebellar pathways influence spinal circuit activity patterns to fine-tune behavioral outputs. The objective of this proposal is to determine how vestibular signals are translated into appropriate compensatory postural adjustments by defining the synaptic circuit by which vestibular neurons govern the activity of spinal motor neurons and interneurons. To surmount the technical difficulties that have limited prior efforts, I propose to use the larval zebrafish. Zebrafish are n excellent system for this line of research because of the accessibility of their brainstem and spinal column, and the strong homologies between zebrafish and mammalian spinal circuits. Thus, circuit mapping between the brainstem and spinal cord can be performed with much greater ease than in mammalian systems, and the results are likely to be applicable across vertebrates. Microcircuit activity can then be translated into behavioral output due to the relativ simplicity of the zebrafish body plan, yielding a complete picture of this vital sensorimotor transformation. In Aim 1, a combination of calcium signaling and electrophysiology in vivo will be used to examine differential recruitment of dorsal and ventral musculature while the animal attempts to right itself from side-lying to upright. The requirement for vestibular signals will be tested in mutant animals missing their otoliths (gravity sensors). These experiments will identify how motor pools are activated by vestibular signals to drive self-righting. In Aim 2, vestibular neurons will be stimulated during in vivo recordings from identified spinal motor neurons to test how vestibulospinal drive is distributed to the appropriate pools of motor neurons for self-righting. Finally, Aim 3 will extend this research to spinal interneurons, to identify how descending inputs regulate interneuronal circuits for highly specific modulation of movement. Impairments in vestibulospinal signaling can cause vertigo and falls, a major health hazard in the elderly. Thus, a complete sensory-to-motor analysis of vestibulospinal signaling will advance our understanding of descending control of behavior and potentially identify strategies for improving human postural control.