Vestibular control of axial motor circuitry

轴向运动电路的前庭控制

• 批准号: 8354525
• 负责人: Martha W Bagnall
• 金额: $ 9.05万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-08 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354525
• 关键词: Animals; Axon; Behavior; Behavior Control; Behavioral; Brain Stem; Calcium; Calcium Signaling; Cells; Classification; Contralateral; Data; Diabetes Mellitus; Dorsal; Dyes; Ear; Elderly; Electrophysiology (science); Electroporation; Environment; Equilibrium; Esthesia; Fishes; Force of Gravity; Future; Goals; Health Hazards; Human; Image; Impairment; Indium; Interneurons; Ipsilateral; Label; Labyrinth; Left; Limb structure; Locomotion; Mammals; Maps; Measures; Methods; Motion; Motor; Motor Neurons; Motor output; Movement; Muscle; Musculoskeletal Equilibrium; Neurons; Neuropathy; Organism; Output; Pathway interactions; Pattern; Phase; Posture; Recruitment Activity; Research; Role; Self-control as a personality trait; Sensory; Side; Signal Transduction; Specificity; Spinal; Spinal Cord; Swimming; Synapses; System; Testing; Therapeutic Intervention; Torque; Training; Transgenic Organisms; Translating; Vertebral column; Vertebrates; Vertigo; Zebrafish; awake; base; cell type; falls; improved; in vivo; limb movement; motor control; mutant; neural circuit; novel; otoconia; research study; sensor; vestibulo-ocular reflex

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. PUBLIC HEALTH RELEVANCE: Vertigo and falls represent a major health hazard in the elderly and those with common neuropathic ailments like diabetes. Although falls are frequently due to impairments in the balance system, it is not known how balance signals from the inner ear normally interact with the spinal cord to drive movements that help maintain posture. This proposal seeks to identify the precise connections between the inner ear and the spinal cord that underlie compensatory postural adjustments, providing the basis for future therapeutic interventions in humans with balance deficits.

描述（由申请人提供）：当动物进行运动或在环境中导航时，良好的姿势和方向控制对于它们至关重要。脊椎动物依靠前庭脊髓系统将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，以稳定和定向自身。尽管该系统存在于所有脊椎动物中并且对于生存至关重要，但由于记录前庭和脊髓神经元的技术困难，特别是在动物运动过程中，对其的研究已经陷入停滞。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式。该提案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补偿性姿势调整。为了克服先前限制的技术困难，我建议使用斑马鱼幼体。斑马鱼是这方面研究的优秀系统，因为它们的脑干和脊柱易于接近，并且斑马鱼和哺乳动物脊髓回路之间具有很强的同源性。因此，脑干和脊髓之间的回路映射比在哺乳动物系统中更容易进行，并且结果可能适用于脊椎动物。由于斑马鱼身体计划相对简单，微电路活动可以转化为行为输出，从而产生这种重要的感觉运动转变的完整图像。在目标 1 中，体内钙信号传导和电生理学的结合将用于检查动物尝试从侧卧到直立时的背侧和腹侧肌肉组织的差异募集。对前庭信号的要求是 在缺失耳石（重力传感器）的突变动物中进行了测试。这些实验将确定前庭信号如何激活运动池以驱动自我恢复。在目标 2 中，前庭神经元将在体内记录过程中受到已识别脊髓运动神经元的刺激，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恢复。最后，目标 3 会将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中间神经元回路，以实现高度特异性的运动调节。前庭脊髓信号传导受损会导致眩晕和跌倒，这是老年人的主要健康危害。因此，对前庭脊髓信号传导进行完整的感觉到运动分析将增进我们对行为下降控制的理解，并有可能确定改善人类姿势控制的策略。 公共卫生相关性：眩晕和跌倒是老年人和患有糖尿病等常见神经性疾病的人的主要健康危害。尽管跌倒常常是由于平衡系统受损造成的，但目前尚不清楚内耳的平衡信号通常如何与脊髓相互作用以驱动有助于保持姿势的运动。该提案旨在确定补偿性姿势调整背后的内耳和脊髓之间的精确连接，为未来对具有平衡缺陷的人类进行治疗干预提供基础。