CRCNS US-French Research Proposal: Brainstem-spinal circuits for control of locomotor steering.

在环境中移动的能力对所有动物的生存至关重要，包括人类。在哺乳动物中，产生和驱动自发运动的神经元位于脊髓中，这些脊髓网络由来自脑干的上游信号控制。大多数哺乳动物运动神经控制的研究都集中在直线轨迹向前运动。然而，脑干和脊髓神经网络如何控制转向运动仍然知之甚少。本研究将调查这个问题，使用实验和计算方法相结合。这项研究的结果将为转向的神经控制以及更广泛的运动的神经控制提供重要的见解。在这个项目中开发的模型可以作为模拟运动障碍和治疗方法的不同方面的试验台。研究结果可以帮助开发新的策略，以恢复脊髓损伤，神经退行性病变和其他运动障碍后的运动功能。这个多学科的项目将研究小鼠运动的神经控制，重点是转向运动的机制。最近发现的一个群体的网状脊髓神经元在脑干的神经细胞网状核（Gi）项目的所有部分的脊髓，并定义的转录因子Chx 10（V2 a神经元）的表达。在实验中激活小鼠的这些神经元诱导了强大的转向运动，这些运动似乎主要是由颈部、上躯干和前肢的运动回路的不对称控制驱动的。这项研究将测试的假设，这些途径代表了一个主要的协调员的运动转向演习。这项研究结合了最先进的生理学，遗传学，药理学和运动跟踪方法与脑干和脊髓电路和动物生物力学的计算建模。体外和体内研究的结果将纳入四足哺乳动物（小鼠）运动的神经生物力学数据驱动模型。该模型将提供机械的解释，并产生可测试的预测，然后将通过实验验证。该项目有以下三个目标。(1)研究网状脊髓V2 a Gi神经元激活对可能参与运动转向行为的脊髓回路的影响，并对这些脑干-脊髓通路和回路进行计算建模：（2）表征运动方向改变过程中小鼠运动的运动学特征，建立小鼠运动的全身神经生物力学模型;（3）研究不同群体的网状脊髓V2 a Gi神经元在运动转向和测试模型预测中的作用，挑战模型假设，并研究一般机制。这项研究将提供一个功能性连接体，将启动和支持转向行为的脑干结构与脊髓和效应肌群中相应的执行回路联系起来。这些研究还将阐明更一般的运动控制机制，如多个节律运动系统的协调，并将有助于开发各种运动障碍和影响脑干和脊髓的损伤后恢复运动的有效方法。该项目由以下NSF项目共同资助：残疾和康复工程，计算神经科学合作研究，鲁棒智能，生物医学系统工程和生物科学新兴前沿理事会。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

The ability to move within the environment is essential for the survival of all animals, including humans. In mammals, the neurons that generate and drive locomotor movements reside in the spinal cord, and these spinal networks are controlled by upstream signals from the brainstem. Most studies of neural control of locomotion in mammals have focused on straight-trajectory forward locomotion. However, how brainstem and spinal neural networks control turning movements remains poorly understood. This study will investigate this question, using a combination of experimental and computational approaches. The results of this study will provide important insights into the neural control of turning and, more broadly, the neural control of locomotion. The models developed in this project can serve as test-beds for simulating different aspects of motor disorders and treatment approaches. Study outcomes can help in the development of novel strategies to restore locomotor function after spinal cord injury, neurodegenerative pathologies, and other motor disorders. This multidisciplinary project will investigate the neural control of locomotion in mice with a focus on mechanisms of turning movements. A recently uncovered population of reticulospinal neurons in the gigantocellular reticular nucleus (Gi) of the brainstem projects to all segments of the spinal cord and is defined by the expression of the transcription factor Chx10 (V2a neurons). Experimentally activating these neurons in the mouse induces robust turning movements that seem to be mostly driven by an asymmetric control of the motor circuits of the neck, upper trunk, and forelimbs. This study will test the hypothesis that these pathways represent a major orchestrator of locomotor turning maneuvers. This study combines state-of-the-art physiological, genetic, pharmacological, and motion tracking approaches with computational modeling of the brainstem and spinal cord circuits and animal biomechanics. The results of in vitro and in vivo studies will be incorporated in a neuro-biomechanical data-driven model of quadrupedal mammalian (mouse) locomotion. The model will provide mechanistic explanations, and generate testable predictions that will then be verified experimentally. The project has the following three objectives. (1) Study the influence of reticulospinal V2a Gi neuron activation on spinal circuits potentially involved in locomotor steering behaviors and computational modeling of these brainstem-spinal pathways and circuits; (2) Characterize kinematics of mouse locomotion during changes of locomotor direction and develop a full-body neuro-biomechanical model of mouse locomotion; (3) Study the role of different populations of reticulospinal V2a Gi neurons in locomotor steering and test model predictions, challenge model assumptions, and investigate general mechanisms. This study will provide a functional connectome linking brainstem structures that initiate and support turning behaviors to the corresponding executive circuits in the spinal cord and effector muscle groups. Studies will also shed light on more general mechanisms of motor control like the coordination of multiple rhythmic motor systems and will be useful for the development of effective methods for recovery of locomotion after various motor disorders and injuries affecting the brainstem and spinal cord.A companion project is being funded by the French National Research Agency (ANR). This project is jointly funded by the following NSF programs: Disability and Rehabilitation Engineering, Collaborative Research in Computational Neuroscience, Robust Intelligence, Engineering of Biomedical Systems, and Directorate for Biological Sciences Emerging Frontiers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.