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

在环境中活动的能力对包括人类在内的所有动物的生存都是至关重要的。在哺乳动物中，产生和驱动运动运动的神经元驻留在脊髓中，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的神经控制研究都集中在直线轨迹向前运动上。然而，脑干和脊髓神经网络如何控制转弯运动仍然知之甚少。这项研究将采用实验和计算相结合的方法来研究这个问题。这项研究的结果将为转向的神经控制，更广泛地说，运动的神经控制提供重要的启示。该项目开发的模型可以作为模拟运动障碍的不同方面和治疗方法的试验台。研究结果有助于开发新的策略来恢复脊髓损伤、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。最近在脑干的巨细胞网状核(GI)中发现了一组网状脊髓神经元，投射到脊髓的所有节段，并由转录因子Chx10(V2a神经元)的表达确定。通过实验激活小鼠的这些神经元，可以诱导出强健的转身运动，这似乎主要是由颈部、上躯干和前肢的运动神经回路的不对称控制驱动的。这项研究将检验这样一种假设，即这些通路代表着运动转弯动作的主要协调者。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，并对脑干和脊髓回路和动物生物力学进行了计算建模。体外和体内研究的结果将被纳入四足哺乳动物(小鼠)运动的神经生物力学数据驱动模型。该模型将提供机械性的解释，并生成可测试的预测，然后通过实验进行验证。该项目有以下三个目标。(1)研究网状脊髓V2a 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)表征小鼠在运动方向改变时的运动学特征，并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V2a 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，并探讨一般机制。这项研究将提供一个连接脑干结构的功能连接体，这些结构启动和支持转向脊髓和效应器肌群中相应的执行回路的行为。研究还将揭示更一般的运动控制机制，如多个有节奏的运动系统的协调，并将有助于开发有效的方法，在影响脑干和脊髓的各种运动障碍和损伤后恢复运动。法国国家研究机构(ANR)正在资助一个配套项目。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、稳健智能、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优势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.