Periodic Reporting for period 4 - LOCOMOUSE (Cerebellar circuit mechanisms of coordinated locomotion in mice) Reporting period: 2019-11-01 to 2020-04-30 Summary of the context and overall objectives of the project A remarkable aspect of brain function is our seemingly effortless ability to generate coordinated movements. How is activity within neural circuits orchestrated to allow us to engage in complex activities like gymnastics, riding a bike, or walking down the street while drinking a cup of coffee? The cerebellum is critical for coordinated movement, and the well-described, stereotyped circuitry of the cerebellum has made it an attractive system for neural circuits research. Much is known about how activity and plasticity in its identified cell types contribute to simple forms of motor learning. In contrast, while gait ataxia, or uncoordinated walking, is a hallmark of cerebellar damage, the circuit mechanisms underlying cerebellar contributions to coordinated locomotion are not well understood. This project developed a quantitative framework for mouse locomotion and combined it with state of the art methods for manipulating neural activity in defined cell populations. This approach allows us to establish causal relationships between neural circuit activity and coordinated motor control, a problem with important implications for both health and disease. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far This project established a quantitative framework for measuring and analyzing mouse locomotor coordination. We developed an automated tracking and analysis system, LocoMouse, and used it to identify specific cerebellum-dependent features of locomotor coordination (Machado et al., eLife 2015). Comparing the specific patterns of locomotor features that result from distinct neural circuit perturbations within and outside the cerebellum (Machado et al., eLife 2015; Correia et al., eLife 2017; Machado et al., eLife 2020; Albergaria et al., bioRxiv 2020) has provided a roadmap for linking distinct gait abnormalities to underlying neural circuits. We also developed a transparent, split-belt treadmill for mice that allowed us to induce acute perturbations to locomotor coordination and analyze how animals learn to restore locomotor symmetry (Darmohray et al., Neuron 2019). Combining this quantitative behavioral approach with genetic circuit dissection has revealed a critical role for cerebellar circuits in the separate control of precise step timing and placement during walking. Together, these experiments have established mouse locomotion as a powerful system for studying the neural control of movement. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The project was successful in its aims and led to several impactful publications and numerous oral and poster presentations by team members and the PI at international conferences and institutes. There are additional ongoing elements of the project that are at various stages of preparation for future publications. Visualization of distinct locomotor deficits in mice with distinct neuropathology-Machado et al 2020
