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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - LOCOMOUSE (Cerebellar circuit mechanisms of coordinated locomotion in mice)

Teaser

Summary

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 aims to identify how distinct regions of the cerebellum contribute to locomotor coordination, and understand how activity in specific neural populations influences locomotion. To this end, we are combining a quantitative behavioral approach with state of the art methods for manipulating and recording neural activity. These experiments will establish causal relationships between neural circuit activity and coordinated motor control, a problem with important implications for both health and disease.

Work performed

One obstacle to understanding how activity within neural circuits gives rise to movements that are coordinated with millimeter and millisecond precision has been the difficulty in extracting quantitative measures of coordination with suitable spatiotemporal resolution. We have developed a custom-built video system (LocoMouse) to analyze mouse locomotor coordination. It uses machine learning algorithms to automatically track continuous paw, snout, and tail trajectories in 3D with high spatiotemporal resolution. Combining the LocoMouse system with genetic manipulations that perturb activity in the cerebellum has allowed us to identify specific, cerebellar contributions to coordinated locomotion. Moreover, we have begun to compare manipulations of neural activity in different regions of the cerebellum, and the rest of the brain, to understand how they work together to coordinate movement across the body during walking.

Final results

The development of the LocoMouse system and its use to reveal specific features of cerebellar ataxia in freely walking mice has firmly established mouse locomotion as a serious model system for understanding the neural basis of motor control. It also provides a solid foundation for completion of the remaining Aims of the project. We have made the LocoMouse software for tracking the moving paws, nose, and tail of locomoting mice freely available (https://github.com/careylab/LocoMouse), to encourage widespread adoption by the community. Ongoing and future work will focus on combining the state-of-the art behavioural analyses that the lab has already established with genetic and electrophysiological tools for dissecting neural circuits. In particular, we are focused on measuring and manipulating neural activity of specific cell-types within the cerebellum and examining their contributions to motor coordination.