A step forward for stress-induced ataxia.

Patients with episodic ataxia type 2 (EA2) display attacks of severe incoordination and dystonia that can be triggered by stress. In a recent study, Snell, Vitenzon, Tara, and colleagues found a mechanistic pathway by which norepinephrine (NE) alters cerebellar Purkinje output to trigger attacks in a mouse model of EA2 and identified a pharmacological intervention that effectively reduces them.

Shared and specific signatures of locomotor ataxia in mutant mice.

Several spontaneous mouse mutants with deficits in motor coordination and associated cerebellar neuropathology have been described. Intriguingly, both visible gait alterations and neuroanatomical abnormalities throughout the brain differ across mutants. We previously used the LocoMouse system to quantify specific deficits in locomotor coordination in mildly ataxic Purkinje cell degeneration mice (pcd; Machado et al., 2015). Here, we analyze the locomotor behavior of severely ataxic reeler mutants and compare and contrast it with that of pcd. Despite clearly visible gait differences, direct comparison of locomotor kinematics and linear discriminant analysis reveal a surprisingly similar pattern of impairments in multijoint, interlimb, and whole-body coordination in the two mutants. These findings capture both shared and specific signatures of gait ataxia and provide a quantitative foundation for mapping specific locomotor impairments onto distinct neuropathologies in mice.

Spatial and Temporal Locomotor Learning in Mouse Cerebellum.

Stable and efficient locomotion requires the precise coordination of movement across the limbs and body. Learned changes in interlimb coordination can be induced by exposure to a split-belt treadmill that imposes different speeds under each side of the body. Here, we demonstrate locomotor learning on a split-belt treadmill in mice. Mouse locomotor adaptation is specific to measures of interlimb coordination, has spatial and temporal components that adapt at different rates, and is context specific. The many similarities between human and mouse locomotor adaptation suggest that this form of locomotor learning is highly conserved across vertebrates. Using a variety of approaches, we demonstrate that split-belt adaptation in mice specifically depends on the intermediate cerebellum but is insensitive to large lesions of the cerebral cortex. Finally, cell-type-specific chemogenetics combined with quantitative behavioral analysis reveals that spatial and temporal components of locomotor adaptation are dissociable on the circuit level. VIDEO ABSTRACT.

A quantitative framework for whole-body coordination reveals specific deficits in freely walking ataxic mice.

The coordination of movement across the body is a fundamental, yet poorly understood aspect of motor control. Mutant mice with cerebellar circuit defects exhibit characteristic impairments in locomotor coordination; however, the fundamental features of this gait ataxia have not been effectively isolated. Here we describe a novel system (LocoMouse) for analyzing limb, head, and tail kinematics of freely walking mice. Analysis of visibly ataxic Purkinje cell degeneration (pcd) mice reveals that while differences in the forward motion of individual paws are fully accounted for by changes in walking speed and body size, more complex 3D trajectories and, especially, inter-limb and whole-body coordination are specifically impaired. Moreover, the coordination deficits in pcd are consistent with a failure to predict and compensate for the consequences of movement across the body. These results isolate specific impairments in whole-body coordination in mice and provide a quantitative framework for understanding cerebellar contributions to coordinated locomotion.