Molecular and neural circuit mechanisms for limb coordination in mice

Abstract

Limb movement is an essential component for animal behavior and any problem therein lead to severe motor defects. As the level of complexity, limb movements can be separated in two categories: locomotion and skilled movement. First, locomotion is a patterned movement involving rhythmic muscle activities. Neuroanatomical knowledges about the locomotion have been well determined as the central pattern generator in the spinal cord which provide neural activities to make rhythmic movements. However, in the field of clinical neurology, there are many locomotor disorders in which etiology remains unclear. In this study, we focused on the sensory ataxia which is a rare movement disorder involving progressive gait abnormality with the loss of sensory functions. Based on the report that a mutation of RNF170 gene causes autosomal-dominant sensory ataxia in humans, we examined that the loss of RNF170 lead to the ADSA-like phenotype. The elimination of RNF170 protein in mouse model cause age-dependent gait abnormality featured as disrupted synchronization of diagonal limb movements and modulation of step sequences, and the loss of sensory faculties such as proprioception and thermal nociception. Remarkably, as the consequence of the loss RNF170 function as degradation of IP3R1 proteins, the level of IP3R1 expression was increased in the spinal cord and cerebellum, not in the cerebral cortex. These result suggests that the neural mechanism in the sensory ataxia is linked with the loss of endogenous RNF170 functions in particular nervous tissues associated with locomotor control. Second, skilled limb movement is a motor program comprised with action patterns to achieve specific goals such as reaching and grasping. The cerebellum has been known to have a key role in adaptive control of skilled limb movement via thalamic projections, however its functional identity is remained unclear. To address this issue, we examined the question how cerebellar output signal is processed in the thalamus associated with the functional connections with other motor circuits during motor behaviors. Using optogenetics, we found that the cerebello-thalamic signals activate muscular activities only when the subject is in moving, not in resting conditions. Remarkably, the degree of muscular activities induced by the cerebello-thalamic signals also can be modulated by the activity of cortico-thalamic circuits. This result suggests the thalamus does not just transfer cerebellar motor signals, but can modulate the intensity of relevant muscle activities via cortico-thalamic pathway.