Mitrevica, Zane; (2025) Biomechanical and neural influences on locomotor gait control in mice. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Locomotion is one of the most fundamental behavioural outputs of the mammalian nervous system, with interlimb coordination, or gait, as a defining feature. While recent technological developments have advanced our understanding of the neural mechanisms behind various locomotor properties, the study of quadrupedal gait has been constrained by its partial dependence on speed and the difficulty to reliably evoke a variety of gaits in genetically tractable quadrupeds like mice. In addition, research on large mammals has highlighted a biomechanical component to gait control, yet experimental manipulation of body mechanics in mice has been problematic due to their small size. In my PhD work, I addressed these challenges by developing a head-fixed locomotor paradigm that decouples the speed- and leg loading-related effects on gait. Specifically, I combined unilateral optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus with head height and surface slope modulation. This paradigm revealed a speed-independent shift in homolateral limb phase preference from strict alternation to a quarter-of-phase more synchronised coordination upon rearward redistribution of leg load. Conversely, hindlimb coordination was influenced by the side of optogenetic stimulation and a combination of speed, total leg load, and a posture-related variable. To explore the neural bases of these associations, I performed analogous experiments in Egr3-knockout mice that lack muscle spindle-mediated proprioception. This deficit reduced, but did not eliminate, the sensitivity of homolateral phase to changes in anteroposterior load distribution, suggesting that muscle spindle afferents contribute to the observed effect, but are not its sole mediator. In contrast, the stimulation side dependence of hindlimb coordination was largely abolished, highlighting a crucial interplay between descending and feedback influences. Altogether, my PhD research provides an entry point to behaviour-driven study of gait circuits and offers insight into the varying roles of biomechanical and neural influences on specific modules of interlimb coordination.

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