The Functional Organization of the Mesencephalic Locomotor Region

Abstract

Locomotion is an essential component of all animal behavior. It is highly conserved across species. Locomotion is defined as movement from one place to another. Studies of locomotion focus on two aspects: (1) the motor program including footfalls and rhythmic swings including maintaining stance under continuous environmental disturbance, which are largely regulated by the spinal cord; (2) the volitional aspect of locomotion including adjusting posture of trunk and leaning to achieve goal-directed locomotion, which require top-down control from the brain. Decades of research on locomotion has revealed the function of central pattern generator and motor programs in regulating the motor synergy during locomotion, but little is known about the circuit that provides top-down control of locomotion direction and initiation.The mesencephalic locomotor region (MLR) has long been identified as a key region for locomotion initiation. Number of studies have shown that stimulation of the MLR can initiate various speed of gait, and it is considered as the central node for integration of top-down control of locomotion. However, limited research has been done investigating how MLR regulate locomotion direction, which is essential in any goal-directed locomotion. Two reasons for this are (1) firstly, the MLR is not an anatomically well-defined region with diverse neuronal populations and connectivity. Technology for identification and manipulation of specific neural population has been extremely challenging. (2) Secondly, monitoring and quantifying locomotion requires high temporal and spatial resolution during free-moving behavior, which has not been approachable without advanced computational image processing tools. Although locomotion is intuitively reflected by rhythmic limb lift-off and footfalls, the MLR does not generate rhythmic activity in limb muscles. Instead, MLR likely coordinates whole-body locomotion. Since any goal-directed locomotion requires direction-specific regulation, it remains unclear how MLR regulate locomotion direction during locomotion initiation.This paper is to examine the role of MLR in controlling goal-directed locomotion. The first experiment investigates the relationship of MLR neural activity and locomotion direction in a goal-directed behavioral task. It shows that MLR glutamatergic neural activity is predominantly modulated by movement direction during target pursuit. There are two types of glutamatergic neurons in MLR. One type responds to forward and backward movement, and the other type responds to steering(left and right) movement. Neurons shows modulatory response to steering prone to positively correlate with ipsilateral direction. Activity of these neurons is modulated by the center of mass movement even in absence of gaits.The second experiment investigates the MLR glutamatergic neurons function in controlling locomotion direction. The function of MLR glutamatergic neurons show heterogenous effect on generating locomotion. Steering and forward-backward locomotion are elicited by separate populations of the MLR glutamatergic neurons. Additionally, the spatial distribution these functional distinct populations follows a topographical map inside the MLR. The rostral and ventral portion is prone to generate steering (left and right movement) locomotion and the dorso-caudal portion is more likely to generate symmetrical forward locomotion. The third experiment examines whether MLR control of steering is achieved through frontal-cortical-pyramidal-to-MLR tract. Results shows that neural activity of motor cortex is bidirectionally modulated by steering velocity. Stimulation of pyramidal cells in supplementary motor cortex elicits similar steering movement as stimulations to MLR glutamatergic neurons. However, stimulation of cortical-MLR tract cannot elicit steering locomotion in free-moving animals.Taken together, our results demonstrate that the MLR are important in controlling locomotion direction by regulating the center of mass movement. And the control of steering movement of MLR is independent of frontal cortex pyramidal tract.