Dopamine Modulates Motor Control in a Specific Plane Related to Support

Abstract

At the acute stage following unilateral labyrinthectomy (UL), rats, mice or guinea pigs exhibit a complex motor syndrome combining circling (HSCC lesion) and rolling (utricular lesion). At the chronic stage, they only display circling, because proprioceptive information related to the plane of support substitutes the missing utricular information to control posture in the frontal plane. Circling is also observed following unilateral lesion of the mesencephalic dopaminergic neurons by 6- hydroxydopamine hydrobromide (6-OHDA rats) and systemic injection of apomorphine (APO rats). The resemblance of behavior induced by unilateral vestibular and dopaminergic lesions at the chronic stage can be interpreted in two ways. One hypothesis is that the dopaminergic system exerts three-dimensional control over motricity, as the vestibular system does. If this hypothesis is correct, then a unilateral lesion of the nigro-striatal pathway should induce three-dimensional motor deficits, i.e., circling and at least some sort of barrel rolling at the acute stage of the lesion. Then, compensation could also take place very rapidly based on proprioception, which would explain the prevalence of circling. In addition, barrel rolling should reappear when the rodent is placed in water, as it occurs in UL vertebrates. Alternatively, the dopaminergic network, together with neurons processing the horizontal canal information, could control the homeostasis of posture and locomotion specifically in one and only one plane of space, i.e. the plane related to the basis of support. In that case, barrel rolling should never occur, whether at the acute or chronic stage on firm ground or in water. Moreover, circling should have the same characteristics following both types of lesions. Clearly, 6-OHDA and APO-rats never exhibited barrel rolling at the acute stage. They circled at the acute stage of the lesion and continued to do so three weeks later, including in water. In contrast, UL-rats, exhibited both circling and barrel rolling at the acute stage, and then only circled on the ground. Furthermore, barrel rolling instantaneously reappeared in water in UL rats, which was not the case in 6-OHDA and APO-rats. That is, the lesion of the dopaminergic system on one side did not compromise trim in the pitch and roll planes, even when proprioceptive information related to the basis of support was lacking as in water. Altogether, these results strongly suggest that dopamine does not exert three-dimensional control of the motor system but regulates postural control in one particular plane of space, the one related to the basis of support. In contrast, as previously shown, the vestibular system exerts three-dimensional control on posture. That is, we show here for the first time a relationship between a given neuromodulator and the spatial organization of motor control.

Fig 1. Fluorescent immunostaining of α-tyrosine hydroxylase (TH) in substantia nigra pars compacta (SNC) and ventral tegmentum area (VTA) of two rats injected with 6-OHDA.

(A) Digital photograph illustrating typical TH immunostaining obtained in SNC and VTA of a rat injected on the left side: the place reached by the extremity of the 6-OHDA cannula is shown by an arrow. TH immunostaining is much weaker on the left side than on the right side indicated by letter R (Scale bar: 800 μm). (B), (C) Graphs giving the mean number (in %) of TH-immunostained neurons per SCN (B) and per VTA (C) between injected side and opposite side. The number of TH-immunostained neurons was measured on both sides for each brain coronal sections containing the SNC and/or the VTA and a ratio was calculated. Then for each nucleus, the mean percentage was calculated as the mean of ratios of immunostained neuron number. In both nuclei, neuron number is much lower on the injected side than on the other side.

Fig 2. Methods used to measure locomotor behavior and to model the 3D trajectories of the different part of the skeleton.

(A) Setup used on overground; 3 cameras permit motion capture of the rat on the ground. (B) Setup used to capture motion of the rat in the water; 2 cameras capture the movement of the rat over the water, and 3 cameras capture the movement underwater. (C) Position of the different markers on the skin of the rat. Green for the head, white for the vertebral column, red for the girdles and blue for the distal part of the limbs. (D) The cutaneous markers and their relative positions on the skull. (E) Head of the rat and the different angles analyzed (3D angle, Pitch_H, Yaw_H and Roll_H). (F) Occipital view of the head and localization of the three semicircular canals. (G) Focus on the vestibular region.

Fig 3. 3D head trajectory showing circling and pivoting behaviors overground or in the water.

The position and trajectory of the head recorded in the 3 dimensions of space by a multi- camera system during 11 seconds (200 Hz) overground (A, B, C) or in the water (D, E, F, G). (A) Example trajectory of rat with unilateral degeneration of the whole nigro-neostriatal dopamine (DA) neuron system by intracerebral injection of 6-hydroxy-DA (6-OHDA) overground; The 6-OHDA rats with a lesion on the left side present only anti-clockwise (ipsiversive to the lesion) circling behavior on the ground. The head trajectory is in the horizontal plane, since the control of the head position is supplied by proprioceptive afferents (limbs, vibrisses). (B) Example trajectory of APO rats over ground; a systemic injection of apomorphine (APO) to a 6-OHDA rat results in pivoting behavior toward the opposite side of the lesion (controversive to the lesion). This is due to the activation of the supersensitive DA receptors, which are deprived of their DA afferences. As in 6-OHDA, the trajectory of the head is also in the horizontal plane. (C) Example of trajectory of left hemi-lateral labyrintectomy rats (UL) over ground; the UL rats explore the environment in a clockwise direction (contraversive to the lesion) with their heads inclined slightly on the lesion side. The trajectory of the head is in horizontal and vertical planes. (D) Example of swimming of the control rat (WT). It explored the environment following the edge of the pool. (E) Example trajectory of 6-OHDA in the water; the respiratory constraint causes the rat to swim with the snout in a more upward position compared to the ground. The sense of rotation and the diameter of the circle are the same as in over ground. The trajectory of the head is slightly in the horizontal plane (F) Example trajectory of APO rats in water. As in over ground, the systemic injection of apomorphine (APO) results in pivoting behavior toward the opposite side of the lesion. The diameter of the trajectory is tighter than 6-OHDA in the water or APO over ground. As in 6-OHDA, the trajectory of the head is in the horizontal plane. (G) Example trajectory of hemi-lateral labyrintectomy rats (UL) in water; the anti-clockwise rolling movements (red arrows) were immediately triggered when the individual attempted to swim. The head position varies highly among the three directions of space. Scale units are in meters. Arrows indicate the direction of the movement.

Fig 4. Skeletal geometry in 6-OHDA rat during circling and in APO rat during pivoting over ground and in water.

Examples reconstructed from films captured at 200 Hz by a multi-cameras system. (A, B) Trajectories of the head and the extremities of the four limbs according to the earth horizontal plane (x,y) during the totality of the sequence of recording (11 s) on the ground. (A) The 6-OHDA rat turns in an anticlockwise direction (ipsiversive side to the lesion). The head describes concentric circles and the snout and the vibrissae are in contact with the surface. Limb data are incomplete because landmarks are often hidden by the body of the rat. However, the hindlimb ipsilateral to the lesion is used as a pivot by the rat during its rotation, and the position of the others footfalls are inside the head trajectory. (B) All the trajectories of the head of the APO rat (the same shows in A after APO injection) are superimposed, and turn in clockwise direction (contraversive side to the lesion). The hind limb ipsilateral to the lesion is used as a pivot, as in the 6-OHDA, but the other limb shows a backward movement inducing the change of the direction of pivoting. The position of the footfalls of the other limbs do not change, and are also inside the trajectories of the head. (C, D) Trajectories of the head and the extremities of the four limbs in the water according to the water surface (x,y) during only one revolution (2.25 s) to facilitate the data visualization. The position of the head in 6-OHDA and APO rat is very horizontal and the snout stays at the limit between the water and the air so that the rat can breathe. (C) The 6-OHDA rat turns as overground, in an anticlockwise direction (ipsiversive side to the lesion). The trajectories of the limbs ipsilateral to the lesion are inside or close to the trajectories of the head. The introduction of a lateral component is characterized by trajectories of the limbs contralateral to the lesion outside of the head trajectories. (D) The APO rat turns as in over ground in a clockwise direction (contraversive side to the lesion). The forelimbs move out of phase, with a stronger lateral component for the forelimb ipsilateral to the lesion. The hindlimbs present alternate movements, the trajectory of the hindlimb contralateral to the lesion is close to the center of rotation, while the hindlimb ipsilateral to the lesion exhibits the larger lateral trajectory. All of these characteristics induce a faster and tighter rotation of the APO rat in comparison with the 6-OHDA rat. HEAD; marker on the snout. RF; Right forelimb. RH; Right hindlimb. LF; Left forelimb. RH; Right hindlimb. Scale units are in meters. Arrows indicate the direction of the movement. The different axis have the same scale in meter.