In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor networks. An increased dopaminergic tone is associated with increase in locomotor activity. In pathological conditions where dopamine cells are lost, such as in Parkinson’s disease, locomotor deficits are traditionally associated with the reduced ascending dopaminergic input to the basal ganglia. However, a descending dopaminergic pathway originating from the substantia nigra pars compacta was recently discovered. It innervates the mesencephalic locomotor region (MLR) from basal vertebrates to mammals. This pathway was shown to increase locomotor output in lampreys, and could very well play an important role in mammals. Here, we provide a detailed account on the newly found dopaminergic pathway in lamprey, salamander, rat, monkey, and man. In lampreys and salamanders, dopamine release in the MLR is associated with the activation of reticulospinal neurons that carry the locomotor command to the spinal cord. Dopamine release in the MLR potentiates locomotor output through a D1-receptor mechanism in lampreys. In rats, stimulation of the substantia nigra pars compacta elicited dopamine release in the pedunculopontine nucleus, a known part of the MLR. In a monkey model of Parkinson’s disease, a reduced dopaminergic innervation of the brainstem locomotor networks was reported. Dopaminergic fibers are also present in human pedunculopontine nucleus. We discuss the conserved locomotor role of this pathway from lamprey to mammals, and the hypothesis that this pathway could play a role in the locomotor deficits reported in Parkinson’s disease.

Significance: In vertebrates, the contribution of dopamine neurons to locomotor control is traditionally attributed to their ascending projections to the basal ganglia that, in turn, project down to brainstem locomotor networks. We recently discovered in lampreys that brainstem networks receive a direct descending dopaminergic input that increases locomotor output. Here, we show that this descending dopaminergic pathway is conserved in higher vertebrates. We found that dopamine is released in salamander brainstem locomotor networks, together with reticulospinal cell activation, known to trigger locomotion. Dopamine is released in rat brainstem locomotor networks, and amphetamine potentiates dopamine release in vivo. Finally, brainstem locomotor networks in human tissue contain dopaminergic terminals. Our findings have important implications for understanding the locomotor role of dopamine in vertebrates.

Locomotion requires the proper sequencing of neural activity to start, maintain, and stop it. Recently, brainstem neurons were shown to specifically stop locomotion in mammals. However, the cellular properties of these neurons and their activity during locomotion are still unknown. Here, we took advantage of the lamprey model to characterize the activity of a cell population that we now show to be involved in stopping locomotion. We find that these neurons display a burst of spikes that coincides with the end of swimming activity. Their pharmacological activation ends ongoing swimming, whereas the inactivation of these neurons dramatically impairs the rapid termination of swimming. These neurons are henceforth referred to as stop cells, because they play a crucial role in the termination of locomotion. Our findings contribute to the fundamental understanding of motor control and provide important details about the cellular mechanisms involved in locomotor termination.

Significance: We found in lampreys that dopaminergic cells from the posterior tuberculum (homologue of the mammalian substantia nigra pars compacta and/or ventral tegmental area) not only send ascending projections to the striatum, but also have a direct descending projection to a brainstem region controlling locomotion—the mesencephalic locomotor region—where it releases dopamine (DA). DA increased locomotor output through a D1 receptor-dependent mechanism. The presence of this descending dopaminergic projection may have considerable implication for our understanding of the role of DA in motor control under physiological and pathological (i.e. Parkinson disease) conditions.

The mesencephalic locomotor region (MLR) is a brain stem area whose stimulation triggers graded forward locomotion. How MLR neurons recruit downstream vsx2⁺ (V2a) reticulospinal neurons (RSNs) is poorly understood. Here, to overcome this challenge, we uncovered the locus of MLR in transparent larval zebrafish and show that the MLR locus is distinct from the nucleus of the medial longitudinal fasciculus. MLR stimulations reliably elicit forward locomotion of controlled duration and frequency. MLR neurons recruit V2a RSNs via projections onto somata in pontine and retropontine areas, and onto dendrites in the medulla. High-speed volumetric imaging of neuronal activity reveals that strongly MLR-coupled RSNs are active for steering or forward swimming, whereas weakly MLR-coupled medullary RSNs encode the duration and frequency of the forward component. Our study demonstrates how MLR neurons recruit specific V2a RSNs to control the kinematics of forward locomotion and suggests conservation of the motor functions of V2a RSNs across vertebrates.