A Brainstem Neural Substrate for Stopping Locomotion

Abstract

Locomotion occurs sporadically and needs to be started, maintained, and stopped. The neural substrate underlying the activation of locomotion is partly known, but little is known about mechanisms involved in termination of locomotion. Recently, reticulospinal neurons (stop cells) were found to play a crucial role in stopping locomotion in the lamprey: their activation halts ongoing locomotion and their inactivation slows down the termination process. Intracellular recordings of these cells revealed a distinct activity pattern, with a burst of action potentials at the beginning of a locomotor bout and one at the end (termination burst). The termination burst was shown to be time linked to the end of locomotion, but the mechanisms by which it is triggered have remained unknown. We studied this in larval sea lampreys (Petromyzon marinus; the sex of the animals was not taken into account). We found that the mesencephalic locomotor region (MLR), which is known to initiate and control locomotion, stops ongoing locomotion by providing synaptic inputs that trigger the termination burst in stop cells. When locomotion is elicited by MLR stimulation, a second MLR stimulation stops the locomotor bout if it is of lower intensity than the initial stimulation. This occurs for MLR-induced, sensory-evoked, and spontaneous locomotion. Furthermore, we show that glutamatergic and, most likely, monosynaptic projections from the MLR activate stop cells during locomotion. Therefore, activation of the MLR not only initiates locomotion, but can also control the end of a locomotor bout. These results provide new insights onto the neural mechanisms responsible for stopping locomotion.The mesencephalic locomotor region (MLR) is a brainstem region well known to initiate and control locomotion. Since its discovery in cats in the 1960s, the MLR has been identified in all vertebrate species tested from lampreys to humans. We now demonstrate that stimulation of the MLR not only activates locomotion, but can also stop it. This is achieved through a descending glutamatergic signal, most likely monosynaptic, from the MLR to the reticular formation that activates reticulospinal stop cells. Together, our findings have uncovered a neural mechanism for stopping locomotion and bring new insights into the function of the MLR.

Deep imaging in the brainstem reveals functional heterogeneity in V2a neurons controlling locomotion

“…This may be, at first glance, surprising for excitatory neurons because locomotor arrest is most commonly thought to rely on inhibitory descending neurons ( 9 ). Yet, a population of excitatory RS neurons whose activity correlates with, and is causal to, locomotor arrests has recently been characterized by electrophysiological recordings in the brainstem of the lamprey, a primitive representative of the vertebrate phylum easily amenable to cellular recordings ( 39 , 40 ). While the genetic identity of these stop-related RS neurons in the lamprey has yet to be determined, our results argue for a conserved active control of locomotor arrest by excitatory descending neurons across vertebrates.…”

A GABAergic and peptidergic sleep neuron as a locomotion stop neuron with compartmentalized Ca2+ dynamics

“…Hierarchy indicates complexity of the respective brains but implies no phylogenetic relationships. Left: Cells that stop or slow down locomotion when activated, in C. elegans (RIS), D. melanogaster larvae (PDM-DNs posterior dorso-medial brain lobe descending neurons 11 ), X. tropicalis tadpoles (GABAergic MHRs, mid-hindbrain reticulospinal neurons), Tr2 cells 70 in the anterior brain of the leech H. medicinalis , glutamatergic neurons in the MLR (mesencephalic locomotion region) and RS stop cells of the cMRRN (reticulospinal cells of caudal middle rhombencephalic reticular nucleus) of the lamprey P. marinus 10,71 , and several types of mammalian stop cells: V2a reticulospinal interneurons in rostral medulla or caudal pons 8 , GABAergic neurons in the MLR, GABAergic and glycinergic neurons in the gigantocellular nucleus (GiA), and glycinergic neurons in the lateral paragigantocellular nucleus (LPGi) 72 . No stop cells were identified in zebrafish.…”

Current Principles of Motor Control, with Special Reference to Vertebrate Locomotion

“…In the lamprey, a subpopulation of reticulospinal neurons in the caudal part of MRRN are activated with a burst of activity when a locomotor episode stops; therefore, they are called stop cells (196,276). Activation of these cells leads to earlier termination of a locomotor episode, whether locomotion is elicited from MLR or by sensory stimuli.…”