Measured motion: searching for simplicity in spinal locomotor networks

Abstract

Spinal interneurons are organized into networks that control the activity and output of the motor system. This review outlines recent progress in defining the rules that govern the assembly and function of spinal motor networks, focusing on three main areas. We first examine how subtle variations in the wiring diagrams and organization of locomotor networks in different vertebrates permits animals to adapt their motor programs to the demands of their physical environment. We discuss how the membrane properties of spinal interneurons, and their synaptic interactions, underlie the modulation of motor circuits and encoded motor behaviors. We also describe recent molecular genetic approaches to map and manipulate the connectivity and interactions of spinal interneurons and to assess the impact of such perturbations on network function and motor behavior.

Figure 1. Amphibian metamorphosis is accompanied by a change in spinal locomotor pattern

(A) Tail-based swimming in pre-metamorphic (stage 64) froglets. By this time, the tail has been resorbed and swimming is now produced by slower, bilaterally-synchronous cycles of hindlimb extension and flexion (upper panel). The isolated spinal cord/brain stem generates a fictive locomotor pattern in which left and right limb extensor motoneurons produce coincident bursts that alternate with bursts in left and right hindlimb flexor motoneurons. Adapted from ref. 16.

Figure 2. A model for the diversification of spinal motor neuron subtypes during vertebrate evolution

Lower branch. Inductive signaling along the dorsoventral axis of the neural tube involves the graded actions of sonic hedgehog (Shh) and Wnt proteins (not shown) secreted by the floor plate and adjacent ventral cells, and the patterned expression of homeodomain (HD) proteins by ventral progenitor cells and post-mitotic neurons. This dorso-ventral patterning pathway recruits expression of the LIM homeodomain proteins Lhx3 and Lhx4 by newly generated motor neurons, assigning a median motor column (MMC) – like identity. In primitive ancestral vertebrates such as the lamprey and hagfish the dominance of this inductive pathway confers all motor neurons with a MMC fate, providing the neural substrate for undulatory locomotor behaviors. Upper branch. Over the course of ∼500 million years of evolution, rostro-caudal inductive signals mediated by retinoids (RA) and fibroblast growth factors (FGF) establish the patterned expression of Hox homeodomain proteins in motor neuron progenitors and post-mitotic motor neurons. The engagement of Hox transcription factors, and an essential Hox accessory factor, FoxP1, drives motor neuron columnar and pool diversification, resulting in the formation of lateral motor column (LMC) neurons and their resident motor pools. This diversification process permits the spinal motor system to innervate the more complex set of peripheral motor targets that characterizes higher vertebrates and underlies intricate tetrapod gait patterns. The key intermediate step in this diversification process is presumed to involve the attenuation of non-canonical Wnt signaling, permitting the generation of motor neurons that lack Lhx3 and Lhx4 expression and progress to a hypaxial motor columnar (HMC) fate (not shown). This ground-state HMC-like column provides the neuronal substrate for the actions of the Hox/FoxP1 transcriptional program. For details, see text and ref 26.

Fig. 3. Locomotor network of the lamprey

Diagrams show schematic representation of the brainstem and spinal components of the neural circuitry that generates rhythmic locomotor activity. A. All neuron symbols denote populations rather than single cells. Descending commands exerted through glutamatergic neurons excite all classes of spinal interneurons and motoneurons. The excitatory interneurons (E) excite all types of spinal neurons, i.e. the inhibitory glycinergic interneurons (I) that cross the midline to inhibit all neuron types on the contralateral side and motoneurons (M). Stretch receptor neurons are of two types; one excitatory (SR-E), which excites ipsilateral neurons and one inhibitory (SR-I), which crosses the midline to inhibit contralateral neurons and provide sensory feedback during actual swimming. In addition, metabotropic receptors are activated during locomotion and are an integral part of the network as indicated in the box below the network (5-HT, dopamine (DA), GABA, tachykinins (TK) and mGluRs). B. Cellular mechanisms contributing to burst termination. During a burst, Ca²⁺ ions entering via NMDA and voltage-dependent channels activate Ca-activated K+ channels (K_Ca) that will have a hyperpolarising effect with different time courses (fast (f) and slow (s)). Similarly the entry of Na⁺ ions (Na) during the burst will activate sodium-dependent K+ channels (K_Na). Voltage-dependent K+ channels activated during the action potential are grouped and indicated as (K_D).

Figure 4. Molecular programs of interneuron diversity in the ventral spinal cord

A. The position of origin of motor neurons (MN) and the four cardinal interneuron populations V0-V3) in the ventral spinal cord. B. Representative examples of interneuron classes derived from distinct ventral progenitor domains. Many of these interneuron subtypes can be distinguished by post-mitotic transcription factor expression, axonal trajectories and transmitter phenotype. C. Schematic diagram depicting proposed circuitry of distinct ventral interneuron classes, defined by transcriptional identity and physiological properties. Although many details of the link between molecular identity, network organization and physiological properties remain unclear, emerging evidence supports the view that molecular determinants of neuronal identity contribute to the assembly of spinal interneuron networks. For details, and references, see text.

Figure 5. Regulation of cellular and locomotor network properties by endogenous neuromodulators

In this schematic diagram, upward red arrow indicates enhanced activity, and downward blue arrow a reduction or depression in activity. Diverse modulatory effects include regulation of burst frequency, NMDA receptor dependent synaptic transmission, spike frequency adaptation, post-inhibitory rebound and phase-dependent presynaptic inhibition.