Spinal Control of Locomotion: Individual Neurons, Their Circuits and Functions

Abstract

Systematic research on the physiological and anatomical characteristics of spinal cord interneurons along with their functional output has evolved for more than one century. Despite significant progress in our understanding of these networks and their role in generating and modulating movement, it has remained a challenge to elucidate the properties of the locomotor rhythm across species. Neurophysiological experimental evidence indicates similarities in the function of interneurons mediating afferent information regarding muscle stretch and loading, being affected by motor axon collaterals and those mediating presynaptic inhibition in animals and humans when their function is assessed at rest. However, significantly different muscle activation profiles are observed during locomotion across species. This difference may potentially be driven by a modified distribution of muscle afferents at multiple segmental levels in humans, resulting in an altered interaction between different classes of spinal interneurons. Further, different classes of spinal interneurons are likely activated or silent to some extent simultaneously in all species. Regardless of these limitations, continuous efforts on the function of spinal interneuronal circuits during mammalian locomotion will assist in delineating the neural mechanisms underlying locomotor control, and help develop novel targeted rehabilitation strategies in cases of impaired bipedal gait in humans. These rehabilitation strategies will include activity-based therapies and targeted neuromodulation of spinal interneuronal circuits via repetitive stimulation delivered to the brain and/or spinal cord.

Keywords: interneurons; locomotion; motoneurons; spinal neural circuits; spinal reflexes.

FIGURE 1

Spinal interneuronal circuits. Wiring diagram reflecting the connections of the monosynaptic Ia excitation, polysynaptic group II excitation, reciprocal Ia, RCs, and Ib inhibitory interneurons in humans. Soleus (SOL) group Ia afferents have monosynaptic excitatory projections to homonymous motoneurons and activate Ia inhibitory interneurons (IaINs) that inhibit tibialis anterior (TA) motoneurons. IaINs affected by SOL Ia afferents are inhibited by RCs activated by recurrent collaterals from SOL motor axons. Extensor-coupled IaINs inhibit contralateral flexor-coupled IaINs, and vice versa. The Ib inhibitory pathway from medial gastrocnemius (MG) to SOL motoneurons is also depicted along with presynaptic inhibitory interneurons acting on group Ia and II afferent terminals. The function of this complex spinal interneuronal circuitry is detrimental to motor output and behavior. Note that neurons within the gray matter of the spinal cord are not indicated per their laminae anatomical position due to illustration constrains.

FIGURE 2

Commissural interneurons of the spinal cord. (A) Projections and terminations of short- and long range commissural interneurons (CINs). (B) CINs play an important role in the control of locomotion by projections to Renshaw cells, Ia inhibitory interneurons and other classes of inhibitory interneurons, and by direct monosynaptic excitation and inhibition to motoneurons. Adapted and modified from Quinlan and Kiehn (2007) and Chédotal (2014).

FIGURE 3

Long propriospinal interneurons (PINs) reciprocally connect the cervical and lumbar spinal cord and contribute to locomotor movement in rodents. (A) Descending PINs form a complex bilateral system with excitatory and inhibitory components to mediate interlimb coordination and to relate information to the CPG. Their cell body is located through all laminae of the cervical cord, but most originate from laminae VII-VIII and the deep dorsal horn. They project to non-motoneuronal elements in similar proportion to the ipsilateral and contralateral rostral lumbar cord through the ventrolateral funiculus (red). The ipsilateral population terminals are evenly distributed throughout the gray matter, whereas the projections of the contralateral population are concentrated in laminae VII-VIII. The vast majority of descending PINs are excitatory both on the ipsilateral or contralateral side but the small inhibitory population terminates ipsilaterally. (B) Ascending PINs form a powerful ipsilateral excitatory pathway from the rostral lumbar cord to motoneurons controlling proximal muscles of the forelimbs. Ascending PINs originate mostly from the intermediate gray in the lumbar spinal cord and preferentially project ipsilaterally with a very limited number of terminals found contralaterally. They project to the intermediate gray matter and the ventral horn throughout the length of the cervical spinal cord. However, a large proportion directly connects to motoneurons in ventrolateral motor nuclei (blue) in caudal cervical segments controlling muscles of the elbow and shoulder. The thickness of the lines represents more PINS. Figure adapted and modified from Flynn et al. (2011) and Brockett et al. (2013).

FIGURE 4

Genetically identified interneurons contributing to locomotion. Schematic of the synaptic connectivity of genetically identified populations of interneurons developing from the ventral spinal cord and involved in (A) intralimb and (B) interlimb coordination during locomotion. Experimentally demonstrated projections are illustrated by a solid line and predicted connectivity with a dashed line. Figure was developed based on Kiehn (2011, 2016) and Gosgnach et al. (2017).

FIGURE 5

Locomotor electromyographic activity in the intact human, monkey, dog, cat, and rat. Duration of leg/hindlimb muscle activity is shown against normalized step cycle that starts at heel or paw contact; shaded areas mark the stance phase duration. Forward walking is shown as a solid black box whilst backward walking is a patterned box. Absent boxes among muscles is due to the lack of available data. Walking muscle activation patterns adopted and modified from Knikou et al. (2009) and La Scaleia et al. (2014) (human EMG); Courtine et al. (2005) (monkey EMG); Deban et al. (2012) and Goslow et al. (1981) (dog EMG); Buford and Smith (1990) and Yakovenko et al. (2002) (cat EMG); Thota et al. (2005) and Courtine et al. (2009) (rat EMG). SOL, soleus; MG, medialis gastrocnemius; LG, lateral gastrocnemius; PL, peroneus longus; TA, tibialis anterior; MH, medial hamstrings; LH, lateral hamstrings; GRC, gracilis; VL, vastus lateral; RF, rectus femoris.