Modeling the mammalian locomotor CPG: insights from mistakes and perturbations

Abstract

A computational model of the mammalian spinal cord circuitry incorporating a two-level central pattern generator (CPG) with separate half-center rhythm generator (RG) and pattern formation (PF) networks is reviewed. The model consists of interacting populations of interneurons and motoneurons described in the Hodgkin-Huxley style. Locomotor rhythm generation is based on a combination of intrinsic (persistent sodium current dependent) properties of excitatory RG neurons and reciprocal inhibition between the two half-centers comprising the RG. The two-level architecture of the CPG was suggested from an analysis of deletions (spontaneous omissions of activity) and the effects of afferent stimulation on the locomotor pattern and rhythm observed during fictive locomotion in the cat. The RG controls the activity of the PF network that in turn defines the rhythmic pattern of motoneuron activity. The model produces realistic firing patterns of two antagonist motoneuron populations and generates locomotor oscillations encompassing the range of cycle periods and phase durations observed during cat locomotion. A number of features of the real CPG operation can be reproduced with separate RG and PF networks, which would be difficult if not impossible to demonstrate with a classical single-level CPG. The two-level architecture allows the CPG to maintain the phase of locomotor oscillations and cycle timing during deletions and during sensory stimulation. The model provides a basis for functional identification of spinal interneurons involved in generation and control of the locomotor pattern.

Introduction

Well co-ordinated locomotor activity can be evoked in the mammalian spinal cord in the absence of input from higher brain centers (e.g., in spinalized animals) and rhythmic sensory feedback following neuromuscular blockade, i.e., during fictive locomotion (see Grillner, 1981; Rossignol, 1996; Orlovsky et al., 1999). Such observations have provided evidence for the existence of a central pattern generator (CPG) that generates the locomotor rhythm and pattern of motoneuron activity (Graham Brown, 1914). There appears to be one CPG controlling each limb (see Yamaguchi, 2004; Zehr and Duysens, 2004) since there can be independent rates of left and right stepping in the legs of man (Dietz, 2003; Yang et al., 2004) and in spinal cats (e.g., Forssberg et al., 1980). Cats can also step with independent rates between the fore and hind limbs (Akay et al., 2006). The spinal cord also contains circuitry for inter-limb coordination, since coordinated stepping between the fore and the hind limbs is seen in animals with a spinal transection at upper cervical levels (Miller and van der Meche, 1976) and gaits remain matched and coordinated in the hind limbs of cats spinalized at mid-thoracic levels when walking on a treadmill (Forssberg et al., 1980).

The first conceptual scheme of the mammalian locomotor CPG responsible for alternating rhythmic extensor and flexor activity was based on a half-center concept (Graham Brown, 1914). According to the classical half-center architecture and its elaboration by Lundberg and colleagues (see Lundberg, 1981), the locomotor rhythm and the alternating activation of flexor and extensor motoneurons within a limb are produced by a single network consisting of two populations of excitatory interneurons (called the flexor and extensor half-centers) coupled together by reciprocal inhibitory connections such that activity in one half-center inhibits activity in the other. The interplay between tonic excitation of the two half-centers, a fatigue process reducing half-center activity over time, and the reciprocal inhibition between the half-centers results in rhythmic alternating activation of flexor and extensor motoneurons. The advantages of the half-center CPG organization include its relative simplicity and the strict alternation and coupling of flexor and extensor activities. This simple half-center architecture, however, is unable to account for a number of observations including the variety of motoneuron firing patterns observed during locomotion (e.g., Grillner, 1981; Stein and Smith, 1997).

The objective of the present study was to develop a computational model of the neural circuitry in the spinal cord that could provide predictions about the organization of the locomotor CPG and the interactions between the CPG and reflex circuits. We wished to create a model that could reproduce and provide explanations for a series of observations obtained in decerebrate adult cats during fictive locomotion induced by continuous electrical stimulation of the brainstem midbrain locomotor region (MLR) following neuromuscular blockade. One advantage of this preparation is that locomotor activity occurs without descending cortical influences, rhythmic sensory feedback, or the effects of systemic drug administration. Furthermore, the use of an adult preparation avoids developmental issues associated with an immature central and peripheral nervous system. Importantly, the pattern of motoneuron activities recorded in the decerebrate, immobilized cat during fictive locomotion is similar to that in intact preparations (Rossignol, 1996). Our intention was to develop a model in which a variety of simulations could be directly compared to data obtained during fictive locomotion in our laboratory. The simulations to be discussed were limited to creating locomotor-like activity in “pure” flexor and extensor motoneurons. The complex activity of motoneurons innervating muscles spanning more than one joint (bifunctional) is not considered here.