Neural mechanisms generating locomotion studied in mammalian brain stem‐spinal cord in vitro

Abstract

The neural control system for generation of locomotion is an important system for analysis of neural mechanisms underlying complex motor acts. In these studies, a novel experimental model using neonatal rat brain stem and spinal cord in vitro was developed for investigation of the locomotor system in mammals. The in vitro brain stem and spinal cord system was shown to retain functional circuitry for locomotor command generation, motor pattern generation, and sensorimotor integration. This system was exploited to investigate neurochemical mechanisms involved in neurogenesis of locomotion. Evidence was obtained for peptidergic and gamma-amino-butyric acid-mediated mechanisms in brain-stem circuits generating locomotor commands. Cholinergic, dopaminergic, and excitatory amino acid-mediated mechanisms were shown to activate spinal cord circuits for locomotor pattern generation. Endogenous N-methyl-D-aspartic acid receptors in spinal networks were found to play a central role in the generation of locomotion. The chemically induced patterns of motor activity and rhythmic membrane potential oscillations of spinal motoneurons were characteristic of those during locomotion in other mammals in vivo. The in vitro brain stem and spinal cord model provides a versatile and powerful experimental system with potentially broad application for investigation of diverse aspects of the neurobiology of mammalian motor control systems.

GABAergic inactivation of the central pattern generators for locomotion in isolated neonatal rat spinal cord.

“…With the preparation used here, however, the time course of the action of various uptake inhibitors does not provide any information about their mode of action. This is the case with not only nipecotic acid and guvacine but also with the compound has been found by Smith et al (1988) (Holstege, 1991). Several findings suggest here that GABAA and GABAB receptors may control the motor outflow differently.…”

“…Comparative studies on both invertebrates and vertebrates have demonstrated that the activity of a CPG can be initiated and modulated by various neurotransmitters (Harris-Warrick, 1988). In mammals, it has been observed that various amines, such as noradrenaline (Barbeau & Rossignol, 1991;Pearson & Rossignol, 1991) and serotonin (Barbeau & Rossignol, 1990;Cazalets, Sqalli-Houssaini & Clarac, 1992), as well as excitatory amino acids (EAAs; Kudo & Yamada, 1987;Smith, Feldman & Schmidt, 1988;Cazalets et al 1992) can modify the CPG activity. One feature which is common to all the neurotransmitters that have been found to control the spinal locomotor CPGs is that they all have activatory effects on the CPG, which means that they are able to initiate or enhance the CPG activity.…”

“…Following the pioneering work performed on lower vertebrates (Roberts, Soffe, Clarke & Dale, 1983;Grillner, Wallen, Dale, Brodin, Buchanan & Hill, 1987) (Kudo & Yamada, 1987;Smith et al 1988;Cazalets et al 1992) or by electrically stimulating inputs to the CPG (Smith et al 1988;Atsuta, Garcia-Rill & Skinner, 1990), it has been shown that the neural networks located in the lumbar spinal cord can generate similar locomotor activity to that observed in the intact animal (Cazalets, Menard, Cremieux & Clarac, 1990c). With this preparation it is possible to study the locomotor mechanisms of mammals in the absence of peripheral feedback, and since there is no blood-brain barrier, most of the neurotransmitters and drugs that are added to the saline have access to the neural circuitry.…”

The synaptic drive from the spinal locomotor network to motoneurons in the newborn rat

“…In mammals, it was only quite recently that these substances were found to play a crucial role. The NMDA receptors were described first as activating the locomotor network in the newborn rat (Smith et al, 1988;Kudo et al, 1991;Cazalets et al, 1992), the cat (Douglas et al, 1993), and the rabbit (Fenaux et al, 1991). We further demonstrated that excitatory amino acids also act on the CPG via non-NMDA receptors (Cazalets et al, 1992;Sqalli-Houssaini et al, 1993b).…”

Role of excitatory amino acids in the generation and transmission of respiratory drive in neonatal rat.

“…The minor role of NMDA receptors in the generation of rhy-thmic respiratory drive in the neonatal rat contrasts with its proposed role in. other rhythmic motor systems such as locomotion in the neonatal rat (Smith, Feldman & Schmidt, 1988), lamprey (Grillner, McLellan, Sigvardt, Wallen & Willen, 1981), chick embryo (Barry & O'Donovan, 1987) and Xenopus embryos (Dale & Roberts, 1984). Indeed, due to the voltage-dependent properties of NMDA receptor-mediated currents, these receptors are hypothesized to have an important role in rhythmogenesis (Grillner, Wallen, Dale, Brodin, Buchanan & Hill, 1987).…”