Connie Chau

Noradrenergic agonists and locomotor training affect locomotor recovery after cord transection in adult cats

In one series of experiments, the effects of noradrenergic, serotonergic, and dopaminergic precursors and agonists on the initiation of locomotion were investigated within the first week after complete spinalization at +13 in five adult cats. In addition, the effects of clonidine and daily locomotor training were investigated during the first week after transection in another cat. The electromyographic (EMG) activity of vastus lateralis (VL) and semitendinosus (St) was recorded bilaterally through percutaneously implanted copper wires in all cats. The movement of the hindlimbs on the treadmill was also simultaneously videorecorded before and after the injection of drugs. Without drug injection, strong and sustained perineal or abdominal stimulation did not induce any prolonged episodes of coordinated stepping on the treadmill during the first week after spinalization. St often had sustained activity, in contrast to VL, in which minimal or no activity was present. Injection of apomorphine (0.3 to 0.5 mg/kg, n = 3), a dopaminergic agonist, or DL-5-HTP (50 mg/kg, n = 2), a serotonergic precursor, failed to induce locomotion at such an early stage after spinalization. In contrast, injection of either L-dopa (50-60 mg/kg, n = 2), a noradrenergic precursor, or clonidine (150 micrograms/kg, n = 2), a noradrenergic agonist, induced locomotion on the treadmill. The animal demonstrated bilateral foot placement on the soles and complete weight support of the hindquarters. The spinal cat could follow the treadmill speed up to 0.80 ms-1. However, these effects disappeared when the NA drugs were tapered off.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological aids to locomotor training after spinal injury in the cat

This Topical Review summarizes some of the work we have done mainly in the cat using agonists and antagonists of various neurotransmitter systems injected intravenously or intrathecally to initiate or modulate the expression of hindlimb locomotion after a spinal lesion at T13. The effects of the same drugs are compared in various preparations: complete spinal, partial spinal or intact cats. This has revealed that there can be major differences in these effects. In turn, this suggests that although the locomotor rhythm might normally be triggered and modulated by the activation of a variety of receptors (noradrenaline, serotonin, glutamate), after spinalization there appears to be a predominance of glutamatergic mechanisms. Recent work also suggests that, in the cat, the integrity of the midlumbar segments is crucial for the expression of spinal locomotion. Taken together, this work raises some hope that a targeted pharmacotherapy with better understood drugs and mode and locus of delivery could become a clinical reality.

Pharmacological Activation and Modulation of the Central Pattern Generator for Locomotion in the Cata

Abstract: Pharmacological agents have been shown to be capable of inducing a pattern of rhythmic activity recorded in muscle nerves or motoneurons of paralyzed spinal cats that closely resembles the locomotor pattern seen in intact cats. Further work, using intraperitoneal or intrathecal injections, suggests that different neurotransmitters may be involved in various aspects of locomotor control, e.g., initiation and modulation of the pattern. Although precursors, agonists or the neurotransmitters themselves of several systems have been investigated (noradrenergic, dopaminergic, serotonergic, glutamatergic), the noradrenergic system seems the most efficient in triggering locomotion in complete spinal cats, with the α‐2 agonists (clonidine, tizanidine, oxymetazoline) being more potent than the α‐1 agonist, methoxamine. Moreover, the potency of the drugs may depend on the time of application after the spinal lesion. In chronic spinal cats capable of spontaneous walking on hindlimbs on the treadmill, all neurotransmitters appear to exert distinct recognizable effects on the locomotor pattern. More recent work also suggests that the effects of drugs may differ significantly depending on the type of spinal lesion. For instance, clonidine further reduces the level of weight support during quadrupedal locomotion of cats with lesions of the ventral‐ventrolateral funiculi, possibly due to an interference of clonidine with essential compensatory mechanisms used by these animals to walk. Such considerations as the type of drugs, type of lesions, and the time after the lesion will be important for future studies in spinal cord injured patients.

Determinants of locomotor recovery after spinal injury in the cat

After a spinalization at the most caudal thoracic spinal segment, the cat can recover locomotion of the hindlimbs when they are placed on a moving treadmill. This chapter summarizes some of the determinants of such a dramatic recovery of motor function. Fundamental to this recovery is undoubtedly the genetically based spinal locomotor generator, which provides an essential rhythmicity to spinal motoneurons and hence the musculature. Other factors are also important, however. Sensory feedback is essential for the correct expression of spinal locomotion because spinal cats, devoid of cutaneous feedback from the hindfeet, are incapable of plantar foot placement. The neurochemical environment also adapts to spinalization, i.e., the loss of all modulation by descending monoaminergic pathways. Post-transection spinal rhythmicity then becomes more dependent on glutamatergic mechanisms. Finally, we argue that the mid-lumbar spinal segments evolve to play a crucial role in the elaboration of spinal locomotion as their inactivation abolishes spinal locomotion. In summary, the above findings suggest that the recovery of spinal locomotion is determined by a number of factors, each of which must now be more fully understood in the ever-continuing effort to improve the rehabilitation of spinal-cord-injured subjects.

The Spinal Cat

A number of reviews have summarized important insights on the role played by various nervous system structures in the control of locomotion (1–8). These reviews have also highlighted the remarkable locomotor capacities of the spinal cord after a complete spinal transection, which removes all the ascending and descending pathways normally exerting important control over spinal cord functions. The purpose of this chapter is to focus specifically on the locomotor capabilities of the spinal cat, not so much to show that “spinal” locomotion resembles “normal” locomotion but rather to illustrate the extent to which the spinal cord can express and adapt its locomotor functions in the absence of these regulatory mechanisms. Does this spinal behavior represent the contribution of the spinal cord to normal locomotion? Probably not, because in all pathologic conditions, the central nervous system utilizes whatever circuitry is available to optimize its functions. It is possible that some mechanisms are less important in the normal cat but become essential for locomotion after spinalization, such as some sensory afferents. Thus, a better understanding of the “physiopathology” of locomotion after spinal cord injury in animal models is important both in highlighting some of the principles that may help understand normal locomotion and in increasing our understanding of some of the mechanisms of recovery of a motor function following a spinal trauma. Such knowledge is important for improving the design of various types of therapeutic approaches in spinal-cord-injured patients (9,10).

Chapter 12 The cat model of spinal injury

Publisher Summary This chapter discusses the changes occurring in the spinal cord that may lead to the re-expression of motor patterns such as hind-limb locomotion. The chapter reviews some aspects of locomotor training with and without the use of drugs, the evolution of pharmacological receptors below the level of lesion. It also discusses the role of various neurotransmitter systems before and after spinalization, the key role played by certain rostral lumbar segments of the spinal cord in the generation of locomotion, and the necessity of cutaneous inputs from the pads for the expression of spinal locomotion. The chapter discusses the recovery of locomotion in adult spinal cats is probably the result of numerous plastic changes occurring at the level of the sensory afferents, cellular properties of neurons and receptors for neurotransmitters. The spinal cord is a complex laminar and segmental structure.

Chapter 16--spinal plasticity in the recovery of locomotion.

Locomotion is a very robust motor pattern which can be optimized after different types of lesions to the central and/or peripheral nervous system. This implies that several plastic mechanisms are at play to re-express locomotion after such lesions. Here, we review some of the key observations that helped identify some of these plastic mechanisms. At the core of this plasticity is the existence of a spinal central pattern generator (CPG) which is responsible for hindlimb locomotion as observed after a complete spinal cord section. However, normally, the CPG pattern is adapted by sensory inputs to take the environment into account and by supraspinal inputs in the context of goal-directed locomotion. We therefore also review some of the sensory and supraspinal mechanisms involved in the recovery of locomotion after partial spinal injury. We particularly stress a recent development using a dual spinal lesion paradigm in which a first partial spinal lesion is made which is then followed, some weeks later, by a complete spinalization. The results show that the spinal cord below the spinalization has been changed by the initial partial lesion suggesting that, in the recovery of locomotion after partial spinal lesion, plastic mechanisms within the spinal cord itself are very important.

Pharmacology of Locomotion in Chronic Spinal Cats

This short review will summarize some of the work we and others have performed in the field of pharmacology of locomotion in cats and indicate the potential benefits of such an approach in clinical situations where we believe that a rational locomotor pharmacotherapy can be developed.