Nathalie Giroux

Autoradiographic study of α1‐ and α2‐noradrenergic and serotonin1A receptors in the spinal cord of normal and chronically transected cats

Serotoninergic and noradrenergic drugs have been shown to initiate and/or modulate locomotion in cats after spinal cord transection and in patients suffering from spinal cord injuries. To establish a firmer basis for locomotor pharmacotherapy, the distribution of α1‐ and α2‐noradrenergic and serotonin1A (5‐HT1A) receptors was examined in the spinal cord of control cats and of from animals with spinal cord transection at T13 some weeks or months previously. In control cats, the highest levels of α1‐noradrenergic receptors, labeled with [3H]prazosin, were found in laminae II, IX, and X. The α2‐noradrenergic receptors, labeled with [3H]idazoxan, were found mainly in laminae II, III, and X, with moderate densities in lamina IX. After spinal transection, both receptors did not change in segments above the lesion. At 15 and 30 days after spinal transection, binding significantly increased in laminae II, III, IV, and X for α2 and in laminae I, II, III, and IX for α1 receptors in lumbar segments. For longer survival times, binding densities returned to near control values. The 5‐HT1A receptors, labeled with [3H]8‐hydroxy‐dipropylaminotetralin, were found mainly in laminae I–IV and X. After spinal transection, binding significantly increased only in laminae II, III, and X of lumbar segments at 15 and 30 days. Thereafter, binding returned to control values. The pronounced upregulation of different monoaminergic receptors observed in the lumbar region in the first month after spinal transection suggests that these receptors may be important during the period when cats normally recover functions such as locomotion of the hindlimbs. J. Comp. Neurol. 406:402–414, 1999.

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.