Recovery of locomotor activity in the adult chronic spinal rat after sublesional transplantation of embryonic nervous cells: specific role of serotonergic neurons

Feraboli-Lohnherr, Delphine; Orsal, D.; Yakovleff, A; Ribotta, Minerva Giménez y; Privat, Alain

doi:10.1007/pl00005597

Cited by 107 publications

(66 citation statements)

References 47 publications

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“…We observed that quipazine enabled hindlimb bipedal stepping in complete spinal mice, an observation consistent with findings reported by Guertin (2004). Quipazine and another serotonin agonist, m-chloropiperazine, have been shown to facilitate locomotion in cats (Barbeau and Rossignol, 1990) and rats (Kim et al, 2001), respectively, and similar improvement was reported when serotonergic embryonic raphe cells were implanted in spinal rats (Feraboli-Lohnherr et al, 1997;Kim et al, 1999;Dumoulin et al, 2000;Ribotta et al, 2000). The mechanism by which serotonin mediates locomotor improvement after SCI is not well understood.…”

Section: Discussionsupporting

confidence: 89%

Spinal Cord-Transected Mice Learn to Step in Response to Quipazine Treatment and Robotic Training

Fong¹,

Cai²,

Otoshi³

et al. 2005

J. Neurosci.

130

126

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In the present study, concurrent treatment with robotic step training and a serotonin agonist, quipazine, generated significant recovery of locomotor function in complete spinal cord-transected mice (T7-T9) that otherwise could not step. The extent of recovery achieved when these treatments were combined exceeded that obtained when either treatment was applied independently. We quantitatively analyzed the stepping characteristics of spinal mice after alternatively administering no training, manual training, robotic training, quipazine treatment, or a combination of robotic training with quipazine treatment, to examine the mechanisms by which training and quipazine treatment promote functional recovery. Using fast Fourier transform and principal components analysis, significant improvements in the step rhythm, step shape consistency, and number of weight-bearing steps were observed in robotically trained compared with manually trained or nontrained mice. In contrast, manual training had no effect on stepping performance, yielding no improvement compared with nontrained mice. Daily bolus quipazine treatment acutely improved the step shape consistency and number of steps executed by both robotically trained and nontrained mice, but these improvements did not persist after quipazine was withdrawn. At the dosage used (0.5 mg/kg body weight), quipazine appeared to facilitate, rather than directly generate, stepping, by enabling the spinal cord neural circuitry to process specific patterns of sensory information associated with weight-bearing stepping. Via this mechanism, quipazine treatment enhanced kinematically appropriate robotic training. When administered intermittently during an extended period of robotic training, quipazine revealed training-induced stepping improvements that were masked in the absence of the pharmacological treatment.

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Section: Discussionsupporting

confidence: 89%

Spinal Cord-Transected Mice Learn to Step in Response to Quipazine Treatment and Robotic Training

Fong¹,

Cai²,

Otoshi³

et al. 2005

J. Neurosci.

130

126

View full text Add to dashboard Cite

show abstract

“…Interestingly, overdose of SSRI in non-SCI patients has been linked to the development of serotonin syndrome, in which hypertonus of lower limbs is often a symptom (Whipp and Waterfield, 2004). In contrast to these negative effects, administration of SSRI in transected animals transplanted with embryonic serotonergic cells improved locomotor recovery (Feraboli-Lohnherr, et al, 1997). Similar studies in contusive SCI models have not yet been reported, but both beneficial as well as detrimental effects of SSRI may be expected depending on the SCI severity and the time of SSRI administration.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of 5-HT2 receptors is involved in the increased H-reflex amplitude after contusive spinal cord injury

Lee

Johnson

Wrathall

2007

Experimental Neurology

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The amplitude of the H-reflex increases chronically after incomplete SCI and is associated with the development of exaggerated hindlimb reflexes. Although the mechanism for this increased H-reflex is not clear, previous studies have shown that pharmacological activation of the 5-HT 2 receptors (5-HT 2 R) can potentiate the monosynaptic reflex. This study tested the hypothesis that increased expression of 5-HT 2 R on motoneurons is involved in increased H-reflex amplitude after a standardized clinically-relevant contusive SCI. Adult female rats were subjected to contusion, complete surgical transection, or a T8 laminectomy only. At 4wks after surgery, H-reflex recordings from the hindpaw plantar muscles of contused rats showed twice the amplitude of that in laminectomy controls or transected rats. To probe the role of 5-HT 2 R in this increased amplitude, dose response studies were done with the selective antagonists, mianserin or LY53857, and the 5-HT 2 R agonist, (±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI). The drugs were intrathecally infused into the lumbar cord while recording the H-reflex. Mianserin did not have any significant effects on the H-reflex after transection, consistent with the loss of distal serotonergic innervation. After contusion, both 5-HT 2 R antagonists reduced the H-reflex reflex amplitude with a significantly higher ID 50 compared to the uninjured controls. The 5-HT 2 R agonist, DOI, significantly increased reflex amplitude in contused but not control rats. Furthermore, while 5-HT immunoreactivity was similar, contused rats displayed increased 5-HT 2A R immunoreactivity in plantar muscle motoneurons compared to uninjured controls. We conclude that increased expression of 5-HT 2 R is likely to be involved in the enhanced H-reflex that develops after contusive SCI.

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“…These results demonstrate that the improved stepping was a function of the repetitive activation of the sensorimotor pathways that was enabled by quipazine treatment. Further evidence that the serotonergic system can be used to facilitate the recovery of locomotion in complete spinal rats has been demonstrated by Orsal and colleagues (Feraboli-Lohnherr et al, 1997;Ribotta et al, 2000). They transplanted embryonic raphe cells secreting 5-HT in the spinal cord distal (T11) to a complete lesion at T8.…”

Section: Use-dependent Plasticitymentioning

confidence: 97%

Training locomotor networks

Edgerton

Courtine

Gerasimenko

et al. 2008

Brain Research Reviews

277

205

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For a complete adult spinal rat to regain some weight-bearing stepping capability, it appears that a sequence of specific proprioceptive inputs that are similar, but not identical, from step to step must be generated over repetitive step cycles. Furthermore, these cycles must include the activation of specific neural circuits that are intrinsic to the lumbosacral spinal cord segments. For these sensorimotor pathways to be effective in generating stepping, the spinal circuitry must be modulated to an appropriate excitability level. This level of modulation is sustained from supraspinal input in intact, but not spinal, rats. In a series of experiments with complete spinal rats, we have shown that an appropriate level of excitability of the spinal circuitry can be achieved using widely different means. For example, this modulation level can be acquired pharmacologically, via epidural electrical stimulation over specific lumbosacral spinal cord segments, and/or by use-dependent mechanisms such as step or stand training. Evidence as to how each of these treatments can "tune" the spinal circuitry to a "physiological state" that enables it to respond appropriately to proprioceptive input will be presented. We have found that each of these interventions can enable the proprioceptive input to actually control extensive details that define the dynamics of stepping over a range of speeds, loads, and directions. A series of experiments will be described that illustrate sensory control of stepping and standing after a spinal cord injury and the necessity for the "physiological state" of the spinal circuitry to be modulated within a critical window of excitability for this control to be manifested. The present findings have important consequences not only for our understanding of how the motor pattern for stepping is formed, but also for the design of rehabilitation intervention to restore lumbosacral circuit function in humans following a spinal cord injury.

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Recovery of locomotor activity in the adult chronic spinal rat after sublesional transplantation of embryonic nervous cells: specific role of serotonergic neurons

Cited by 107 publications

References 47 publications

Spinal Cord-Transected Mice Learn to Step in Response to Quipazine Treatment and Robotic Training

Spinal Cord-Transected Mice Learn to Step in Response to Quipazine Treatment and Robotic Training

Up-regulation of 5-HT2 receptors is involved in the increased H-reflex amplitude after contusive spinal cord injury

Training locomotor networks

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