Anatomical study of serotonergic innervation and 5-HT1A receptor in the human spinal cord

Perrin, Florence E.; Gerber, Yannick Nicolas; Teigell, Marisa; Lonjon, Nicolas; Boniface, Guillaume; Bauchet, Luc; Rodrı́guez, José J.; Hugnot, Jean‐Philippe; Privat, Alain

doi:10.1038/cddis.2011.98

Cited by 41 publications

(25 citation statements)

References 36 publications

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“…Serotonin staining in naïve animals identified bilateral fiber bundles adjacent to the lateral horn of the gray matter which descended throughout the length of the spinal cord. This pattern of staining is similar to what has been demonstrated in the published literature [ 46 ]. Double-labeling of naïve mouse spinal cord sections showed these serotonergic fibers stained positive for the neuronal markers neurofilament and MAP2, although neurofilament does not predominantly label these fibers [ 47 ].…”

Section: Resultssupporting

confidence: 90%

Inhibition of NADPH Oxidase Activation in Oligodendrocytes Reduces Cytotoxicity Following Trauma

et al. 2013

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Spinal cord injury is a debilitating neurological disorder that initiates a cascade of cellular events that result in a period of secondary damage that can last for months after the initial trauma. The ensuing outcome of these prolonged cellular perturbations is the induction of neuronal and glial cell death through excitotoxic mechanisms and subsequent free radical production. We have previously shown that astrocytes can directly induce oligodendrocyte death following trauma, but the mechanisms regulating this process within the oligodendrocyte remain unclear. Here we provide evidence demonstrating that astrocytes directly regulate oligodendrocyte death after trauma by inducing activation of NADPH oxidase within oligodendrocytes. Spinal cord injury resulted in a significant increase in oxidative damage which correlated with elevated expression of the gp91 phox subunit of the NADPH oxidase enzyme. Immunohistochemical analysis confirmed the presence of gp91 phox in oligodendrocytes in vitro and at 1 week following spinal cord injury. Exposure of oligodendrocytes to media from injured astrocytes resulted in an increase in oligodendrocyte NADPH oxidase activity. Inhibition of NADPH oxidase activation was sufficient to attenuate oligodendrocyte death in vitro and at 1 week following spinal cord injury, suggesting that excitotoxicity of oligodendrocytes after trauma is dependent on the intrinsic activation of the NADPH oxidase enzyme. Acute administration of the NADPH oxidase inhibitor apocynin and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate channel blocker 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione significantly improved locomotor behavior and preserved descending axon fibers following spinal cord injury. These studies lead to a better understanding of oligodendrocyte death after trauma and identify potential therapeutic targets in disorders involving demyelination and oligodendrocyte death.

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Section: Resultssupporting

confidence: 90%

Inhibition of NADPH Oxidase Activation in Oligodendrocytes Reduces Cytotoxicity Following Trauma

et al. 2013

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“…235,236 Wheel running following an incomplete SCI stimulates serotoninergic fibers regrowth and improves locomotor recovery. 237 In the human spinal cord, serotoninergic processes have been identified within the ventral horn surrounding motoneurons, as well as in the intermediolateral region, 238 similar to what is reported for rodents and non-human primates. The lack of monoamines after SCI is clearly detrimental for locomotor performance and providing exogenous monoamines to improve recovery definitely has potential for success, at least in animal models.…”

Section: From Step-training Dependent Plasticity To Functional Recovesupporting

confidence: 67%

Rehabilitation Strategies after Spinal Cord Injury: Inquiry into the Mechanisms of Success and Failure

Côté

Murray

Lemay

2017

Journal of Neurotrauma

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Body-weight supported locomotor training (BWST) promotes recovery of load-bearing stepping in lower mammals, but its efficacy in individuals with a spinal cord injury (SCI) is limited and highly dependent on injury severity. While animal models with complete spinal transections recover stepping with step-training, motor complete SCI individuals do not, despite similarly intensive training. In this review, we examine the significant differences between humans and animal models that may explain this discrepancy in the results obtained with BWST. We also summarize the known effects of SCI and locomotor training on the muscular, motoneuronal, interneuronal, and supraspinal systems in human and non-human models of SCI and address the potential causes for failure to translate to the clinic. The evidence points to a deficiency in neuronal activation as the mechanism of failure, rather than muscular insufficiency. While motoneuronal and interneuronal systems cannot be directly probed in humans, the changes brought upon by step-training in SCI animal models suggest a beneficial re-organization of the systems' responsiveness to descending and afferent feedback that support locomotor recovery. The literature on partial lesions in humans and animal models clearly demonstrate a greater dependency on supraspinal input to the lumbar cord in humans than in non-human mammals for locomotion. Recent results with epidural stimulation that activates the lumbar interneuronal networks and/or increases the overall excitability of the locomotor centers suggest that these centers are much more dependent on the supraspinal tonic drive in humans. Sensory feedback shapes the locomotor output in animal models but does not appear to be sufficient to drive it in humans.

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“…The 5-HT expressed by these intraspinal neurons was dependent upon the absence of 5-HT fibers as 5-HT from the descending input repressed expression of 5-HT from these intraspinal neurons. In the human spinal cord, Perrin et al ( 2011 ) have mapped 5-HT profiles in the thoracic and lumbar segments, finding a similar neuroanatomical localization to that of rodents and non-human primates where serotonergic processes were identified primarily within the ventral horn surrounding motoneurons as well as also in the intermediolateral region and in the superficial part of the dorsal horn.…”

Section: -Ht and Anatomical Localization Of Its Neural Pathwaysmentioning

confidence: 92%

“…The use of 5-HT receptor agonists in animals after an acute spinal transection has been shown to produce restoration of motoneuron excitability (Harvey et al, 2006 ; Li et al, 2007 ; Musienko et al, 2011 ; Sławińska et al, 2014a ). Work by various researchers have demonstrated that locomotor-activated spinal neurons, which constitute the CPG network, are innervated by serotonergic fibers (Johnson et al, 2002 ; Perrin et al, 2011 ; Sławińska et al, 2014b ) and that 5-HT is released within these sites during locomotor activity (Gerin et al, 2008 ). Together, these results have shown that serotonergic innervation and the availability of 5-HT in the lumbar cord (Antri et al, 2002 ) are critical for the restoration of hind limb motor function following SCI.…”

Section: Alterations In 5-ht Receptor Activity After Scimentioning

confidence: 99%

The role of the serotonergic system in locomotor recovery after spinal cord injury

Ghosh

Pearse

2015

Front. Neural Circuits

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Serotonin (5-HT), a monoamine neurotransmitter synthesized in various populations of brainstem neurons, plays an important role in modulating the activity of spinal networks involved in vertebrate locomotion. Following spinal cord injury (SCI) there is a disruption of descending serotonergic projections to spinal motor areas, which results in a subsequent depletion in 5-HT, the dysregulation of 5-HT transporters as well as the elevated expression, super-sensitivity and/or constitutive auto-activation of specific 5-HT receptors. These changes in the serotonergic system can produce varying degrees of locomotor dysfunction through to paralysis. To date, various approaches targeting the different components of the serotonergic system have been employed to restore limb coordination and improve locomotor function in experimental models of SCI. These strategies have included pharmacological modulation of serotonergic receptors, through the administration of specific 5-HT receptor agonists, or by elevating the 5-HT precursor 5-hydroxytryptophan, which produces a global activation of all classes of 5-HT receptors. Stimulation of these receptors leads to the activation of the locomotor central pattern generator (CPG) below the site of injury to facilitate or improve the quality and frequency of movements, particularly when used in concert with the activation of other monoaminergic systems or coupled with electrical stimulation. Another approach has been to employ cell therapeutics to replace the loss of descending serotonergic input to the CPG, either through transplanted fetal brainstem 5-HT neurons at the site of injury that can supply 5-HT to below the level of the lesion or by other cell types to provide a substrate at the injury site for encouraging serotonergic axon regrowth across the lesion to the caudal spinal cord for restoring locomotion.

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Anatomical study of serotonergic innervation and 5-HT1A receptor in the human spinal cord

Cited by 41 publications

References 36 publications

Inhibition of NADPH Oxidase Activation in Oligodendrocytes Reduces Cytotoxicity Following Trauma

Inhibition of NADPH Oxidase Activation in Oligodendrocytes Reduces Cytotoxicity Following Trauma

Rehabilitation Strategies after Spinal Cord Injury: Inquiry into the Mechanisms of Success and Failure

The role of the serotonergic system in locomotor recovery after spinal cord injury

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