Corticospinal circuit plasticity in motor rehabilitation from spinal cord injury

Serradj, Najet; Agger, Sydney; Hollis, Edmund R.

doi:10.1016/j.neulet.2016.12.003

Cited by 31 publications

(20 citation statements)

References 141 publications

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“…We observed a similar result after cortical stroke, Inpp5k overexpression enhanced sprouting of intact CSNs into the denervated side of the spinal cord without enhancing functional recovery. Without additional stimuli that can guide labile arbors to correct postsynaptic targets, such as rehabilitative training (Wahl et al, 2014; Serradj et al, 2017; Loy et al, 2018; Torres-Espin et al, 2018; Loy and Bareyre, 2019), it is not surprising that significant functional recovery is not observed after monogenic intervention.…”

Section: Discussionmentioning

confidence: 99%

Inositol Polyphosphate-5-phosphatase K (Inpp5k) enhances sprouting of corticospinal tract axons after CNS trauma

Kauer

Fink

et al. 2021

Preprint

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Failure of CNS neurons to mount a significant intrinsic growth response after trauma results in chronic functional deficits after spinal cord injury. Approaches to identify novel axon growth activators include transcriptional and repressor screening of embryonic cortical and retinal ganglion neurons in vitro. These high throughput approaches have identified several candidates; however, their inability to comprehensively model the adult CNS has resulted in their exploitation in vivo failing to stimulate significant anatomical and functional gains. To identify novel cell autonomous axon growth activators while maintaining CNS complexity, we screened intact adult corticospinal neurons (CSNs) undergoing functional plasticity after unilateral pyramidotomy. RNA-seq of intact sprouting corticospinal tract (CST) axons showed an enrichment of genes in the 3-phosphoinositide degradation pathways, including six 5-phosphatases. We explored whether Inositol Polyphosphate-5-phosphatase K (Inpp5k) could enhance CST axon growth in clinical models of CNS trauma. Overexpression of Inpp5k in intact adult CSNs enhanced sprouting of intact CST terminals into the denervated cervical cord after pyramidotomy and cortical stroke lesion. Inpp5k overexpression also stimulated sprouting of CST axons in the cervical cord after acute and chronic severe thoracic spinal contusion. We show that Inpp5k stimulates axon growth by elevating the density of active cofilin in the cytosol of labile growth cones, thus stimulating actin polymerization and enhancing microtubule protrusion into distal filopodia. This study identifies Inpp5k as a novel CST growth activator and underscores the veracity of using in vivo transcriptional screening to identify the next generation of cell autonomous factors capable of repairing the damaged CNS.

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Section: Discussionmentioning

confidence: 99%

Inositol Polyphosphate-5-phosphatase K (Inpp5k) enhances sprouting of corticospinal tract axons after CNS trauma

Kauer

Fink

et al. 2021

Preprint

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“…Rehabilitation programs such as physical therapy and occupational therapy are established treatment strategies for SCI patients [40, 41], that have been reported to be effective even for complete SCI patients [42]. Physiological exercise after SCI is reported to activate the reorganization of neuronal network in the distal part of the lesion [43], with passive locomotive training even inducing recovery of motor function in cats with complete SCI [44]. The effects of electrical stimulation are believed to induce functional recovery after SCI through a similar process [45], but the mechanisms underlying the restorative effect of rehabilitation for SCI remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Pathological changes of distal motor neurons after complete spinal cord injury

et al. 2019

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Traumatic spinal cord injury (SCI) causes serious disruption of neuronal circuits that leads to motor functional deficits. Regeneration of disrupted circuits back to their original target is necessary for the restoration of function after SCI, but the pathophysiological condition of the caudal spinal cord has not been sufficiently studied. Here we investigated the histological and biological changes in the distal part of the injured spinal cord, using a mice model of complete thoracic SCI in the chronic stage (3 months after injury). Atrophic changes were widely observed in the injured spinal cord both rostral and caudal to the lesion, but the decrease in area was mainly in the white matter in the rostral spinal cord while both the white and gray matter decreased in the caudal spinal cord. The number of the motor neurons was maintained in the chronic phase of injury, but the number of presynaptic boutons decreased in the lumbar motor neurons caudal to the lesion. Using laser microdissection, to investigate gene expressions in motor neurons caudal to the lesion, we observed a decrease in the expressions of neuronal activity markers. However, we found that the synaptogenic potential of postsynapse molecules was maintained in the motor neurons after SCI with the expression of acetylcholine-related molecules actually higher after SCI. Collectively, our results show that the potential of synaptogenesis is maintained in the motor neurons caudal to the lesion, even though presynaptic input is decreased. Although researches into SCI concentrate their effort on the lesion epicenter, our findings suggest that the area caudal to the lesion could be an original therapeutic target for the chronically injured spinal cord.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0422-3) contains supplementary material, which is available to authorized users.

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“…It is important to note that locomotion, especially after SCI, involves sensorimotor networks above and below the lesion (Giszter et al, 2010; Shah et al, 2013). Several studies have shown that cortical reorganization supports recovery following SCI (Manohar et al, 2017; Serradj et al, 2016; Moxon et al, 2014; Foffani et al, 2016; Xerri et al, 2012; van den Brand et al, 2012; Kao et al, 2009; Giszter et al, 2008). For example, Moxon et al 2013 showed that the state of somatosensory cortical networks following neonatal SCI plays a major role in locomotor output induced by the 5-HT 2 R agonist mCPP.…”

Section: Discussionmentioning

confidence: 99%

Serotonin receptor and dendritic plasticity in the spinal cord mediated by chronic serotonergic pharmacotherapy combined with exercise following complete SCI in the adult rat

Ganzer

Beringer

Shumsky

et al. 2018

Experimental Neurology

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Severe spinal cord injury (SCI) damages descending motor and serotonin (5-HT) fiber projections leading to paralysis and serotonin depletion. 5-HT receptors (5-HTRs) subsequently upregulate following 5-HT fiber degeneration, and dendritic density decreases indicative of atrophy. 5-HT pharmacotherapy or exercise can improve locomotor behavior after SCI. One might expect that 5-HT pharmacotherapy acts on upregulated spinal 5-HTRs to enhance function, and that exercise alone can influence dendritic atrophy. In the current study, we assessed locomotor recovery and spinal proteins influenced by SCI and therapy. 5-HT, 5-HTR, 5-HTR, and dendritic densities were quantified both early (1 week) and late (9 weeks) after SCI, and also following therapeutic interventions (5-HT pharmacotherapy, bike therapy, or a combination). Interestingly, chronic 5-HT pharmacotherapy largely normalized spinal 5-HTR upregulation following injury. Improvement in locomotor behavior was not correlated to 5-HTR density. These results support the hypothesis that chronic 5-HT pharmacotherapy can mediate recovery following SCI, despite acting on largely normal spinal 5-HTR levels. We next assessed spinal dendritic plasticity and its potential role in locomotor recovery. Single therapies did not normalize the loss of dendritic density after SCI. Groups displaying significantly atrophied dendritic processes were rarely able to achieve weight supported open-field locomotion. Only a combination of 5-HT pharmacotherapy and bike therapy enabled significant open-field weigh-supported stepping, mediated in part by restoring spinal dendritic density. These results support the use of combined therapies to synergistically impact multiple markers of spinal plasticity and improve motor recovery.

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Corticospinal circuit plasticity in motor rehabilitation from spinal cord injury

Cited by 31 publications

References 141 publications

Inositol Polyphosphate-5-phosphatase K (Inpp5k) enhances sprouting of corticospinal tract axons after CNS trauma

Inositol Polyphosphate-5-phosphatase K (Inpp5k) enhances sprouting of corticospinal tract axons after CNS trauma

Pathological changes of distal motor neurons after complete spinal cord injury

Serotonin receptor and dendritic plasticity in the spinal cord mediated by chronic serotonergic pharmacotherapy combined with exercise following complete SCI in the adult rat

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