Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery

Wang, Ying; Wu, Wei; Wu, Xiangbing; Sun, Yan; Zhang, Yi P.; Deng, Ling-Xiao; Walker, Melissa J.; Qu, Wenrui; Chen, Chen; Liu, Nai-Kui; Han, Qi; Dai, Heqiao; Shields, Lisa B. E.; Shields, Christopher B.; Sengelaub, Dale R.; Jones, Kathryn J.; Smith, George M.; Xu, Xiao–Ming

doi:10.7554/elife.39016

Cited by 46 publications

(41 citation statements)

References 75 publications

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“…Apart from primary injury, neurons are particularly susceptible to secondary molecular events after SCI, including oxidative stress and cell apoptosis. Due to the poor regenerative capacity of neurons, inhibition of the secondary response after SCI to maintain neuron survival is a potential strategy for recovery after SCI ( Wang et al, 2018 ; Li et al, 2019 ; Ohtake et al, 2019 ). In the present study, we observed that the expression of Brd4 increased around lesion sites after SCI, primarily in neurons.…”

Section: Discussionmentioning

confidence: 99%

“…The physiological progression of SCI involves two phases, the primary injury, which is caused by an immediate mechanical insult, then the secondary injury, which arises following the initial damage that triggers a series of molecular events, including the inflammatory response, endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress and axonal demyelination, exacerbating the initial injury and affecting neural repair for a several weeks ( Silva et al, 2014 ; Brommer et al, 2016 ). Currently, separate or combined methods to target secondary responses may be beneficial for maintaining neural tissue survival and improving long-term functional recovery ( Wang et al, 2018 ; Li et al, 2019 ; Zheng et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Xiang

Lin

et al. 2020

Front. Cell. Neurosci.

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Spinal cord injury (SCI) is a destructive neurological disorder that is characterized by impaired sensory and motor function. Inhibition of bromodomain protein 4 (Brd4) has been shown to promote the maintenance of cell homeostasis by activating autophagy. However, the role of Brd4 inhibition in SCI and the underlying mechanisms are poorly understood. Thus, the goal of the present study was to evaluate the effects of sustained Brd4 inhibition using the bromodomain and extraterminal domain (BET) inhibitor JQ1 on the regulation of apoptosis, oxidative stress and autophagy in a mouse model of SCI. First, we observed that Brd4 expression at the lesion sites of mouse spinal cords increased after SCI. Treatment with JQ1 significantly decreased the expression of Brd4 and improved functional recovery for up to 28 day after SCI. In addition, JQ1-mediated inhibition of Brd4 reduced oxidative stress and inhibited the expression of apoptotic proteins to promote neural survival. Our results also revealed that JQ1 treatment activated autophagy and restored autophagic flux, while the positive effects of JQ1 were abrogated by autophagy inhibitor 3-MA intervention, indicating that autophagy plays a crucial role in therapeutic effects Brd4 induced by inhibition of the functional recovery SCI. In the mechanistic analysis, we observed that modulation of the AMPK-mTOR-ULK1 pathway is involved in the activation of autophagy mediated by Brd4 inhibition. Taken together, the results of our investigation provides compelling evidence that Brd4 inhibition by JQ1 promotes functional recovery after SCI and that Brd4 may serve as a potential target for SCI treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Xiang

Lin

et al. 2020

Front. Cell. Neurosci.

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“…Many receive inputs from supraspinal motor systems, and after unilateral lesion, corticospinal tract (CST) or reticulospinal (ReST) tract axons can sprout onto cervical PNs to relay these motor commands past the lesion site (Bareyre et al, 2004 ; Filli et al, 2014 ). After injury PNs upregulate GAP-43, neurotrophic factors, tubulins, and neurofilaments, all of which contribute to elongation and axonal sprouting (Fernandes et al, 1999 ; Siebert et al, 2010 ; Taccola et al, 2018 ; Wang et al, 2018 ). Indeed, 8 weeks after unilateral thoracic hemisection, long descending PNs bypassing the lesion undergo distal sprouting and show a doubling of connectivity onto lumbosacral motoneurons (Bareyre et al, 2004 ).…”

Section: Plasticity Mechanisms That Are Hypothesized To Enable Ees Tomentioning

confidence: 99%

Epidural Electrical Stimulation: A Review of Plasticity Mechanisms That Are Hypothesized to Underlie Enhanced Recovery From Spinal Cord Injury With Stimulation

Eisdorfer

Smit

Keefe

et al. 2020

Front. Mol. Neurosci.

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Spinal cord injury (SCI) often results in lifelong sensorimotor impairment. Spontaneous recovery from SCI is limited, as supraspinal fibers cannot spontaneously regenerate to form functional networks below the level of injury. Despite this, animal models and humans exhibit many motor behaviors indicative of recovery when electrical stimulation is applied epidurally to the dorsal aspect of the lumbar spinal cord. In 1976, epidural stimulation was introduced to alleviate spasticity in Multiple Sclerosis. Since then, epidural electrical stimulation (EES) has been demonstrated to improve voluntary mobility across the knee and/or ankle in several SCI patients, highlighting its utility in enhancing motor activation. The mechanisms that EES induces to drive these improvements in sensorimotor function remain largely unknown. In this review, we discuss several sensorimotor plasticity mechanisms that we hypothesize may enable epidural stimulation to promote recovery, including changes in local lumbar circuitry, propriospinal interneurons, and the internal model. Finally, we discuss genetic tools for afferent modulation as an emerging method to facilitate the search for the mechanisms of action.

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“…The central nervous system (CNS) is a comprehensive, dynamic system. Examples of neural plasticity, whether at the level of the tissue, the cell, or at the genetic level, can be found during development, throughout the progression of the disease, or after injury (Kempermann et al, ; Kim, Kumar, Jo, & Kim, ; Zholudeva et al, ) However, nerve regeneration is still faced with a variety of problems, including (a) lack of neurotrophic factors, (b) primary and secondary apoptosis of nerve cells, and (c) microenvironment at the site of injury not conducive to axon regeneration (Dyck, Kataria, Akbari‐Kelachayeh, Silver, & Karimi‐Abdolrezaee, ; Huang, Mao, Chen, & Liu, ; Y. Wang et al, ). In recent years, exosomes, drugs and pharmacology, surgical repair of nerve defects, neurotrophic factors, tissue engineering, and genetic engineering have become mainstream research methods in the field of spinal cord injury (SCI; Bellver‐Landete et al, ; Cheng et al, ; Zhou et al, ).…”

Section: Introductionmentioning

confidence: 99%

Signatures of altered DNA methylation gene expression after central and peripheral nerve injury

Shi

Zhou

Wang

et al. 2019

Journal Cellular Physiology

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Nerve damage can lead to movement and sensory dysfunction, with high morbidity and disability rates causing severe burdens on patients, families, and society. DNA methylation is a kind of epigenetics, and a great number of previous studies have demonstrated that DNA methylation plays an important role in the process of nerve regeneration and remodeling. However, compared with the central nervous system, the peripheral nervous system shows stronger recovery after injury, which is related to the complex microenvironment and epigenetic changes occurring at the site of injury. Therefore, what common epigenetic changes between the central and peripheral nervous systems remain to be elucidated. We first screened differential methylation genes after spinal cord injury and sciatic nerve injury using whole‐genome bisulfite sequencing and methylated DNA immunoprecipitation sequencing, respectively. Subsequently, a total of 16 genes had the same epigenetic changes after spinal cord injury and sciatic nerve injury. The Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to identify the critical biological processes and pathways. Furthermore, a protein−protein interaction network analysis indicated that Dnm3, Ntrk3, Smurf1, Dpysl2, Kalrn, Shank1, Dlg2, Arsb, Reln, Bmp5, Numbl, Prickle2, Map6, and Htr7 were the core genes. These outcomes may provide novel insights into the molecular mechanism of the subacute phase of nerve injury. These verified genes can offer potential diagnostic and therapeutic targets for nerve injury.

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Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery

Cited by 46 publications

References 75 publications

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Epidural Electrical Stimulation: A Review of Plasticity Mechanisms That Are Hypothesized to Underlie Enhanced Recovery From Spinal Cord Injury With Stimulation

Signatures of altered DNA methylation gene expression after central and peripheral nerve injury

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