Activation of MAP2K signaling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201350 | GEO | 2022/12/31
REPOSITORIES: GEO
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Project description:Functional deficits persist after spinal cord injury (SCI) because axons in the adult mammalian central nervous system (CNS) fail to regenerate. However, modest levels of spontaneous functional recovery are typically observed after trauma, and are thought to be mediated by the plasticity of intact circuits. The mechanisms underlying intact circuit plasticity are not delineated. Here, we characterize the in vivo transcriptome of sprouting intact neurons from ngr1 null mice after partial SCI. We identify the lysophosphatidic acid signaling modulators Lppr1 and Lpar1 as intrinsic axon growth modulators for intact corticospinal motor neurons after adjacent injury. Furthermore, in vivo Lpar1 inhibition or Lppr1 overexpression enhances sprouting of intact corticospinal tract axons and yields greater functional recovery after unilateral brainstem lesion in wild type mice. Thus, the transcriptional profile of injury-induced sprouting of intact neurons reveals targets for therapeutic enhancement of axon growth initiation and new synapse formation.
2017-03-13 | GSE94482 | GEO
Project description:In response to cortical stroke and unilateral corticospinal tract degeneration, compensatory sprouting of spared corticospinal fibers is associated with recovery of skilled movement in rodents. To date, little is known about the molecular mechanisms orchestrating this spontaneous rewiring. In this study, we provide insights into the molecular changes in the spinal cord tissue after large ischemic cortical injury in adult female mice, with a focus on factors that might influence the re-innervation process by contralesional corticospinal neurons. We mapped the area of cervical grey matter re-innervation by sprouting contralesional corticospinal axons after unilateral photothrombotic stroke of the motor cortex in mice using anterograde tracing. The mRNA profile of this re-innervation area was analyzed using whole-genome sequencing to identify differentially expressed genes at selected time points during the recovery process. Bioinformatic analysis revealed two phases of processes: Early after stroke (4-7 days post injury), the spinal transcriptome is characterized by inflammatory processes, including phagocytic processes as well as complement cascade activation. Microglia are specifically activated in the denervated corticospinal projection fields in this early phase. In a later phase (28-42 days post injury), biological processes include tissue repair pathways with up-regulated genes related to neurite outgrowth. Thus, the stroke-denervated spinal grey matter, in particular its intermediate laminae, represents a growth-promoting environment for sprouting corticospinal fibers originating from the contralesional motor cortex. This data set provides a solid starting point for future studies addressing key elements of the post-stroke recovery process, with the goal to improve neuroregenerative treatment options for stroke patients.
2019-04-30 | GSE128623 | GEO
Project description:Molecular mechanisms over differentiation and differential axonal targeting of distinct neuron subtypes in the cerebral cortex are beginning to be elucidated. These studies have focused on controls that specifically distinguish one subtype of neocortical projection neurons, e.g. corticospinal motor neurons (CSMN), from closely related corticothalamic projection neurons (CThPN) or intracortical callosal projection neurons (CPN). CSMN are located in layer V of the neocortex and make synaptic connections to motor output circuitry in the spinal cord and brainstem. CSMN axons form the corticospinal tract (CST), which is the major motor output pathway from the motor cortex and critically controls voluntary movement. CSMN somatotopically and precisely target specific segments along the rostrocaudal axis of the spinal cord, the molecular basis for which remains unknown. We used microarrays to examine gene expression differences between two CSMN subpopulations that target different levels of the spinal cord - CSMN-C (which extend axons to the brainstem and cervical spinal cord) and CSMN-L (which preferrrentially extend axons to the thoracic and lumbar spinal cord). We compared CSMN-C vs CSMN-L gene expression at 3 critical developmental time points (previously described in Arlotta et a., 2005)
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Project description:The cerebral cortical tissue of murine embryo and pluripotent stem cell-derived neurons can survive in adult brain and extend axons to the spinal cord. These features suggest that cell transplantation can be a strategy to reconstruct the corticospinal tract (CST). It is unknown, however, which cell population makes for safe and effective donor cells. To address this issue, we grafted the cerebral cortex of E14.5 mouse to the brain of adult mouse and found that the cells in the graft extending axons along the CST expressed CTIP2. By using CTIP2:GFP knockin mouse embryonic stem cells, we identified L1CAM as a cell surface marker to enrich CTIP2+ cells. We sorted L1CAM+ cells from E14.5 mouse brain and confirmed that they extended a larger number of axons along the CST compared to L1CAM- cells. Our results suggest that sorting L1CAM+ cells from the embryonic cerebral cortex enriches subcortical projection neurons to reconstruct the CST.
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Project description:Spinal cord injury (SCI) is a devastating clinical condition resulting in significant disabilities for affected individuals. Apart from local injury within the spinal cord, SCI patients develop a myriad of complications characterized by multi-organ dysfunction. Some of the dysfunctions are directly related to the disrupted integrity of sensory afferents from DRGs, which signal to both the spinal cord and peripheral organs. Some classes of DRG neurons undergo axonal sprouting both peripherally and centrally after spinal cord injury. Such physiological and anatomical re-organization of afferent axons after SCI contributes to both adaptive and maladaptive plasticity, which may be modulated by activity/exercise. In this study, we collected comprehensive gene expression data in whole dorsal root ganglia (DRGs) throughout the levels below the injury comparing the effects of SCI with and without activity/exercise.
2019-04-29 | GSE125630 | GEO
Project description:Deficiency of arginase is associated with hyperargininemia, and unlike the other disorders of the urea cycle, the major mechanism of metabolism of nitrogen in terrestrial mammals, are characteristic and prominent features that include spastic diplegia/tetraplegia, clonus, and hyperreflexia; loss of ambulation, intellectual disability and progressive neurological decline are other signs. To gain greater insight into the unique neuromotor features, we performed gene expression profiling of the motor cortex of a well-characterized murine model of the disorder. Co-expression network analysis suggested an abnormality with myelination, which was supported by limited existing human data. Utilizing electron microscopy, marked dysmyelination was detected in 2-week-old homozygous ARG1 knockout mice. The corticospinal tract was found to be adversely affected, supporting dysmyelination as the cause of the unique neuromuscular features and implicating oligodendrocyte impairment in a deficiency of hepatic ARG1. Following neonatal hepatic gene therapy to express ARG1, the subcortical white matter, pyramidal tract, and corticospinal tract all showed a remarkable recovery in terms of myelinated axon density and ultrastructural integrity with active wrapping of axons by nearby oligodendrocyte processes. These findings support the following conclusions: first, arginase deficiency is a leukodystrophy affecting the brain and spinal cord while sparing the peripheral nervous system; and second, neonatal AAV hepatic gene therapy can rescue the defects associated with myelinated axons, strongly implicating the functional recovery of oligodendrocytes after restoration of hepatic arginase activity. These findings support the consideration of early restoration of hepatic arginase activity in those afflicted with arginase deficiency.
2019-06-01 | GSE132058 | GEO
Project description:Spinal cord injury (SCI) is a devastating condition resulting in permanent and irreversible deficits. Despite regeneration attempts, the neurons fail due to several dysfunctions. A number of studies have already revealed that, following SCI, microRNAs show two opposite kinds of alterations, one detrimental and one protective. However, there is still little evidence of specific microRNAs involved in axon regrowth. The aim of this project is the characterization of microRNA expression changes in sensorimotor cortex and corticospinal motor neurons, whose axons are severed by SCI.
2021-04-21 | GSE89517 | GEO
Project description:Spinal cord injury (SCI) is a devastating condition resulting in permanent and irreversible deficits. Despite regeneration attempts, the neurons fail due to several dysfunctions. A number of studies have already revealed that, following SCI, microRNAs show two opposite kinds of alterations, one detrimental and one protective. However, there is still little evidence of specific microRNAs involved in axon regrowth. The aim of this project is the characterization of microRNA expression changes in sensorimotor cortex and corticospinal motor neurons, whose axons are severed by SCI.
2021-08-13 | GSE90452 | GEO
Project description:Depending on the severity of a CNS injury, in humans as well as in experimental animal models certain degrees of functional recovery are observed. Rodent studies have provided much evidence for underlying anatomical changes involving neurite outgrowth of both spared and axotomized fiber tracts, also referred to as sprouting. Following a thoracic spinal cord injury (SCI) in adult rats, axotomized fibers of the hindlimb corticospinal tract (CST) were found to sprout into the cervical spinal cord at different rostrocaudal levels. Anterograde tracings showed that these new collaterals of motor cortical hindlimb fibers project into the intermediate laminae of the cervical grey matter, particularly pronounced at the level of cervical segment three (C3). The molecular cues which induce the growth and guide these sprouts of hindlimb CST fibers are unknown. We hypothesize that sectreted factors and guidance and adhesion molecules are specifically expressed in the intermediate laminae of the cervical spinal cord to direct and target the ingrowth of the sprouting hindlimb CST fibers. To test our hypothesis the transcription profile of the target region of sprouts was investigated with RNA sequencing of total RNA extracted from the intermediate laminae (IV-VII) of the spinal gray matter at cervical level C3. Four major comparisons were performed, which were then again compared to each other. The first comparison was between samples of animals with an SCI sacrificed at four different time points after injury (1, 3, 6, 12 weeks after injury). The second and third comparison was between samples of rats with a SCI compared to their sham controls sacrificed at the same time point after surgery (1 week or 12 weeks respectively). The fourth comparison was between samples from animals of the two control groups, rats with a sham surgery which were either sacrificed at one or at twelve weeks after injury. We found that most changes in gene expression ocurred at one week after SCI and least changes occured at twelve weeks after SCI, suggesting that the largest effects on a global level of gene expression occur during early time points after injury. Interestingly, also we also found changes in gene expression when comparing the samples from the two control groups, which suggests that sham surgery consisting of a laminectomy is sufficient to induce transcriptional changes in the spinal cord. This is the first study to provide insight into transcriptional changes in the target region of sprouts investigating the role of the cervical spinal cord (target region) for sprouting of hindlimb CST fibers.
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Project description:Transected spinal cord injury (SCI) results in significant structural disruption of the spinal cord. The reconstruction of neural pathways following SCI faces several key challenges, including inadequate endogenous neural stem cells (NSCs) and poor neurogenesis in natural repair process, and concerns related to the long-term survival of neurons following exogenous transplantation. In the current study, we report an oligonucleotide aptamer drug (Apt19S) which is first proven to recruit endogenous NSCs to the site of injury following SCI, and therefore develop a bionic spinal cord scaffold that can sustainedly release Apt19S and neurotrophin-3 (NT-3) to provide the neurogenic niche with the necessary mechanical properties and support for in situ spinal cord repair. The bionic scaffold successfully recruited a significant number of endogenous NSCs in vivo and established a neurogenic niche that was abundant in NT-3, thereby promoting neuronal differentiation and the formation of neuronal networks Regenerated nerve fibers including 5-hydroxytryptamine-positive nerve fibers and corticospinal tract grew robustly into the injury site and generated synaptic connections with the newborn neurons. Collectively, our findings indicate that our aptamer-based bionic spinal cord scaffold elicits a robust neurogenesis process in situ, breaking the limitations imposed by poor self-repair ability in the adult spinal cord.
2023-10-19 | GSE245409 | GEO