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International Journal of Molecular... Oct 2020Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Its pathophysiology comprises... (Review)
Review
Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Its pathophysiology comprises acute and chronic phases and incorporates a cascade of destructive events such as ischemia, oxidative stress, inflammatory events, apoptotic pathways and locomotor dysfunctions. Many therapeutic strategies have been proposed to overcome neurodegenerative events and reduce secondary neuronal damage. Efforts have also been devoted in developing neuroprotective and neuro-regenerative therapies that promote neuronal recovery and outcome. Although varying degrees of success have been achieved, curative accomplishment is still elusive probably due to the complex healing and protective mechanisms involved. Thus, current understanding in this area must be assessed to formulate appropriate treatment modalities to improve SCI recovery. This review aims to promote the understanding of SCI pathophysiology, interrelated or interlinked multimolecular interactions and various methods of neuronal recovery i.e., neuroprotective, immunomodulatory and neuro-regenerative pathways and relevant approaches.
Topics: Animals; Humans; Spinal Cord; Spinal Cord Injuries; Spinal Cord Regeneration
PubMed: 33066029
DOI: 10.3390/ijms21207533 -
Annual Review of Neuroscience Jul 2022Locomotion is a universal motor behavior that is expressed as the output of many integrated brain functions. Locomotion is organized at several levels of the nervous... (Review)
Review
Locomotion is a universal motor behavior that is expressed as the output of many integrated brain functions. Locomotion is organized at several levels of the nervous system, with brainstem circuits acting as the gate between brain areas regulating innate, emotional, or motivational locomotion and executive spinal circuits. Here we review recent advances on brainstem circuits involved in controlling locomotion. We describe how delineated command circuits govern the start, speed, stop, and steering of locomotion. We also discuss how these pathways interface between executive circuits in the spinal cord and diverse brain areas important for context-specific selection of locomotion. A recurrent theme is the need to establish a functional connectome to and from brainstem command circuits. Finally, we point to unresolved issues concerning the integrated function of locomotor control.
Topics: Brain; Brain Stem; Locomotion; Spinal Cord
PubMed: 34985919
DOI: 10.1146/annurev-neuro-082321-025137 -
Nature Nov 2020Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons. Here we show that a crush injury to the spinal cord in neonatal...
Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal-but not adult-microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system.
Topics: Animals; Animals, Newborn; Axons; Cicatrix; Fibronectins; Homeostasis; Mice; Microglia; Protease Inhibitors; RNA-Seq; Single-Cell Analysis; Spinal Cord; Spinal Cord Injuries; Spinal Cord Regeneration; Wound Healing
PubMed: 33029008
DOI: 10.1038/s41586-020-2795-6 -
Nature Nov 2022A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal...
A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord applied during neurorehabilitation (EES) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EES in mice. We applied single-nucleus RNA sequencing and spatial transcriptomics to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EES, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.
Topics: Animals; Humans; Mice; Neurons; Paralysis; Spinal Cord; Spinal Cord Injuries; Walking; Electric Stimulation; Lumbosacral Region; Neurological Rehabilitation; Sequence Analysis, RNA; Gene Expression Profiling
PubMed: 36352232
DOI: 10.1038/s41586-022-05385-7 -
Physiological Reviews Jul 2020Itch is a topic to which everyone can relate. The physiological roles of itch are increasingly understood and appreciated. The pathophysiological consequences of itch... (Review)
Review
Itch is a topic to which everyone can relate. The physiological roles of itch are increasingly understood and appreciated. The pathophysiological consequences of itch impact quality of life as much as pain. These dynamics have led to increasingly deep dives into the mechanisms that underlie and contribute to the sensation of itch. When the prior review on the physiology of itching was published in this journal in 1941, itch was a black box of interest to a small number of neuroscientists and dermatologists. Itch is now appreciated as a complex and colorful Rubik's cube. Acute and chronic itch are being carefully scratched apart and reassembled by puzzle solvers across the biomedical spectrum. New mediators are being identified. Mechanisms blur boundaries of the circuitry that blend neuroscience and immunology. Measures involve psychophysics and behavioral psychology. The efforts associated with these approaches are positively impacting the care of itchy patients. There is now the potential to markedly alleviate chronic itch, a condition that does not end life, but often ruins it. We review the itch field and provide a current understanding of the pathophysiology of itch. Itch is a disease, not only a symptom of disease.
Topics: Animals; Humans; Neurons; Pruritus; Skin; Spinal Cord
PubMed: 31869278
DOI: 10.1152/physrev.00017.2019 -
Nature Dec 2022The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the... (Review)
Review
The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the central nervous system as central sites of neuro-immune interactions. Although the nervous and immune systems both function to maintain homeostasis, under rare circumstances, they can develop pathological interactions that lead to neurological or psychiatric diseases. Here we discuss recent findings that dissect the key anatomical, cellular and molecular mechanisms that enable neuro-immune responses at the borders of the brain and spinal cord and the implications of these interactions for diseases of the central nervous system.
Topics: Brain; Immune System; Neuroimmunomodulation; Spinal Cord; Humans; Nervous System Diseases
PubMed: 36517712
DOI: 10.1038/s41586-022-05474-7 -
Molecular Medicine Reports Jun 2021Spinal cord injury (SCI) is one of the most debilitating of all the traumatic conditions that afflict individuals. For a number of years, extensive studies have been... (Review)
Review
Spinal cord injury (SCI) is one of the most debilitating of all the traumatic conditions that afflict individuals. For a number of years, extensive studies have been conducted to clarify the molecular mechanisms of SCI. Experimental and clinical studies have indicated that two phases, primary damage and secondary damage, are involved in SCI. The initial mechanical damage is caused by local impairment of the spinal cord. In addition, the fundamental mechanisms are associated with hyperflexion, hyperextension, axial loading and rotation. By contrast, secondary injury mechanisms are led by systemic and cellular factors, which may also be initiated by the primary injury. Although significant advances in supportive care have improved clinical outcomes in recent years, a number of studies continue to explore specific pharmacological therapies to minimize SCI. The present review summarized some important pathophysiologic mechanisms that are involved in SCI and focused on several pharmacological and non‑pharmacological therapies, which have either been previously investigated or have a potential in the management of this debilitating injury in the near future.
Topics: Animals; Cyclooxygenase Inhibitors; Humans; Minocycline; Neuroprotective Agents; Spinal Cord; Spinal Cord Injuries
PubMed: 33846780
DOI: 10.3892/mmr.2021.12056 -
Nature Reviews. Neurology Jan 2021Although lesion size is widely considered to be the most reliable predictor of outcome after CNS injury, lesions of comparable size can produce vastly different... (Review)
Review
Although lesion size is widely considered to be the most reliable predictor of outcome after CNS injury, lesions of comparable size can produce vastly different magnitudes of functional impairment and subsequent recovery. This neuroanatomical-functional paradox is likely to contribute to the many failed attempts to independently replicate findings from animal models of neurotrauma. In humans, the analogous clinical-radiological paradox could explain why individuals with similar injuries can respond differently to rehabilitation. We describe the neuroanatomical-functional paradox in the context of traumatic spinal cord injury (SCI) and discuss the underlying mechanisms of the paradox, including the concepts of lesion-affected and recovery-related networks. We also consider the various secondary complications that further limit the accuracy of outcome prediction in SCI and provide suggestions for how to increase the predictive, translational value of preclinical SCI models.
Topics: Animals; Humans; Models, Animal; Recovery of Function; Spinal Cord; Spinal Cord Injuries
PubMed: 33311711
DOI: 10.1038/s41582-020-00436-x -
Nature Communications Sep 2021Single-cell RNA sequencing data can unveil the molecular diversity of cell types. Cell type atlases of the mouse spinal cord have been published in recent years but have...
Single-cell RNA sequencing data can unveil the molecular diversity of cell types. Cell type atlases of the mouse spinal cord have been published in recent years but have not been integrated together. Here, we generate an atlas of spinal cell types based on single-cell transcriptomic data, unifying the available datasets into a common reference framework. We report a hierarchical structure of postnatal cell type relationships, with location providing the highest level of organization, then neurotransmitter status, family, and finally, dozens of refined populations. We validate a combinatorial marker code for each neuronal cell type and map their spatial distributions in the adult spinal cord. We also show complex lineage relationships among postnatal cell types. Additionally, we develop an open-source cell type classifier, SeqSeek, to facilitate the standardization of cell type identification. This work provides an integrated view of spinal cell types, their gene expression signatures, and their molecular organization.
Topics: Animals; Atlases as Topic; Cell Nucleus; Datasets as Topic; Mice; Neurons; RNA-Seq; Single-Cell Analysis; Spatial Analysis; Spinal Cord; Transcriptome
PubMed: 34588430
DOI: 10.1038/s41467-021-25125-1 -
Nature Neuroscience May 2022Severe spinal cord injury in adults leads to irreversible paralysis below the lesion. However, adult rodents that received a complete thoracic lesion just after birth...
Severe spinal cord injury in adults leads to irreversible paralysis below the lesion. However, adult rodents that received a complete thoracic lesion just after birth demonstrate proficient hindlimb locomotion without input from the brain. How the spinal cord achieves such striking plasticity remains unknown. In this study, we found that adult spinal cord injury prompts neurotransmitter switching of spatially defined excitatory interneurons to an inhibitory phenotype, promoting inhibition at synapses contacting motor neurons. In contrast, neonatal spinal cord injury maintains the excitatory phenotype of glutamatergic interneurons and causes synaptic sprouting to facilitate excitation. Furthermore, genetic manipulation to mimic the inhibitory phenotype observed in excitatory interneurons after adult spinal cord injury abrogates autonomous locomotor functionality in neonatally injured mice. In comparison, attenuating this inhibitory phenotype improves locomotor capacity after adult injury. Together, these data demonstrate that neurotransmitter phenotype of defined excitatory interneurons steers locomotor recovery after spinal cord injury.
Topics: Animals; Interneurons; Locomotion; Mice; Neurotransmitter Agents; Phenotype; Spinal Cord; Spinal Cord Injuries
PubMed: 35524138
DOI: 10.1038/s41593-022-01067-9