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BDNF-Induced Plasticity of Spinal Circuits Underlying Pain and Learning  

Sandra M. Garraway

Understanding of the various types of plasticity that occur in the spinal cord, as well as understanding of spinal cord functions, has vastly improved over the past 50 years, mainly due to an increase in the number of research studies and review articles on the subject. It is now understood that the spinal cord is not merely a passive conduit of neural impulses. Instead, the spinal cord can independently execute complex functions. Numerous experimental approaches have been utilized for more targeted exploration of spinal cord functions. For example, isolating the spinal cord from supraspinal influences has been used to demonstrate that simple forms of learning can be performed by spinal neuronal networks. Moreover, reduced preparations, such as acute spinal cord slices, have been used to show that spinal neurons undergo different types of modulation, including activity-dependent synaptic modification. Most spinal cord processes, ranging from integration of incoming sensory input to execution of locomotor outputs, involve plasticity. Nociceptive processing that leads to pain and spinal learning is an example of plasticity that is well-studied in the spinal cord. At the neural level, both processes involve an interplay of cellular mediators, which include glutamate receptors, protein kinases, and growth factors. The neurotrophin brain-derived neurotrophic factor (BDNF) has also been implicated in these processes, specifically as a promoter of both pro-nociception and spinal learning mechanisms. Interestingly, the role of BDNF in mediating spinal plasticity can be altered by injury. The literature spanning approximately 5 decades is reviewed and the role of BDNF is discussed in mediating cellular plasticity underlying pain processing and learning within the spinal cord.


Plasticity in the Regenerating Nervous System of the Lamprey, a “Simple” Vertebrate  

William Rodemer, Jianli Hu, and Michael E. Selzer

Human spinal cord injury (SCI) results in long-lasting disabilities due to the failure of damaged neurons to regenerate. The barriers to axon regeneration in mammalian central nervous system (CNS) are so great, and the anatomy so complex that incremental changes in regeneration brought about by pharmacological or molecular manipulations can be difficult to demonstrate. By contrast, lampreys recover functionally after a complete spinal cord transection (TX), based on regeneration of severed axons, even though lampreys share the basic organization of the mammalian CNS, including many of the same molecular barriers to regeneration. And because the regeneration is incomplete, it can be studied by manipulations designed to either inhibit or enhance it. In the face of reduced descending input, recovery of swimming and other locomotor functions must be accompanied by compensatory remodeling throughout the CNS, as would be required for functional recovery in mammals. For such studies, lampreys have significant advantages. They have several large, identified reticulospinal (RS) neurons, whose regenerative abilities have been individually quantified. Other large neurons and axons are visible in the spinal cord and can be impaled with microelectrodes under direct microscopic vision. The central pattern generator for locomotion is exceptionally well-defined, and is subject to significant neuromodulation. Finally, the lamprey genome has been sequenced, so that molecular homologs of human genes can be identified and cloned. Because of these advantages, the lamprey spinal cord has been a fertile source of information about the biology of axon regeneration in the vertebrate CNS, and has the potential to serve as a test bed for the investigation of novel therapeutic approaches to SCI and other CNS injuries.


Plastic Changes After Spinal Cord Injury  

Kaitlin Farrell, Megan R. Detloff, and John D. Houle

Spinal cord injury has instantaneous, destructive effects on bodily functions, as readily demonstrated by muscle paralysis and non-responsiveness to sensory stimulation. This primary response has underlying features at molecular, cellular, tissue and organ levels which will, in a relatively brief time, initiate a secondary cascade of events that exacerbates the extent of the primary focus of damage. Interestingly, the initial extent of motor and sensory loss often is followed by limited, but significant spontaneous functional recovery. Recovery may be due to intrinsic central pattern generators such as for locomotion, the uncovering of dormant anatomical and physiological pathways such as the crossed phrenic for respiration, or to the sprouting of undamaged axons within the spinal cord to establish new connections around or across the injury site. Together the responses to injury and spontaneous efforts for repair represent plastic changes in the central nervous system (CNS) that may result in meaningful functional outcomes, though aberrant sprouting is a possible negative consequence of neuroplasticity that lends caution to the desire for extensive but uncontrolled sprouting.


Gut Dysbiosis and Recovery of Function After Spinal Cord Injury  

Kristina A. Kigerl and Phillip G. Popovich

Spinal cord injury (SCI) disrupts the autonomic nervous system (ANS) and impairs communication with organ systems throughout the body, resulting in chronic multi-organ pathology and dysfunction. This dysautonomia contributes to the pronounced immunosuppression and gastrointestinal dysfunction seen after SCI. All of these factors likely contribute to the development of gut dysbiosis after SCI—an imbalance in the composition of the gut microbiota that can impact the development and progression of numerous pathological conditions, including SCI. The gut microbiota are the community of microbes (bacteria, viruses, fungi) that live in the GI tract and are critical for nutrient absorption, digestion, and immune system development. These microbes also communicate with the CNS through modulation of the immune system, production of neuroactive metabolites and neurotransmitters, and activation of the vagus nerve. After SCI, gut dysbiosis develops and persists for more than one year from the time of injury. In experimental models of SCI, gut dysbiosis is correlated with changes in inflammation and functional recovery. Moreover, probiotic treatment can improve locomotor recovery and immune function in the gut-associated lymphoid tissue (GALT). Since different types of bacteria produce different metabolites with unique physiological and pathological effects throughout the body, it may be possible to predict the prevalence or severity of post-injury immune dysfunction and other related comorbidities (e.g., metabolic disease, fatigue, anxiety) using microbiome sequencing data. As research identifies microbial-derived small molecules and the genes responsible for their production, it is likely that it will become feasible to manipulate these molecules to affect human biology and disease.


Enhancing the Regeneration of Neurons in the Central Nervous System  

Romain Cartoni, Frank Bradke, and Zhigang He

Injured axons fail to regenerate in the adult mammalian central nervous system, representing a major barrier for effective neural repair. Both extrinsic inhibitory environments and neuron-intrinsic mechanisms contribute to such regeneration failure. In the past decade, there has been an explosion in our understanding of neuronal injury responses and regeneration regulations. As a result, several strategies have been developed to promote axon regeneration with the potential of restoring functions after injury. This article will highlight these new developments, with an emphasis on cellular and molecular mechanisms from a neuron-centric perspective, and discuss the challenges to be addressed toward developing effective functional restoration strategies.


Mechanisms of Behavioral Changes After Spinal Cord Injury  

Karim Fouad, Abel Torres-Espín, and Keith K. Fenrich

Spinal cord injury results in a wide range of behavioral changes including impaired motor and sensory function, autonomic dysfunction, spasticity, and depression. Currently, restoring lost motor function is the most actively studied and sought-after goal of spinal cord injury research. This research is rooted in the fact that although self-repair following spinal cord injury in adult mammals is very limited, there can be some recovery of motor function. This recovery is strongly dependent on the lesion size and location as well as on neural activity of denervated networks activated mainly through physical activity (i.e., rehabilitative training). Recovery of motor function is largely due to neuroplasticity, which includes adaptive changes in spared and injured neural circuitry. Neuroplasticity after spinal cord injury is extensive and includes mechanisms such as moderate axonal sprouting, the formation of new synaptic connections, network remapping, and changes to neuron cell properties. Neuroplasticity after spinal cord injury has been described at various physiological and anatomical levels of the central nervous system including the brain, brainstem, and spinal cord, both above and below injury sites. The growing number of mechanisms underlying postinjury plasticity indicate the vast complexity of injury-induced plasticity. This poses important opportunities to further enhance and harness plasticity in order to promote recovery. However, the diversity of neuroplasticity also creates challenges for research, which is frequently based on mechanistically driven approaches. The appreciation of the complexity of neuronal plasticity and the findings that recovery is based on a multitude and interlinked adaptations will be essential in developing meaningful new treatment avenues.


Somatosensory System Organization in Mammals and Response to Spinal Injury  

Corinna Darian-Smith and Karen Fisher

Spinal cord injury (SCI) affects well over a million people in the United States alone, and its personal and societal costs are huge. This article provides a current overview of the organization of somatosensory and motor pathways, in the context of hand/paw function in nonhuman primate and rodent models of SCI. Despite decades of basic research and clinical trials, therapeutic options remain limited. This is largely due to the fact that (i) spinal cord structure and function is very complex and still poorly understood, (ii) there are many species differences which can make translation from the rodent to primate difficult, and (iii) we are still some way from determining the detailed multilevel pathway responses affecting recovery. There has also been little focus, until recently, on the sensory pathways involved in SCI and recovery, which are so critical to hand function and the recovery process. The potential for recovery in any individual depends on many factors, including the location and size of the injury, the extent of sparing of fiber tracts, and the post-injury inflammatory response. There is also a progression of change over the first weeks and months that must be taken into account when assessing recovery. There are currently no good biomarkers of recovery, and while axon terminal sprouting is frequently used in the experimental setting as an indicator of circuit remodeling and “recovery,” the correlation between sprouting and functional recovery deserves scrutiny.


Using Neural Stem Cells to Enhance Repair and Recovery of Spinal Circuits After Injury  

Itzhak Fischer and Shaoping Hou

Spinal cord injury is characterized by a complex set of events, which include the disruption of connectivity between the brain and the periphery with little or no spontaneous regeneration, resulting in motor, sensory and autonomic deficits. Transplantation of neural stem cells has the potential to provide the cellular components for repair of spinal cord injury (SCI), including oligodendrocytes, astrocytes, and neurons. The ability to generate graft-derived neurons can be used to restore connectivity by formation of functional relays. The critical requirements for building a relay are to achieve long-term survival of graft-derived neurons and promote axon growth into and out of the transplant. Recent studies have demonstrated that mixed populations of glial and neuronal progenitors provide a permissive microenvironment for survival and differentiation of early-stage neurons, but inclusion of growth factors with the transplant or cues for directional axon growth outside the transplant may also be needed. Other important considerations include the timing of the transplantation and the selection of a population of neurons that maximizes the effective transmission of signals. In some experiments, the essential neuronal relay formation has been developed in both sensory and motor systems related to locomotion, respiration, and autonomic functions. Despite impressive advances, the poor regenerative capacity of adult CNS combined with the inhibitory environment of the injury remain a challenge for achieving functional connectivity via supraspinal tracts, but it is possible that recruitment of local propriospinal neurons may facilitate the formation of relays. Furthermore, it is clear that the new connections will not be identical to the original innervation, and therefore there needs to be a mechanism for translating the resulting connectivity into useful function. A promising strategy is to mimic the process of neural development by exploiting the remarkable plasticity associated with activity and exercise to prune and strengthen synaptic connections. In the meantime, the sources of neural cells for transplantation are rapidly expanding beyond the use of fetal CNS tissue and now include pluripotent ES and iPS cells as well as cells obtained by direct reprogramming. These new options can provide considerable advantages with respect to preparation of cell stocks and the use of autologous grafting, but they present challenges of complex differentiation protocols and risks of tumor formation. It is important to note that although neural stem cell transplantation into the injured spinal cord is primarily designed to provide preclinical data for the potential treatment of patients with SCI, it can also be used to develop analogous protocols for repair of neuronal circuits in other regions of the CNS damaged by injury or neurodegeneration. The advantages of the spinal cord system include well-defined structures and a large array of quantitative functional tests. Therefore, studying the formation of a functional relay will address the fundamental aspects of neuronal cell replacement without the additional complexities associated with brain circuits.


Plasticity of Stepping Rhythms in the Intact and Injured Mammalian Spinal Cord  

Serge Rossignol

The spinal cord is a prime example of how the central nervous system has evolved to execute and retain movements adapted to the environment. This results from the evolution of inborn intrinsic spinal circuits modified continuously by repetitive interactions with the outside world, as well as by developing internal needs or goals. This article emphasizes the underlying neuroplastic spinal mechanisms through observations of normal animal adaptive locomotor behavior in different imposed conditions. It further explores the motor spinal capabilities after various types of lesions to the spinal cord and the potential mechanisms underlying the spinal changes occurring after these lesions, leading to recovery of function. Together, these observations strengthen the idea of the immense potential of the motor rehabilitation approach in humans with spinal cord injury since extrinsic interventions (training, pharmacology, and electrical stimulation) can modulate and optimize remnant motor functions after injury.


Achieving Adaptive Plasticity in the Spinal Cord  

James W. Grau

The traditional view of central nervous system function presumed that learning is the province of the brain. From this perspective, the spinal cord functions primarily as a conduit for incoming/outgoing neural impulses, capable of organizing simple reflexes but incapable of learning. Research has challenged this view, demonstrating that neurons within the spinal cord, isolated from the brain by means of a spinal cut (transection), can encode environmental relations and that this experience can have a lasting effect on function. The exploration of this issue has been informed by work in the learning literature that establishes the behavioral criteria and work within the pain literature that has shed light on the underlying neurobiological mechanisms. Studies have shown that spinal systems can exhibit single stimulus learning (habituation and sensitization) and are sensitive to both stimulus–stimulus (Pavlovian) and response–outcome (instrumental) relations. Regular environmental relations can both bring about an alteration in the performance of a spinally mediated response and impact the capacity to learn in future situations. The latter represents a form of behavioral metaplasticity. At the neurobiological level, neurons within the central gray matter of the spinal cord induce lasting alterations by engaging the NMDA receptor and signal pathways implicated in brain-dependent learning and memory. Of particular clinical importance, uncontrollable/unpredictable pain (nociceptive) input can induce a form of neural over-excitation within the dorsal horn (central sensitization) that impairs adaptive learning. Pain input after a contusion injury can increase tissue loss and undermines long-term recovery.