Despite the intrinsically greater capacity for axons to regenerate in injured peripheral nerves than after injury to the central nervous system, functional recovery after most nerve injuries is very poor. A need for novel treatments that will enhance axon regeneration and improve recovery is substantial. Several such experimental treatments have been studied, each based on part of the stereotypical cellular responses that follow a nerve injury. Genetic manipulations of Schwann cells that have transformed from a myelinating to a repair phenotype that either increase their production of axon growth-promoting molecules, decrease production of inhibitors, or both result in enhanced regeneration. Local or systemic application of these molecules or small molecule mimetics of them also will promote regeneration. The success of treatments that stimulate axonal protein synthesis at the site of the nerve injury and in the growing axons, an early and important response to axon injury, is significant, as is that of manipulations of the types of immune cells that migrate into the injury site or peripheral ganglia. Modifications of the extracellular matrix through which the regenerating axons course, including the stimulation of new blood vessel formation, promotes the navigation of nascent regenerating neurites past the injury site, resulting in greater axon regeneration. Experimental induction of expression of regeneration associated gene activity in the cell bodies of the injured neurons is especially useful when regenerating axons must regenerate over long distances to reinnervate targets. The consistently most effective experimental approach to improving axon regeneration in peripheral nerves has been to increase the activity of the injured neurons, either through electrical, optical, or chemogenetic stimulation or through exercise. These activity-dependent experimental therapies show greatest promise for translation to use in patients.
Axon Regeneration in Peripheral Nerves
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.
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.