Recovering from traumatic brain and spinal cord injury: generation of new neurons in the adult mammalian central nervous system

Caused by a damaging blow to the brain or spinal cord, traumatic injury to the central nervous system is - as the name suggests - a traumatic experience for individuals. Currently, there are 200,000 people living in the United States with Spinal Cord Injury (SCI), accumulating a lifetime cost of up to $3 million in severe cases ((Spinal Cord Injury (SCI): Fact Sheet [Fact sheet]. (2010, November 4). Retrieved from Center for Disease Control and Prevention website. )). SCI is most often the result of car accidents, military service, or any other occurrence in which the spine is at risk of being damaged by a powerful impact. The after effect can be extremely severe, depending on the degree of the injury. In the worst cases, a person suffering from SCI may completely lose motor function and be permanently paralyzed. In addition, traumatic injury to the head can disrupt daily life by causing loss of coordination, convulsions, seizures, and repeated vomiting ((Mayo Clinic Staff. (2012, October 12). Traumatic brain injury: Symptoms. )). Clearly, traumatic injuries to the nervous system are devastating. Why are brain and spinal cord injuries so serious? The answer lies in the inability of neurons to efficiently regenerate in the adult mammalian central nervous system (CNS).

Unlike muscle cells or skin cells, neuronal cells do not efficiently regenerate to compensate for the lost and damaged cells in the adult mammalian CNS. In instances of spinal injuries, two neurons critical for mediating movement are affected: Upper and Lower Motor Neurons. Upper Motor Neurons are charged with the task of relaying messages from the brain to Lower Motor Neurons. Once the message reaches the Lower Motor Neuron, a signal is fired, telling the muscle to contract. These controlling messages are transferred via structures called axons. When there is a sudden blow to the spinal cord, the spine is compressed and fractured, crushing and destroying the message-carrying axons ((NIDS spinal cord injury information page. (n.d.). Retrieved from National Institute of Neurological Disorders and Stroke website.)). These axons fail to regenerate, and the affected neurons do not survive following the disruption of crucial communication. Thus, damages to the CNS are irreversible and have major permanent consequences.

So, exactly what can we do about injuries to the brain and spinal cord? In short, the very best we can do at the moment is to minimize damage to the nervous system. There are rehabilitation programs that include physical therapies, but if the damage is too severe, the rehabilitation can do little to bring back lost function due to failure to replace dead neurons. However, new and exciting data challenge the classical dogma that adult CNS neurons cannot regenerate: the brain does, in fact, attempt to generate new neurons following traumatic injury! Experimental mouse data show how injuries to the brain do indeed induce neuronal regeneration, albeit the regenerative process is inefficient ((Kernie, S., & Parent, J. (2010). Forebrain neurogenesis after focal ischemic and traumatic brain injury. Neurobiology of Disease. )). Understanding the underlying molecular basis for neuronal regenerative failure is crucial for the future of novel regenerative medicine, providing a glimmer of hope for successful treatments of traumatic brain and spinal cord injuries.

Proposed 100 years ago, the existence of neural stem cells and adult neurogenesis (the process in which mature neurons are generated from precursor cells) is now widely accepted in the scientific field ((Kernie, S., & Parent, J. (2010). Forebrain neurogenesis after focal ischemic and traumatic brain injury. Neurobiology of Disease. )). In the normal adult brain, new neurons are constantly made in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dendate gyrus ((Arvidsson, A., Collin, T., Kirik, D., & Kokaia, Z. (2002)). Neuronal replacement from endogenous precursors in the adult brain after stroke. Nature Medicine. ). Neural stem cells (NSC) are first made in the SVZ and are then turned into neural precursor cells (NPC) when they embark on a long journey to another area in the brain called the olfactory bulb, involved in the perception of smell. Once the NPCs reach the olfactory bulb, they differentiate into mature neuron cells ((Doetsch, F., Callie, I., Lim, D., & Alvarez-Buylla, A. (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. )).

Figure 1: The human subventricular zone (SVZ). Throughout adulthood, there is constant neurogenesis in the SVZ, making it a potential source for new neurons for brain remodeling following traumatic injury. Image taken from Wikipedia ((Human subventricular zone [Photograph]. (n.d.). Retrieved from http://en.wikipedia.org/wiki/File:Human_subventricular_zone.jpg)).

 

These pre-neuron stem cells derived from the SVZ have been a major topic of interest for regenerative medicine, as they have been proposed as a source of new neurons for neural repair following brain injuries. Indeed, previous studies with mice have shown that the SVZ is a source for new neurons following traumatic events. In mice with induced mechanical injuries to the brain, the injuries stimulated the SVZ to undergo neurogenesis ((Kernie, S., & Parent, J. (2010). Forebrain neurogenesis after focal ischemic and traumatic brain injury. Neurobiology of Disease.))  Successful brain remodeling process requires adherence to the following sequence of events: 1) NPC’s are generated in the SVZ; 2) NPC’s migrate to injury sites; 3) NPC’s differentiate to mature neurons, followed by survival and successful integration of new neurons into existing neural circuits ((Kishimoto, N., Shimizu, K., & Sawamoto, K. (2012). Neuronal regeneration in a zebrafish model of adult brain injury. Disease Models and Mechanisms. )). However, this process is not accomplished efficiently in the adult mammalian brain.

In 1928, Ramon y Cajal described how the ends of injured axons become “dystrophic endballs” and incapable of regeneration ((Yiu, G., & He, Z. (2006). Glial inhibition of CNS axon regeneration. Nature Reviews Neuroscience. )). In contrast, recent studies have shown how these “dystrophic endballs” are actually highly active structures that are stalled in a hostile injured environment. Outside of the spinal cord, these injured axons can grow over long distances ((Yiu, G., & He, Z. (2006). Glial inhibition of CNS axon regeneration. Nature Reviews Neuroscience.  )). In addition, there are neurons in the dorsal root ganglia (DRG) that have an axon both inside the spinal cord and outside of the spinal cord. Only the axon outside of the spinal cord can regenerate, suggesting the presence of inhibitory factors exclusively in the spinal cord ((Yiu, G., & He, Z. (2006). Glial inhibition of CNS axon regeneration. Nature Reviews Neuroscience.  )).

What exactly are these factors? A number of them have been suggested to proposed to play a role in preventing the neurons from regenerating successfully in the CNS. One such factor is chondroitin sulphate proteoglycans (CSPGs), released by support cells in the CNS as a reaction to an injury ((McKeon, R. J., Schreiber, R., Rudge, J., & Silver, J. (1991). Reduction of neurite growth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. Journal of Neuroscience. )). Normally, there are support cells in the CNS that work like neuronal janitors: they “clean up” the injury site and aid in normal maintenance of other neurons. However, these CSPGs released by these support cells result in glial scarring, which is an environment that is inhibitory to neuronal regeneration. Perhaps in successful neuronal regenerative therapy, glial scarring must be prevented after an injury through controlling support cells and the levels of CSPGs released.

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Figure 2: Representation of injury site in the spinal cord. After an injury occurs, support cells called astrocytes (colored red) surround the injury site. Release of inhibitory factors by astrocytes called CSPG’s result in glial scarring, preventing neuronal structures and neuronal cells to regenerate. Image taken from PubMed ((Yiu, G., & He, Z. (2006). Glial inhibition of CNS axon regeneration. Nature Reviews Neuroscience.))

How far are we to the finish line of neural regenerative success? We have come a long way in the past few decades, but still not quite there, yet. We now understand that after an injury to the brain, there is an attempt to generate new neurons. However, successful neuronal regeneration is thwarted by a hostile environment in the CNS, such as release of inhibitory factors resulting in glial scarring. Further insight into the molecular mechanism of glial scarring may allow scientists to prevent such scarring, permitting neurons to regenerate successfully. Although the data is new and exciting, there is still much that is unknown. In the world of neuronal regeneration research, scientists are on the way to elucidate the conundrum of CNS neuroregeneration.

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