The Brain Wave: Fishing for better brain repair therapeutics

The inability of central nervous system (CNS) neurons to regenerate constitutes the greatest challenge to the development of therapies for nervous system disorders and injuries. Unlike muscle or skin tissue, neurons in the brain and the spinal cord suffer from a severe regenerative failure. This lack of regenerative ability explains why neurodegenerative disorders and traumatic injuries to the CNS are so devastating. For example, there are 200,000 people currently living in the United States with Spinal Cord Injury, accumulating a lifetime cost of up to $3 million. Neurodegenerative diseases, such as Alzheimer’s, comprise a significant economic and social burden to individuals and society.

Because the CNS lacks the ability to repair itself, damage to the brain and spinal cord is often irreversible and results in the permanent loss of important functions such as cognition and motor behavior. More importantly, there is not single drug or therapy that can reverse or even slow neuronal loss. The lack of a successful treatment or cure compels the clinical need for more efficacious therapy that satisfactorily restores neurons or halts the progression of diseases.

In our search for this successful therapy, one animal may hold the key to unlocking the secret to the next generation of brain repair therapeutics. Striped and no longer than one and a half inches, zebrafish (Danio rerio) have the remarkable ability to regrow parts of many organs that we cannot, including the heart and the brain. Although this ability to regenerate the brain has fascinated neuroscientists for years, the biological mechanism underlying this neural regenerative success remains elusive. Understanding what makes zebrafish brains different than ours is the million dollar question in the development of more effective brain repair strategies.

First of all, why would anyone even consider using zebrafish to study human diseases? The zebrafish has a completely tractable genome that is easily amenable to genetic manipulation techniques, paving the way for studies into the function of genes. The fish genome also has 85 percent homology with the human gene counterparts and is capable of expressing human genes with phenotypes. Consequently, the zebrafish is an established model to study many different neurological diseases, including epilepsy and Lou Gehrig’s disease. Furthermore, zebrafish are cheap, easy to maintain and are able to produce hundreds of embryos at once, making them a cost-effective and high-throughput animal model.

How do zebrafish regrow their brains? Before delving into this question, let’s first discuss neural regeneration in the context of mammals. One canonical hypothesis to explain mammalian neural regenerative failure is the inherent CNS environment that inhibits successful regeneration. For instance, sensory neurons have one axon that splits into two different processes: one heads to the spinal cord, and the other heads to the periphery — the skin, for example. Whereas the peripheral branch can regenerate from a cut, the central branch cannot.

Subsequent studies show that astrocytes, a type of non-neuronal support cell, could be responsible for the inhibitory environment in the CNS. Following traumatic injuries, astrocytes swell up in a process known as reactive gliosis. Astrocytes then release a set of factors that form a physical barrier around the injury site called a glial scar. Although this barrier seems to prevent the spread of damage to other areas, it also prevents axons from regrowing.

Strikingly, zebrafish do not form a glial scar, a scar formed from non-neuronal cells in the nervous system. After researchers poked a hole in their heads, the zebrafish brains remarkably recovered completely within a year. There is no discernible difference between the injury site right after injury and one year later, as if nothing had happened.

What accounts for this lack of a glial scar? Interestingly, there is still a contentious debate in the zebrafish field about whether or not bona fide astrocytes exist in the zebrafish nervous system. During the early development of the nervous system, cells known as radial glia serve as progenitor cells. After development, radial glia lose their long processes and become astrocytes or neural stem cells in the adult brain. In zebrafish, however, it seems that radial glia only become adult neural stem cells, since no one has been able to definitively identify an astrocyte in the zebrafish nervous system. Without astrocytes, it may be possible that zebrafish cannot form a glial scar, allowing neuronal regeneration to occur in a permissive environment.

At the end of the day, there is still a lot to learn about neuronal regeneration in both the zebrafish and mammalian brains. Of course, a zebrafish is not a human. However, if we can understand the similarities and differences between the zebrafish regenerative success and the mammalian failure, we may be able to develop novel therapies aimed at enhancing the regenerative response in humans.