A Fishy Solution: Zebrafish Help Us Understand Neurological Disorders

Last year, my 95-year-old grandfather passed away from Alzheimer’s disease. Although he lived a long life, it was hard to watch him slowly forget the people and places he loved. Unfortunately, my grandfather’s story is all too common. Almost 1 out of every 7 individuals worldwide suffers from a disease of the brain or nerves, aka a neurological disorder.

We know astonishingly little about how to prevent and treat neurological disorders. However, we may be able to find answers in a surprising source: fish. Apart from their culinary value, fish provide key insights into human development and disease. The zebrafish in particular is helping us understand how connections between neurons develop and why disorders like Alzheimer’s occur in the human brain. Through zebrafish research, we may be able to understand—and in turn find solutions to—complex neurological diseases. 

Deep Dive: Why zebrafish are useful model organisms

Named for their black stripes, zebrafish live in freshwater environments and have a backbone. This should not surprise you if you’ve ever had to debone a fish in the kitchen. 

Zebrafish are a great addition to the lab because they are related to humans. That’s right—your family just got a whole lot bigger! The last common ancestor of zebrafish and humans lived more than 400 million years ago. As descendants of this ancestor passed on different features to their offspring, they adapted to distinct environments and gave rise to various species of aquatic and land animals. 

The last common ancestor between zebrafish and humans lived more than 400 million years ago (MYA). 

Although they’re much more distantly related than that third cousin you once met at a family reunion, zebrafish share 70% of human genes! Because of this genetic overlap, as well as new tools that make it easier to manipulate genetic information, we can create zebrafish models of human diseases. For example, Alzheimer’s disease, the most common degenerative brain disease, is associated with neuron death and excess buildup of certain proteins in the brain. By creating zebrafish that make too much of these harmful proteins, researchers have created a highly informative model that exhibits many key features of Alzheimer’s.

Despite the fact that we have many similarities, it’s important to remember that aquatic relatives also differ from us in many ways. Since zebrafish lay eggs, their embryos don’t develop within a uterus. This is an advantage for researchers because it means that they can study embryos as early as the first cell division without fear of harming their mother.

Young zebrafish embryos don’t have pigmentation. Like the friendly ghost, Casper, zebrafish are transparent for several days after fertilization. This means that scientists can easily use a variety of colorful proteins and dyes to label specific structures within them. These dyes help researchers look at specific parts of the zebrafish. Recently, researchers used dyes to track how features of Alzheimer’s disease, such as cell death, develop in real time in zebrafish models. This would not have been possible in humans or other model organisms that are opaque.

Colorful fluorescent proteins can be used to label cells and other structures in zebrafish. Photo credit: Sweta Narayan, Prince Lab, University of Chicago

Follow the Leader: How scientists are using zebrafish to study developing neural circuits

While many neurological disorders, like Alzheimer’s and Parkinson’s, develop late in life, some are present at birth. For example, developmental facial paralysis results from abnormalities in the formation or activity of the facial nerve. This paralysis can lead to dramatic facial disfiguration and can affect a child’s ability to speak, eat, and express emotions.

In order to understand why babies get facial nerve paralysis, we first need to understand how the facial nerve normally forms. In the lab of University of Chicago Professor Victoria Prince, I use zebrafish to study how the facial neurons develop and create important connections in the brain.

During early development, the nervous system lays down pathways called cranial nerves, which connect our brain to various parts of our body. These cranial nerves play essential roles in our everyday life. For example, as you move your eyes across this sentence, the fourth cranial nerve, aka the trochlear nerve, allows your eyes to rotate.

The organization of the cranial nerves is similar in many vertebrates. A great example of this is the facial nerve, which connects our brain to muscles in our face that control facial expressions. The neurons of the facial nerve are born in a part of the brain located at the base of our skull called the hindbrain. In humans, mice, and zebrafish, the facial neurons must migrate before they can connect with their muscle targets.

The Prince Lab has shown that the first facial neuron to begin migrating is special and irreplaceable. Think of this first neuron like the leader in a conga line. This leader sets the direction and pace of motion. Without the leader, the remainder of the conga line would not be able to go anywhere. Similarly, the leading facial neuron, which we call the ‘pioneer,’ is essential for proper migration. When the pioneer neuron is removed, the rest of the facial neurons are unable to reach their final destination.

In my research, I use cutting-edge techniques to study the pioneer neuron in more detail. I label facial neurons with a color-changing protein called KAEDE, which turns from green to red when zapped with UV light. By zapping the first neuron in a migrating chain, i.e. the pioneer neuron, I am able to tell this neuron apart from its neighbors. Because zebrafish embryos are transparent, I can take videos of developing zebrafish and watch the migration of pioneer neurons in real time! These studies allow me to track the timing of pioneer neuron migration and study the characteristics of this amazing cell.

I labeled the individual neurons in the zebrafish hindbrain using green and red fluorescent proteins. The red marks the pioneer neuron.
Photo credit: Sweta Narayan, Prince Lab, University of Chicago

Although it is unclear whether pioneers lead facial neuron migration in humans, the Prince Lab’s work in zebrafish is still helping us understand how the facial nerve forms. In the future, this research may help us better understand how facial development goes wrong in patients who have developmental facial paralysis.

Get Your Feet Wet: Support neurological disease research

Next time you go to an aquarium like the Shedd, think about how much you can learn from the organisms staring at you across the glass. Fish are helping us understand how and why neurological diseases occur—this is the first step to finding a solution!

You can help the millions of Americans who, like my grandfather, suffer from neurological disorders by donating to the American Brain Foundation. Find out how the organization supports brain research at: https://www.americanbrainfoundation.org/how-to-help/.

The Prince lab uses fish like these to understand how the facial nerve forms.
Photo credit: Sweta Narayan, Prince Lab, University of Chicago

Sweta Narayan is a fourth year undergraduate student at the University of Chicago. She is interested in developmental biology and plans to pursue a career in medicine. Find her on LinkedIn.

Sweta’s article is part of a collaboration between the Illinois Science Council and the University of Chicago.