Newsletter Article for Research Foundation

There’s something fishy happening in the field of brain research. New methods of experimentation have allowed scientists at the University of California at San Francisco (UCSF) to visualize meaningful processes in the brain that were previously only inferred. Using funds from Brain Research Foundation’s (BRF) Seed Grant Program, an innovative tool was unlocked in the form of a striped vertebrate with small, transparent brains– the zebrafish.

This new research, led by Haruna Nakajo, Ph.D. with support from Nick Silva, Ph.D. and overseen by Anna Victoria Molofsky, M.D., Ph.D., offers a tangible look inside the brain. A quick anatomy refresher­: the brain and spinal cord make up our central nervous system (CNS), which relies on billions of neurons (nerve cells) to send and receive messages throughout the body. These communications occur at sites called synapses. All these processes are housed within a structural support system called the extracellular matrix (ECM).

The UCSF research has focused on a specific type of brain cell, microglia, which are less responsible for signal-sending but instead serve as the immune system of the brain. Accounting for 10% of our brain cells, microglia help clean up protein, microbes, and dead cells that might be dangerous for the CNS[i]. Additionally, as described by Dr. Molofsky, they help to remodel the structural support system of the brain and pave the way for new synapses to form, a groundbreaking concept that reveals a novel function for microglia[ii].

For most, these concepts of communication and remodeling in the brain exist only in theory. How could one possibly visualize these processes occurring in real time? That’s where zebrafish come in. Though mice have long been the preferred species to perform research on due to their anatomical and genetic similarities to humans, a growing method of study involves using zebrafish, due to their unique brains. “It's very small and transparent,” Dr. Molofsky explains. “But it's very similar to our brains and has all the same types of neurons. It has microglia, just like our brains, but it develops in an egg, outside of a uterus, which is totally transparent until it's about 14 days old. So, we can look directly into the brain.”

That’s not to say that fish and mammalian brains are completely identical; rather, there are certain regions that mimic the human brain more closely than previously thought. Once it was established that the hindbrain region of the zebrafish brain housed microglia that interacted with synapses similarly to those of a mammalian brain, the team was able to invest in zebrafish and start asking deeper questions. However, this meant making the considerable transition from mice to fish, a time-consuming and costly endeavor for a laboratory primarily using the former.

“That's where seed funding from [organizations] like BRF really becomes important because you have to be able to take a leap of faith to try something totally new,” Dr. Molofsky says. Not only did she have to familiarize herself with the care and behavior of a new model organism, she also had to hire post-doctoral fellows who had experience working with fish in a scientific setting. Nick Silva, Ph.D., learned to work with zebrafish during graduate school at the University of Michigan while Haruna Nakajo, Ph.D. garnered expertise in fish behavior during her Ph.D. training in Japan. “BRF was helpful in that transition of organism, being able to take that risk. We knew that it was an investment that would take time to pay off.”

It certainly has. Dr. Molofsky and her team have hypothesized that when microglia interact with a synapse, it releases enzymes that remodel the surrounding ECM, clearing space for new synapses to form. By using live imaging and tagging microglia and neurons with different colors, their interactions can be visualized under a microscope, offering new information about their behavior and relationship with one another. “You can say these things, but until you actually see it happening, you don't believe it,” Dr. Molofsky explained. The fish became a powerful tool in visualizing the processes that were previously only hypotheses[iii]. “I've been able to try this new way of looking at things that lets us look at it in real time, in a way that we couldn't before.”

Children’s brains are often referred to as being like sponges. As Dr. Molofsky explained, that’s because most synapse formation is happening in early childhood, with the peak being between one and two years of age. After that, there is a reduction in the number of synapses in the brain. As we grow, the strong synapses are preserved and the weak ones are taken away, as the adult brain becomes more defined, and the focus becomes on specific learning.

Microglia are essential for this housekeeping activity within the brain, and as immune cells they harness signals from the immune system to do it. However, Dr. Molofsky described the flip side of this. “It does raise the question of what happens if we have too much of a good thing, right?” There is a hypothesis that some mental illnesses, such as schizophrenia, may be due to too much synapse elimination. Alternatively, viral illnesses may spur overactivity that could contribute to certain diseases. “What happens if the virus drives that immune response into overdrive? Do we get microglia getting rid of parts of the brain that we need?”

Alzheimer’s disease, a neurodegenerative disorder that affects about one in nine people over age 65, is also applicable when asking these questions.[iv] “Many of the top risk genes in Alzheimer's disease are expressed in microglia. So, microglia have become a huge focus of understanding Alzheimer's.”

Dr. Molofsky and her team continue to further their research in the hopes of bringing even more clarity to the relationship between microglia and brain disease. By adding zebrafish as a model organism, cutting-edge visualization of brain activity helps bring about a better understanding of some of the most common and often devastating brain diseases. Grants such as those offered by BRF allow scientists the opportunity to expand into new arenas of research, enabling them to ask pivotal questions and gain valuable answers. “We really wanted to follow the science and be able to take that risk,” she concluded.

 

Donations to BRF directly contribute to breakthroughs in science relating to neurological disorders. To aid in funding innovation, please contact Sandra Jaggi, Director of Philanthropy at sjaggi@thebrf.org. You may also visit https://www.thebrf.org/get-involved/ to discover additional methods of involvement. Thank you for being a part of positive change.