BRF newsletter 062124 pages (1) - Flipbook - Page 4
BRF Funding Leads to Bold N
There’s something 昀椀shy happening in the 昀椀eld 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, an innovative tool
was unlocked in the form of a striped vertebrate with small,
transparent brains–the zebra昀椀sh.
This new research, led by Haruna Nakajo, Ph.D. with
support from Nick Silva, Ph.D. and overseen by 2021 BRF
Seed Grant* recipient, Anna Victoria Molofsky, M.D., Ph.D.,
o昀昀ers a tangible look inside the brain. As many know, 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 speci昀椀c type of
brain cell, microglia, which are less responsible for signalsending 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 CNSi.Additionally, as reported by Dr.
Molofsky, they help to remodel the structural support
system, or the ECM, of the brain and pave the way for new
synapses to form, a groundbreaking concept that reveals a
novel function for microglia.ii
Left to right: Dr. Haruna Nakajo, Dr. Nick Silva, Dr. Anna Molofsky,
Dr. Lisa Randolph
Bringing Abstract Processes to Life
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 zebra昀椀sh come in. Though mice have long
been preferred for research due to their anatomical and
genetic similarities to humans, a growing method of study
involves using zebra昀椀sh, 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.”(image shown opposite)
That’s not to say that 昀椀sh 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 zebra昀椀sh brain housed microglia that interacted with
synapses similarly to those of a mammalian brain, the team
was able to invest in zebra昀椀sh and start asking deeper
questions. However, this meant making the considerable
transition from mice to 昀椀sh, a time-consuming and costly
endeavor for a laboratory primarily using the former.
“That’s where seed funding from 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 昀椀sh
in a scienti昀椀c se琀琀ing. Dr. Silva learned to work with zebra昀椀sh
during graduate school at the University of Michigan while
Dr. Nakajo garnered expertise in 昀椀sh behavior during her
Ph.D. training in Japan.
BRF’s Seed Grant has paid o昀昀. 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
di昀昀erent colors, their interactions can be visualized
under a microscope, o昀昀ering 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 昀椀sh became
*Dr. Molofsky's 2021 BRF Seed Grant was funded by the Carl & Marilynn Thoma Foundation
4 Brain Research Foundation Summer 2024