Featured Scientist: Nicholas W.
Postdoctoral Scholar in Neurobiology
Name: Nicholas W.
Birthplace: Sunnyvale, CA
Field of Study: Neurobiology
What organism do you study?: Mus musculus (mice!)
Favorite thing about science: The more you learn, the more questions you have! As you do research, you end up discovering things that people never knew before!
"How do drugs of abuse change the brain?"
Our brains let us think, feel, and control our bodies, but drugs can affect the way our brains function, and can even change our brains permanently. At Stanford, I study how brain cells connect to one another (Figure 1), and how drugs of abuse like cocaine change brain circuits. To understand how drugs affect the brain, I take potentially dangerous tools like viruses, make them safe, and then use them to see how brain cells are connected before and after drug use.
Figure 1. Brain cells (blue) receive connections (purple) from many other cells in the brain.
The first question I want to ask is "do cocaine-activated cells in one part of the brain preferentially connect with cocaine-activated cells in other parts of the brain?". To answer this question, I need a way to see the connections. Normally, it would be very hard to make a tool to do this. However, there exist things in nature that are already very good at targeting brain cells and spreading across these connections. What are these things? Brain viruses! By changing a brain virus like rabies virus (Figure 2), we can both make the virus safe to use, and also express a glowing protein so that we can see brain connections under a microscope.
Figure 2. Regular rabies can infect mammalian brain cells
Figure 3. "Safe" rabies cannot infect mammalian brain cells
To make the rabies virus safe, I “fool” the virus into thinking it’s a bird virus, and can’t infect mammals like mice or humans (Figure 3). Even if you were exposed to this “bird” virus, nothing would happen, making it safe to work with. Now, I can trick brain cells that are affected by cocaine into thinking that they’re bird cells by having them make a bird protein. Once this bird protein is on the surface of the brain cell, rabies can infect these cells, while leaving the rest of the brain alone (Figure 4). The modified rabies then makes all brain cells that are connected to the cocaine-affected cells glow green, letting me see the complicated brain circuits impacted by cocaine under a microscope (Figure 5). To learn more about how scientists use rabies virus to understand the brain, check out this fantastic article!
We can see green cells all throughout the brain, showing that cocaine-activated cells in one place connect with brain cells in many other places. Many of these connected cells are themselves activated by cocaine, showing that cocaine cells like to connect with each other. In comparison, cells not activated by cocaine formed many fewer connections with cocaine cells. This allows brain signals related to a cocaine experience to travel from one place to another along a special "track", distinct from other types of signals.
If you think of brain connections like train tracks, the next thing we want to know is "does cocaine take over existing tracks to affect the way we feel, or does it make new tracks?" To figure this out, I compare brains from animals exposed to cocaine only once with animals that were exposed to cocaine many times. I can then see how their brains change with repeated drug use. If cocaine use makes new tracks, we will be able to see different patterns of brain connections.
Figure 5. The red dots show brain cells that are activated by cocaine. The green dots are cells connected to cocaine cells.
Figure 4. Mammalian cells expressing bird proteins can be infected by rabies, causing them and the cells they are connected to to glow.
Since I originally saw that cocaine cells connect with other cocaine cells all throughout the brain, I hypothesized that perhaps repeated cocaine exposure would make all of these connections even stronger. However, when I tested this hypothesis, that's not what I saw, to my surprise! After repeated drug use, cocaine cells still preferentially connected with other cocaine cells, but most of these connections stayed the same. Only a single part of the brain had cells that connected even more strongly after repeated cocaine exposure. What might this mean?
With repeated drug use, animals (including humans) can become addicted to the drug, making it harder to stop using the drug over time. I hypothesized that the changes in brain connectivity that I saw might lead to changes in behavior that are seen in addicted mice. To test this hypothesis, I used a tool that lets us turn off the connections from cocaine cells in the brain area I observed earlier. We saw that if we turned off these connections, we could prevent mice from behaving like addicted mice! Even though our initial hypothesis that all connections get stronger was wrong, we observed a special connection and found that this connection may be important for drug-related behavior. Being able to revise your thinking based on new evidence is one of the most important aspects of science!
What questions is Nicholas asking?
I've learned a lot as a neurobiologist at Stanford! I started with the question "how do drugs of abuse change the brain?", and based on my findings, I have all sorts of new questions I want to ask! Some questions include:
How does cocaine change the size and shape of connections between brain cells?
Do other drugs of abuse, such as opioids, change brain circuits in similar ways to cocaine?
Can we develop therapies that stop drugs from changing brain organization, and can these treatments prevent or disrupt drug addiction?
Do you have any questions about being a neuroscientist? Want to know more about brains, or how drugs of abuse can affect our minds and bodies?
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Image of a mouse brain where rabies-labeled cells are colored yellow.