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A Series of Incremental Steps

Stanford Neurosciences Institute, NeuWrite West
Jan 16 2018

By Isabel Low

When I first got to graduate school, I spent most of each day in one building on campus. Each morning I left my apartment, got on my bike, and followed the same route to the building. At the end of the day it was back onto my bike and down the route home. If a seminar was in an unfamiliar building, I left plenty of time to find my way there, orienting myself with familiar landmarks, like the main quad in the center, or the particularly tall tower to the east. When my schedule changed, I stitched together old routes between buildings, taking a circuitous, but reliable path. I leaned heavily on the map in my phone and, as the weeks went on, my world widened.

One year later, I now take a different route to campus depending on if I’m biking or walking (the biking route is longer, but avoids a massive hill); when I encounter construction, I can quickly calculate the fastest detour; and I often find myself having taken a familiar path without even noticing the steps along the way. Where did this mental map of campus come from? Or, put another way, how is it that my brain helps me to navigate my environment?

As a graduate student in neuroscience, answering this question is both my job and my passion. I’m following in some pretty big footsteps. In 2014 three neuroscientists, John O’Keefe, May-Britt Moser, and Edvard Moser, were awarded the Nobel Prize for discovering a variety of brain cells that together comprise “an ‘inner GPS’ in the brain”.[1] Different brain cells represent different aspects of navigation: Some of those cells tell me where I am at this moment, others tell me the direction I’m pointing in, and still others how fast I’m moving. The Nobel press release presents a succinct and compelling story: three incredible scientists have deciphered the inner workings of the brain. What the press release cannot capture is the work of the army of graduate students—along with technicians and post-doctoral researchers—that went into that tidy story and, even more invisible, the work still to come.

I want to understand how the cells of this internal GPS communicate differently in different situations. For example, how do these cellular representations change when I am wandering campus, compared to when I am focused and moving towards a specific goal? In studying navigation, I’m striving to make my own contributions to the grand legacy of Nobel Laureates. But my day to day reality is not quite as glamorous as the press releases might lead you to expect. Most days I feel more like an amateur veterinarian, carpenter, and electrician than a scientist. I build things, break them, and put them back together again. Mostly I drink a lot of coffee. I’m trying to figure out how our brains help us navigate our world, but that shining scientific discovery lies at the end of a twisting path.

I can’t listen in on the cells in my own brain as I explore campus. Instead, I use mice to eavesdrop on the brain in ways we cannot yet do in humans, listening in on single navigation cells while the mouse explores. Then I can see how the cellular signals change when the mouse is focused, compared to when she is bored or inattentive. Except there’s one major complication: to record from the brain, I need the mouse’s head to be perfectly still—even a millimeter of movement would destroy my recording. To keep a mouse’s head still as she scampers around a box, snuffling into corners and scarfing down Cheerios is a seemingly impossible task. On good days, the design process for my experiments feels like working through a logic puzzle. On bad days it’s more of a dark labyrinth, full of traps and with no guarantee of a way out.

What kind of environment can be explored in full while never moving? The answer lies in virtual reality. If the mouse runs on a wheel while watching a movie of a virtual hallway, she will feel as though she’s running, while I keep her head perfectly still. My virtual reality set-up, didn’t arrive in a box one day, fully-assembled; it had to be built almost from scratch. We have no lab-electrician to wire connections, no programmer to code up a virtual environment, no carpenter to build the framework. Almost every piece is imagined, designed, built, and maintained by me or another graduate student in the lab. My running wheel is a four-inch wide slice of foam roller (literally what you might find at the gym for massaging sore muscles). The virtual hallway plays on three computer screens, one in front of the mouse and one on each side—a deluxe Imax theater for mice. As the wheel spins, it sends speed information to the computer, which syncs to my virtual hallway so that the walls slide convincingly by as the mouse runs.

Stanford Neurosciences Institute, NeuWrite West

Minderer, M., Harvey, C. D., Donato, F. & Moser, E. I. Neuroscience: Virtual reality explored. Nature 533, 324–325 (2016)

By inching my way through the winding maze of nested conditions and catch-22s, I have mostly built my set-up. Along with the running wheel, there’s the automated reward for each time the mouse finishes a lap, which also needs to sync to the virtual reality; the wires from the electrode itself; the light to illuminate the top of the mouse’s head; ground wires for everything—in the end I have a mess of wires. If something isn’t working, I plug and unplug, untangle, re-solder, re-code until it starts working again.

Of course, once my set-up was built, there was another hurdle to clear: I had to get the mouse on the wheel. I had never touched a mouse before graduate school, but the steps sounded simple. Grasp the tail firmly, but not too firmly, and lift the mouse from one place to another. It wasn’t simple. For the first several weeks of my training, each experiment I conducted started with long minutes of chasing a mouse around her cage with my hands, usually ending with a clumsy grip on her tail. Over time, the mice and I adjusted to each other. I learned to anticipate the way a mouse moves in a cage. They took turns scampering over my palm to get used to my scent, becoming comfortable with being held by a human.

Most of my days begin and end with the mice. In the morning, I bring them upstairs to start the day’s tasks—they explore, I eavesdrop on their brains’ activity. In the evening, I unplug the recording devices and put the mice away for the night, finishing by sweeping up the pile of tiny poops that has collected at the base of the running wheel.

How I feel about this day-to-day work hinges on a delicate combination of how much progress I’m making and how much sleep I’ve gotten lately. Most days I take pride that I am slowly improving at dozens of varied tasks. I look at my completed rig and see the culmination of hours of hard work, proof that I’ve learned skills I never thought I would know. Sometimes, sleep-deprivation and stress make the weight of tasks still to come and puzzles yet to solve feel unbearable. Often, I simply get lost in the minutiae. I spend ten hours training mice, soldering connections, and scrounging up the pieces I need to fix my set-up, then drop into bed without a second thought.

It is easy to lose track of where I’m coming from, and where all this work is leading me. Even as a second year graduate student, at the very beginning of what will be both an exciting adventure and an excruciating slog, I often forget the hundreds of other young scientists that are with me on this journey. The science we see most often is polished, wrapped up into a neat story with a pretty bow.  I read a scientific article and it seems so clean and straightforward. I see a Nobel press release and feel a mixture of awe and intimidation at the grand scale of the discoveries. But then my efforts come together and I’m eavesdropping on a single cell as the mouse runs, oblivious to my presence in her brain. I remember the reality of the scientific story. Behind each journal article, each press release, each incredible scientific discovery, there is a series of incremental steps, taken by coffee-fueled graduate students navigating a winding path.

[1] "The 2014 Nobel Prize in Physiology or Medicine - Press Release". Nobelprize.org.Nobel Media AB 2014. Web. 9 Dec 2017. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2014/press.html>

 

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