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David Linden

David Linden

David Linden

on the formation of memory, the fun of lab work
and his recent book The Compass of Pleasure

What do you research?

I’ve been here at Hopkins for nearly 20 years now, and we work on trying to understand the molecular basis of memory storage in the brain. When people think of learning and memory, they usually think of memory for facts and events—declarative memory. That kind of memory is very interesting, but it’s extraordinarily difficult to study molecularly. Our focus has been a very simple form of learning: learning that is accomplished in the cerebellum, the baseball-sized thing that hangs off the back of the brain. It’s not involved in initiating movement, but it controls your ability to coordinate movements and gain motor learning. The cerebellum is a much simpler system that we can understand in depth.

Can you give an example of how the cerebellum helps us learn?

LINDEN: As information streams into the cerebellum, the cells inside forms new circuits—ways in which the neurons are connected to one another. Imagine an air puff is repeatedly sent into your eye as you hear a tone. The air puff information flows into the brain in one way, and the tone information flows into the brain in another way. These two streams collide with one another in the cerebellum. When the air puff and the tone occur at the same time over and over again, the streams collide repeatedly, leading to a change in how the neurons connect and communicate with one another. That change is what forms the memory in the cerebellum. At that point, when you hear the tone you will automatically blink, even if there is no air puff.

We’ve spent a lot of time trying to discover how the collisions of information in the circuit change the properties of neurons to create a memory. Understanding this process in great molecular detail allows us to make very strong predictions, and to find subtle manipulations we can do to test specific characteristics of memory formation.

How do you study these circuits in the cerebellum?

LINDEN: We are cellular physiologists, so we record electrical signals from brain cells. We do that using tiny electrodes or coloring the cells with fluorescent dyes that indicate if the charge in the cell changes. We spend a lot of time manipulating genes and proteins in individual neurons. One experiment is to interfere with a specific gene—by removing it or mutating it—and see whether the strength of connections between different cerebellum neurons changes. We can also watch the activity of neurons in the brain of a mouse itself. Right now we’re developing a task where a mouse has to reach in a certain way in order to get a food pellet, and we watch the electrical activity in the brain change as a result of experience. We can see it in extraordinarily great detail.

So how did you get into science?

LINDEN: I was a geeky kid and I knew I wanted to be a scientist from about first grade. I saw Jacques Cousteau on TV, so I wanted to be a marine biologist—like every other kid in California. But I also thought the brain was really cool. When I was a sophomore at Berkeley, I had to declare my major, and I couldn’t decide between neuroscience and marine biology … so I dropped out of college.

What did you do from there?

LINDEN: I had two motivations: I wanted to figure out whether I really liked marine biology or not, and I also wanted to make a whole lot of money and drive around North America with my girlfriend. So that’s what I did. I was a commercial scuba diver, collecting marine samples and surveying the marine environment, which was about the highest paying legal job that a 19-year-old can do.

Eventually, though, I realized that marine ecology is the kind of field where you can go your entire career in science and never know whether your idea was right or not. I was too much of a control freak for that. I belonged in a lab. After a few years I went back to college to be a neuroscientist. Memory storage was a big, mostly unsolved question in the field, and it seemed like a good thing to work on.

Your recent book, The Compass of Pleasure, brings neuroscience to mainstream readers. Why did you decide to write it?

LINDEN: I was looking for a story to tell in neuroscience where there’d been a lot of new advances, but it hadn’t yet been explained for the public. Pleasure processing seemed like the best topic to write about even though I don’t actually work on it in the lab. In a way, I prefer to write about things I don’t work on at all. When I have had to write about things that I actually work on in my own lab, what comes out is way more detailed than any lay person wants to read.

Why did you start writing books in the first place?

LINDEN: I was on sabbatical in Cambridge, England, when I wrote my first book, The Accidental Mind. A lot of professors on sabbatical like to get out from behind the desk and into a lab, doing things with their own hands again. I never stopped doing that, so I kind of needed a break from the lab at that point. I thought about how I’m always complaining that I don’t like many books about the brain written for general audiences, and so I decided to write my own.

Was the process of writing your second book easier?

LINDEN: Writing The Compass of Pleasure was a little bit easier because my skills were better, but mostly just because I was confident that I could do it. For me, it takes about a hundred days to write a book. My books are just 210-250 pages, because my goal is to get a person who’s never read a science book before to walk into the bookstore, see a book about human behavior, pick it up because they’re interested in the topic, and buy it. If the book is some big fat brick, the chance of them doing that is going to be much lower. After I write the book, it takes about another 100 days to deal with the illustrations, the proofs, and the marketing. That means running around doing interviews for print and radio and TV.

You’ve been at Hopkins for almost 20 years, and, as you’ve said, you still work in the lab. That seems like a rarity.

LINDEN: There are a handful of us. Not many, but there are a few others. Part of the reason that I still do bench science is because the kind of experiments that I do are extremely addictive. Recording from living cells gives information in real time, which makes it really fun. Over the years I’ve also gotten really good at it, so I get a lot of work done during the time I spend doing recordings.

Another advantage is that I can do experiments that are very risky. I can do the kind of experiments that if I gave them to a student or a postdoc to do, and they failed, their career would go down in flames. I’ve had experiments, for example, that it took five years to get working. But, for a student, that would be a tremendous disaster. In the end, though, some of the most exciting results come from long-shot experiments.

--Interviewed by Maryalice Yakutchik, written by Sarah Lewin

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