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In Vivo

By Susan Conova

Esteemed neuroscientists are at a loss to explain my incredible memory. Let me give you just one example.

A few months ago an old family friend was in town and wanted to meet. I hadn’t seen
Ken Miller (left) and Larry Abbott (right) with students and researchers in the new Center for Theoretical Neuroscience.
Ken Miller (left) and Larry Abbott (right) with students and researchers in the new Center for Theoretical Neuroscience.
“Uncle Dave” in 20 years. As I approached our prearranged meeting spot, I was a little worried. How would I recognize him? Would I have to resort to asking complete strangers, “Are you my Uncle Dave?” But when I spotted a 60-ish man with a round face, glasses, and dark hair, my 20-year-old memory resurfaced and I recognized him instantly. Like I said: Incredible.

“We have no clue how you can do this,” admits theoretical neuroscientist Ken Miller, Ph.D., professor of physiology and cellular biophysics. “On one level, we understand a lot about the machinery of the brain – its cells, the synapses, the molecules – and on a broader descriptive level we know that different regions of the brain perform specific tasks. But we don’t know the computations it performs. We don’t even know how you can see an object when you open your eyes.”

“Neuroscience understands how information gets into the brain and how motor movements get out,” says Larry Abbott, Ph.D., professor of physiology and cellular biophysics. “It’s the whole middle ground that’s completely missing.”

To explain the middle ground and truly understand how the brain works, it is no longer sufficient to rely on molecular biology, genetics, and cell biology. Detailed knowledge of cells, synapses and molecules does not automatically lead to an understanding of how a memory forms or how vision works. It is now necessary to develop theory and models to bridge the two levels, Drs. Miller and Abbott say.

Realizing the need for neuroscience theory, in fall 2005 Columbia established the Center for Theoretical Neuroscience, one of the few places in the country with a critical mass of theorists in one place. Directed by Drs. Miller and Abbott, the center includes Ning Qian, associate professor of physiology and cellular biophysics, who’s been at Columbia since 1994, and two new recruits, Liam Paninski, Ph.D., assistant professor of statistics, and Stefano Fusi, Ph.D., senior research associate in the Center for Neurobiology and Behavior. A physics professor from Princeton, Bill Bialek, Ph.D., has joined the center on a visiting basis.

Despite the need for theoretical neuroscience, until recently the field didn’t garner much respect.

“With some notable exceptions, model building in neuroscience has not been very productive, partly because it’s easy to build a model that explains something,” says one of Dr. Abbott’s most recent collaborators, Eric Kandel, M.D., University Professor of Physiology & Cellular Biophysics, Psychiatry, and Biochemistry & Molecular Biophysics. “But what a model needs to do is make predictions that you can test experimentally to see if its suppositions are correct. Ken and Larry have been breaking new ground in that regard by collaborating with experimental neuroscientists.”

Drawn To a New Frontier

Most members of the center are among a pioneering wave of mathematicians and physicists who have switched to neuroscience. Dr. Abbott used to be a particle physicist (one of his last papers was titled “Constraints on the Neutrino Mass from Supernova Data”); Dr. Fusi was a quantum physicist, and Dr. Miller had completed all requirements except the dissertation for a Ph.D. in physics, receiving an M.S. on the way, before theoretical neuroscience got hold of him and he switched to a Ph.D. program in neuroscience.

“People are drawn to physics because they’re interested in fundamental problems,” Dr. Miller says. “All the fundamental questions about how the brain works are still wide open.”
Like my remarkable ability to recognize my friend Dave. First, I had to remember who Dave was. How did that memory last so long?

Dr. Fusi, who works on memory with Dr. Abbott, says that everyone’s memory is incredible (OK, so it’s not just me). When people are shown 10,000 pictures and then shown the pictures one week later, they will be about 80 percent accurate in identifying the ones they saw before,” Dr. Fusi says.

But Dr. Fusi noticed that if older memory models were correct, no one would remember a single picture (and I should have forgotten about Dave a long time ago). In fact, I should have forgotten him only a few minutes after meeting him.

One problem in modeling memory stems from two contradictory aspects of our memory: We are fast learners and so our synapses can change rapidly to record a memory. But we’re also good at retaining those memories for decades and for that synapses need to be rigid and stable. Memory models must combine these two conflicting characteristics.

Drs. Fusi and Abbott realized that models that predicted that memory is unrealistically short relied on outdated notions of synapses. When researchers first realized decades ago that synapses are responsible for creating and storing memories, they envisioned a simple on-off switch. When a memory is stored the synapse is switched on and strengthens; when a memory is forgotten the synapse is switched off and weakens.

But newer data show that synapses are actually more complicated and a cascade of biochemical changes occur during memory formation. Some changes occur quickly, like the increase in membrane receptors, and others like protein synthesis take longer. Drs. Fusi and Abbott used that newer data and produced a highly accurate, first-ever model that shows how we can both learn well and remember well. The findings were published in the Feb. 17, 2005, issue of Neuron.

“The cascade of changes that occur in a synapse has largely been written off as ‘biology is always complicated’ but our model suggests that complexity is there because it’s required to make memory work,” Dr. Abbott says.

“We’re still a long way from explaining how you recognized your friend,” Dr. Miller says, “but we think that with theorists and experimentalists working together we can get there.”