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Memories Are Made of This

  Memories Are Made of This  

By Tom Fields-Meyer • Illustrations by Noma Bar

After losing his memory, a writer seeks to understand the elusive nature of our recollections and how they are created, retained and recalled.

I never gave much thoughft to how my memory works until the day it stopped working. One morning, just before I turned 50, I was in my closet, choosing a shirt. Then — snap — I was lying in the emergency room, an IV tube in my arm and a neurologist asking me questions.

Four hours had passed.

My wife gently filled me in. That morning, I had become disoriented. When I didn’t recall our lunch plans with friends, she figured it was just run-of-the-mill absentmindedness. But when I didn’t seem to know that our oldest son was away at college, she grew concerned.

As she drove me to the hospital, I kept repeating the same series of questions, in the same order: We’re going to the hospital? Did you bring my wallet? What about my glasses?

She feared I’d suffered a stroke, but at the ER, a CT scan showed no brain hemorrhaging. Nor did I display any of the physical symptomsf typical of stroke.



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I do remember what the doctor told me as the fog lifted. “This is benign,” he said. The diagnosis: transient global amnesia. In other words, an inexplicable temporary memory loss. A brain MRI and an EEG confirmed there was no damagfe — or explanation.

Within days, I returned to my routine, but the doctor explained that I’d never recall those four hours. And I couldn’t help but feel disoriented and perplexed. How could I forget in a blink who came to dinner last night? Or that I had authored a book? If I define myself by the accumulation of my memories, what did it mean that they could all just disappear? What exactly is a memory, and where do our memories live?

fAs it turns out, a wide range of researchers at UCLA is working to answer such questions, seeking to understand, in the most fundamental and profound ways, how our memory works. “There are very few places around the world that have as many highly successful memory researchers as UCLA,” says Alcino Silva, PhD, director of the Integrative Center for Learning and Memory and Distinguished Professor in the Departments of Neurobiology, Psychiatry and Biobehavioral Sciences and Psychology.

And with our population aging, the topic has never been more relevant. “Next to cancer, Alzheimer’s disease is probably the most feared illness,” says Gary Small, MD (FEL ’83), director of the UCLA Longevity Center and professor of psychiatry and biobehavioral sciences. At age 65, you have a 10-percent risk of Alzheimer’s disease. By the time you turnf 85, it’s closer to 50 percent. But concern about memory isn’t limited to the elderly, Dr. Small says. “In fact, some studies show that the average 45-year-old already is showing cognitive decline.”

SO I SET OUT TO LEARN ABOUT THE WORKINGS OF MY MEMORY. Mine was hardly a new exploration; scientists and philosophers have been pondering the mysteries of memory since at least 2,300 years ago, when Aristotle postulated that our minds are a tabula rasa upon which our thoughts and memories are inscribed. Of this blank slate, he wrote, in On the Soul: “What it thinks must be in it just as characters may be said to be on a writing-tablet on which as yet nothing stands written: this is exactly what happens with the mind.”

  Dr. Alcino Silva  
  Dr. Alcino Silva: “We’ve shown ... that the way the brain allocates information to specific cells is not random, but highly regulated. This is important because by regulating what cells have which memory, we can link memories across time, so that one memory reminds us of another.”
Photo: Tawnie Silva

At UCLA, members of the faculty have, for decades, been working in that tradition to advance our understanding. In 1971, for example, Joaquín M. Fuster, MD, PhD, discovered and described the first “memory cells” ever found in the primate brain. Dr. Fuster’s work on memory at UCLA, where today he is professor emeritus of psychiatry and biobehavioral sciences, continued to evolve. In recent years, he and his colleagues have been utilizing the modern science of neuroimaging to clarify how the cerebral cortex stores and retains memory.

Among the first lessons that I learned in my own exploration is that memory encompasses a lot more than I had considered. Mayank Mehta, PhD, professor of physics, neurology and neurobiology and head of the W.M. Keck Center for Neurophysics at UCLA, offers a thought experiment to explain the workings of memory. Sitting behind his desk in his office on the UCLA campus, Dr. Mehta slowly sweeps his left arm horizontally through the air, from left to right, and challenges me to try to catch his hand.

It seems straightforward enough, but then Dr. Mehta enumerates the remarkably complex calculations and processes my brain must undertake to accomplish something as simple as predicting when a moving hand will arrive in a certain space in a certain period of time. “Even in trying to do this simple thing, your brain is using an enormous amount of memory and complicated math,” he says.

“When we think about memory, most people think of something like ‘Where did I park my car?’ But you use a lot of memory without even realizing it.” Stanfding near the edge of a cliff, for example, one unconsciously adjusts leg muscles based on memory of how to avoid a dangerous fall. Even shifting one’s body in a chair requires remembering how various combinations of positions help to maintain balance.

To put his own work in context, Dr. Mehta explains that memory research has evolved in three significant phases over the past half-century. First, scientists pinpointed which brain regions were responsible for specific types of memory: The hippocampus is necessary for spatial memory or following a conversation; the basal ganglia is needed for learning how to ride a bicycle.

A new wave of research focused on two areas. Neurophysiology looked closely at the workings of neurons and changes in synapses, while other researchers focused on the activity of neurons in animal behaviors. But working separately, scientists in these various fields can achieve only a limited understanding of memory, Dr. Mehta says. “Each individual synapse is highly complex, and each individual neuron does something highly complex,” he says. “The big question is, how is all of this working together?”

  Memories Are Made of This  
  In this image of a memory being created, synapses (pink and orange) between sensory (green) and motor (blue) neurons from the sea slug Aplysia californicaare are strengthened as new proteins are synthesized.
Image: Courtesy of Dr. Kelsey C. Martin

Dr. Mehta places his own work in a new wave of memory research examining emergent phenomena, a process he compares to watching a flock of geese fly rather than observing a single bird. “Each individual bird has no idea what it’s doing,” he says, “but a collection of birds flying has an interesting pattern.”

While there are plenty of experimental data and many theories about memory, what is needed, Dr. Mehta says, is an integrated approach in which the experiments and mathematical theories are tied together. “We need a new breed of researchers who are not only conversant with complex mathematics, but also are unafraid of the complexity of biological data or of doing sophisticated experiments.”

This integrated approach has yielded significant new insights. For example, Dr. Mehta’s research showed how neurons in the hippocampus rapidly construct maps of space, on the fly, using synaptic plasticity, and how neural rhythms play a crucial role in generating these maps. “These insights linking synapses to neurons and behavior would not have been possible if they had been done only with good experiments or only with good mathematical work; the integration between the two was crucial.”

One fascinating way his lab has studied the workings of spatial memory is by recording the activity of many individual neurons simultaneously while rats navigate a maze in immersive virtual reality. Dr. Mehta explains that in remembering how to get places, we typically use a variety of sensory input: visual cues, scents, sounds, textures. In virtual reality, with only visual cues, the rats appeared to be able to keep track of distances, but they failed to create the kind of mental map they would in the real world. The rat experiment had another surprising result. When the rat was operating in the virtual world, 60 percent of its neurons stopped firing, a phenomenon Dr. Mehta can’t fully explain. But he says that with the large number of people experiencing virtual reality either for entertainment, military training or other purposes, it’s worth investigating the impact of the experience on the brain.

On the other hand, he says the fact that so many neurons shut down so easily offers promise of finding ways to do the opposite: to enhance memory. “There’s potential for revolutionary technologies,” he says, “to activate the brain and do all kinds of things.”

WHILE THE IMAGE OF SMALL, FURRY CREATURES scurrying through a virtual-reality maze is both fascinating and cute, what I really want to know is more basic: What is a memory? It’s not a new question, says Kelsey C. Martin, MD, PhD, professor of biological chemistry, psychiatry and biobehavioral sciences and interim dean of the David Geffen School of Medicine at UCLA. “There’s been a long debate about whether or not there is something called an engram, a physical location of the memory,” she says.

Our memories, Dr. Martin says, exist in the brain’s circuitry, enmeshed within the vast network of connections among our brain cells and not collected in a single repository. Each of us has about 85-billion neurons, and each of those is connected through more than a thousand synapses to other neurons. This circuit of 100-trillion connections forms the foundation of our ability to perceive, feel, imagine — and remember.

  Dr. Kelsey C. Martin  
  Dr. Michael Fanselow  
  Top: Dr. Kelsey C. Martin: “I want to understand when a person has had an experience that changes the structure of his or her brain, what happens? And I think about it on a molecular level.” Photo: Ann Johansson Bottom: Dr. Michael Fanselow: “Traumatic memories, unless treated, will stay with you forever. They never go away. We’re doing exciting things to determine how we can reverse these physiological changes and get the brain back to a normal state.” Photo: Reed Hutchinson

Dr. Martin’s work focuses on how our experiences alter those connections through a phenomenon called synaptic plasticity. “Who we are is a combination of our genes — what we’ve inherited — and the experiences we have,” she says. “To me, it’s hard to think of a more profound definition of what our identity is.”

The idea that memory exists within the brain’s circuitry rather than being focused in any one place is more than a century old. Long before scientists understood molecular biology, the Spanish neuroscientist Santiago Ramón y Cajal, who won the Nobel Prize in Physiology or Medicine in 1906, hypothesized that memories are stored as changes in the number of connections that form between brain cells.

A cell biologist, Dr. Martin explores precisely how those changes occur. “I want to understand which genes get turned on and off to be able to change connections in a permanent way,” she says.

Dr. Martin’s interest in memory stems from both her drive to bring relief for such conditions as Alzheimer’s disease and her passion for cell biology. “I want to understandf when a person has had an experience that changes the structure of his or her brain, what happens?” she says. “And I think about it on a molecular level.”

Her interest in the mind goes back to Harvard College, where she majored in English literature because she was fascinated with closely observing how people behave. Later, after earning her MD and PhD from Yale University, she did postdoctoral work at Columbia University with Nobel laureate Eric Kandel, MD, as he studied sea slugs to gain insights into how neurons store memories. Dr. Martin later advanced that work at UCLA, where, using brain cells from a sea slug and a fluorescent dye, she and her team actually imaged a long-term memory as it was being created in the process of proteins forming between the neurons.

“My work has moved to a subcellular level,” she says. “We’re not looking at a single neuron, but rather the synaptic connection that a neuron forms with another cell.”

She is an active participant in the Integrative Center for Learning and Memory, a forum for a variety of specialists — cell biologists, brain-imaging specialists, systems neuroscientists, computational experts and others — to regularly meet, discuss current research and learn from each other.

The implications of her work are profound, both for improving memory and for interfering with it in beneficial ways. Understanding exactly how memories are stored in the brain’s circuitry could lead to therapeutic benefits for people suffering from various forms of dementia. And knowing how to alter synaptic changes might help scientists find ways to rid people of debilitating traumatic memories. “That’s a good side of plasticity, that you could interfere in ways that help people,” Dr. Martin says.

HELPING PEOPLE RECOVER FROM SUCH DAMAGING MEMORIES is a central focus for another UCLA memory researcher, Michael Fanselow, PhD, Distinguished Professor of Behavioral Neuroscience. Dr. Fanselow studies how we form “fear memories” and, in particular, how memories rooted in fear can lead to crippling levels of anxiety and traumatic-memory disorders.


The Father of Memory

Joyce Brandman


Joaquín M. Fuster, MD, PhD
Photo: Ann Johansson

The idea that our memories are made of connections among the mesh of neurons in the brain originated with the Spanish neuroscientist Santiago Ramón y Cajal near the end of the 19th century. Almost 80 years later, another Spaniard, working 6,000 miles away, at UCLA, would, for the first time, identify and describe “memory cells” within that network in the primate brain.

The pioneering work of Joaquín M. Fuster, MD, PhD, from the mid-1950s onward to understand cognitive function laid the foundation for much of the memory research now being done at UCLA and elsewhere, making him, in some respect, the patriarch of modern memory science — padre de la memoria. His nine books and numerous articles and chapters explore the mysteries of the cerebral cortex, and his autobiography occupies nearly 40 pages in a collection that illuminates the history of neuroscience. An endowed chair at UCLA carries his name: the Joaquín Fuster Chair in Cognitive Neuroscience.

Dr. Fuster, who today is professor emeritus of psychiatry and biobehavioral sciences and who continues his research at the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, was born in Barcelona in 1930, where he grew up amid the turmoil of the Spanish Civil War (his father was a medic on the Republican side) and World War II. After training as a psychiatrist and earning his MD from the University of Barcelona, he came to UCLA in 1956 as a fellow (he joined the psychiatry and anatomy faculties in 1960) and received his PhD from Spain’s University of Granada in 1967. An intellectual disciple of his famous countryman — a first-edition from 1904 of Cajal’s Textura del Sistema Nervioso del Hombre y de Los Vertebrados is proudly displayed among the volumes on the bookshelf of Dr. Fuster’s impeccably tidy office — he always has been fascinated by the hidden workings of the human brain and mind.

In his research into the mechanisms of memory, Dr. Fuster brought space technology into his laboratory. After training monkeys to perform memory tasks — selecting a specific color or shape after having heard earlier an associated tone, for example — he and his students applied small probes that had been modified from ones designed to cool electronic components of satellites in space. The probes temporarily chilled selected areas of a monkey’s cortex, impairing short-term memory and the associated task. But when the area was rewarmed, memories were reawakened, and the monkey was again able to perform the task. As those memories came back online under normalized conditions and temperature, the researchers could record and measure the electrical firing of memory-retaining neurons, thus confirming the presence of “memory cells,” which are temporarily activated within the larger network. Dr. Fuster’s landmark research was published in Science in 1971.

Dr. Fuster describes these memory cells as a window onto the liberally distributed networks that make up our long-term memory, snippets among the whole that we require for retention of information in “working memory” to make future choices and decisions. His findings would later be confirmed in humans through the evolving science of brain imaging.

— David Greenwald

“Neuron Activity Related to Short-Term Memory,” Science, August 13, 1971

Dr. Fanselow has his own idea of the most widespread misconceptions about memory. Most people, he says, assume that memory is mostly about recalling the past. “That’s a nice byproduct,” he says, “but what we really need is to be able to anticipate the future, so that we’re prepared.”

That’s where the role of fear comes in. In evolutionary terms, if an animal misses an opportunity to eat or mate, the chance is likely to come again. “But if I fail to protect myself against a threat,” Dr. Fanselow says, “I most likely am dead.”

While fear helps us to protect ourselves, our fear memories are so strong and overpowering that when they’re misdirected, they pose challenges. When our brains remember things — often subconsciously — that we don’t need to remember, the result can be disabling levels of anxiety. The National Institutes of Health estimates that as many as one-in-three Americans suffers from an anxiety disorder at some time in his or her life, making anxiety the most common psychological or mental problem. Among the most debilitating forms of anxiety is post-traumatic stress.

Dr. Fanselow seeks ways to make emotional memories appropriate to the situation. “We look at how we can make fear memories specific only to threatening situations,” he says, “and seek to get a handle on the anxiety that’s not serving us.”

Significantly, we aren’t always conscious of what we remember. Just as putting on a pair of pants requires a complex combination of memorized skills that we’re hardly aware our bodies are recalling, we can experience fear memories without even realizing it or understanding their origin. Dr. Fanselow gives the example of a worker buried alive in a construction accident and deprived of oxygen. “Later,” he says, “he can’t remember any of the events that happened, but he still experiences post-traumatic stress, still has nightmares.”

Helping patients to overcome such challenging anxiety disorders requires far more than simply offering reassurance that the person need not be afraid. Instead, Dr. Fanselow says, “you really have to retrain the brain” through cognitive behavior therapy, a process of exposing the individual to the frightening experience while making sure no negative outcome occurs.

Dr. Fanselow is investigating other promising interventions. His lab has isolated a particular protein involved in creating memories that appears to be elevated in the case of traumatic stress. His team is working in animal studies to find ways to block the protein, diminishing the overly strong reactions that lead to disabling levels of anxiety.

“Traumatic memories, unless treated, will stay with you forever. They never go away,” Dr. Fanselow says. “But we’re doing exciting things to determine how we can reverse these physiological changes and get the brain back to a normal state.”

PART OF WHAT MAKES UCLA SUCH A FERTILE PLACE for memory research is that scientists working on such problems are not in isolation. Dr. Silva notes one significant paper on memory that drew on the work of five different UCLA labs. “Some of the work we have done in our lab we couldn’t have done anywhere else,” he says. “Collaboration isn’t just about being warm and nice; it’s about doing science that you couldn’t otherwise do.”

His own lab works on trying to understand memory on multiple levels — the genetic, protein, cellular, circuitry — with a particular emphasis on the genetic basis of learning and memory. “We look at how you can trace the story from molecules to behaviors,” he says.

Some of Dr. Silva’s early work focused on how genes regulate the changes in connections between brain cells. Just as changing hard discs is critical for a computer’s memory, he says, changing these connections between neurons is critical for learning and memory.

That work has led to promising breakthroughs for people with genetic disorders that affect memory and learning. Dr. Silva’s team studies neurofibromatosis, Noonan syndrome, tuberous sclerosis and other genetic conditions that have an impact on learning. Previously, scientists assumed that since these conditions stifled brain development so early in life, it was impossible to restore cognitive function later in life.

But in studies of mice, Dr. Silva’s team found ways to repair large learning and memory deficits in adults with the condition. That led to clinical trials in human adults that are beginning to show promise. “This gives us hope that these neurodevelopmental disorders may not be as hopeless as people have thought,” Dr. Silva says.

Another focus of Dr. Silva’s work has been studying memory allocation, the way the brain stores memories. It’s known that different parts of the brain handle different types of memory. The prefrontal cortex, for example, is crucial for working memory, the ability to remember and use relevant information while in the middle of a task, while explicit memory — conscious, intentional recollection — depends heavily on the hippocampus, and emotional memory is tied to the amygdala.

“What we’ve shown is that the way the brain allocates information to specific cells is not random, but highly regulated. This is important because by regulating what cells have which memory, we can link memories across time, so that one memory reminds us of another,” Dr. Silva says.

Since he’s immersed in memory research, I ask Dr. Silva about what people most misunderstand about memory. He explains that our memories are both far less reliable and far less comprehensive than most people assume. “Memory is more about forgetting than it is about remembering, actually,” he says.

By way of example, he explains how different your brain’s memories of a trip to Paris can be from the images in the hundreds of photos you might take. You might remember seeing the Eiffel Tower or enjoying a fine meal, but not the man in the black scarf you saw walking across the Champs-Élysées or the waiter who breezed by you during dinner at Tour d’Argent. “When our memories become too faithful,” he says, “they become a burden to us.”

It is a profound thought — and one that makes me a little less disturbed about that morning I’ll never remember.

Tom Fields-Meyer is a freelance writer in Los Angeles and the author of Following Ezra: What One Father Learned About Gumby, Otters, Autism, and Love from His Extraordinary Son (New American Library, 2011).  

















































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