05.2020 | THE SCIENTIST 33© ISTOCK.COM, LEBAZELE
Rats and equations help researchers develop a theory of how the human brain
keeps track of past experiences.BY CATHERINE OFFORDMemories of Time
N
o matter how he looked at the data, Albert Tsao couldn’t see
a pattern. Over several weeks in 2007 and again in 2008,
the 19-year-old undergrad trained rats to explore a small
trial arena, chucking them pieces of tasty chocolate cereal by way
of encouragement. He then recorded the activity of individual neu-
rons in the animals’ brains as they scampered, one at a time, about
that same arena. He hoped that the experiment would offer clues as
to how the rats’ brains were forming memories, but “the data that it
gave us was confusing,” he says. There wasn’t any obvious pattern to
the animals’ neural output at all.
Then enrolled at Harvey Mudd College in California, Tsao was
doing the project as part of a summer internship at the Kavli Institute
for Systems Neuroscience in Norway, in a lab that focused on epi-
sodic memory—the type of long-term memory that allows humans
and other mammals to recall personal experiences (or episodes), such
as going on a first date or spending several minutes searching for
chocolate. Neuroscientists suspected that the brain organizes these
millions of episodes partly according to where they took place. The
Kavli Institute’s Edvard Moser and May-Britt Moser had recently
made a breakthrough with the discovery of “grid cells,” neurons that
generate a virtual spatial map of an area, firing whenever the animal
crosses the part of the map that that cell represents.^1 These cells, the
Mosers reported, were situated in a region of rats’ brains called the
medial entorhinal cortex (MEC) that projects many of its neurons
into the hippocampus, the center of episodic memory formation.
Inspired by the findings, Tsao had opted to study a region
right next to the MEC called the lateral entorhinal cortex (LEC),
which also feeds into the hippocampus. If the MEC provided
spatial information during memory formation, he and others
had reasoned, maybe the LEC provided something else, such
as information about the content of the experience itself. Tsao
had been alternating the color of the arena’s walls between tri-
als, from black to white and back again, to see if LEC neurons
showed consistently different firing patterns in each case. But
he was coming up empty-handed.While Tsao struggled to make sense of his data, a researcher on
the other side of the Atlantic Ocean was tackling a seemingly un-
related problem. Marc Howard, a theoretical and computational
neuroscientist then at Syracuse University, had filled a chalkboard
with equations describing how the brain might achieve the com-
plex task of organizing memories, according not to where they were
formed, but to when. His mathematical model showed that if the
passing of time was represented in a certain way in neural circuits,
then that time signal could be converted into a series of mental “time
stamps” during memory formation to help the brain organize past
experiences in chronological order. Without data to confirm his
model, however, the idea remained just that: an idea.
It would be several years before the two researchers became aware
of each other’s work. By the time they did, neuroscientists had started
thinking in new ways about how the brain keeps track of when expe-
riences occurred. Today, the theoretical and experimental advances
made by Howard, Tsao, and others in this field are helping to reshape
researchers’ understanding of how episodic memories are formed, and
how they might influence our perception of the past and future.
Back in 2008, however, Tsao was focused on finishing col-
lege. When his second summer in Norway came to an end, he
left the Kavli Institute and his confusing dataset behind, and
returned to California.Another dimension
When the cognitive neuroscientist Endel Tulving coined the term
“episodic memory” in a book chapter in 1972, he observed that recall-
ing the content of memories was linked to a strong subjective sense
of where and when an episode took place. The where component
has been a focus of neuroscientific research for decades. In 1971,
University of College London neuroscientist John O’Keefe discov-
ered place cells, neurons in the hippocampus that fire in response to
an animal being in specific locations.^2 He shared the Nobel Prize in
Physiology or Medicine with the Mosers in 2014 for their discovery
of grid cells in the MEC, and several studies published since sug-