No matter how he looked at the data, Albert Tsao couldnt 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 neurons 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 wasnt 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 episodic memorythe 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 Institutes 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. 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.

Together, these cells coded for time.

May-Britt Moser, Kavli Institute

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 arenas walls between trials, 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 complex 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 others work. By the time they did, neuroscientists had started thinking in new ways about how the brain keeps track of when experiences 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 college. When his second summer in Norway came to an end, he left the Kavli Institute and his confusing dataset behind, and returned to California.

When the cognitive neuroscientist Endel Tulving coined the term episodic memory in a book chapter in 1972, he observed that recalling 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 OKeefe discovered place cells, neurons in the hippocampus that fire in response to an animal being in specific locations. 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 suggest that grid cells help the hippocampus generate place cells during memory formation.

How the brain encodes the when of memories has received far less attention, notes Andy Lee, a cognitive neuroscientist at the University of Toronto. Space is something we see, its easy to manipulate. . . . Its somewhat easier for us to grasp intuitively, he says. Time is much harder to study.

Despite the thorniness of the subject, researchers have established in the last decade or so that the brain has multiple ways to tell time, says Dean Buonomano, a behavioral neuroscientist at the University of California, Los Angeles, and author of the 2017 book Your Brain is a Time Machine. Time is integral to many biological phenomena, from circadian rhythms to speech perception to motor control or any other task involving prediction, Buonomano adds.

One of the biggest breakthroughs in understanding time as it relates to episodic memory came a few years after Tsao completed his internship, when the late Boston University neuroscientist Howard Eichenbaum and colleagues published evidence of time cells in the hippocampus of rats. Hints of time-sensitive cells in the hippocampus had been trickling out of labs for a couple of years, but Eichenbaums study showed definitively that certain cells fire in sequence at specific timepoints during behavioral tasks: a rat trained to associate a stimulus with a subsequent reward would have one hippocampal neuron that peaked in activity a couple hundred milliseconds after the stimulus was presented, another that peaked in activity a few hundred milliseconds after that, and so onas if the hippocampus were somehow marking the passage of time.

The findings, which are beginning to be extended to humans thanks to work by Lees group and a separate team at the University of Texas Southwestern, among others, generated interest in the representation of time alongside space in episodic memories. Yet it was unclear what was telling these cells when to fire, or what role, if any, they played in the representation of time passing within and between individual episodic memories. For Marc Howard, long fascinated by questions about the physical nature of time and the brains perception of it, the puzzle was a captivating one.

In the years leading up to Eichenbaums paper, Howard and his postdoc Karthik Shankarhad been developing a mathematical model based on the idea that the brain could create a proxy for the passage of time using a population of temporal context cells that gradually changes its activity. According to this model, all neurons in this population become active following some input (a sensory stimulus, for example), and then relax, one by one, creating a gradually decaying signal that is unique from moment to moment. Then, during memory formation, the brain converts this signal into a series of sequentially firing timing cells, which log moments within a memory. The same framework could also work to tag entire episodes according to the order in which they took place.

The specific mathematical details of the modelin particular, the use of an operation called a Laplace transform to describe how temporal context cells compute time, and the inversion of that transform to describe the behavior of the hypothesized timing cellsnicely recapitulated several known features of episodic memory, such as the fact that its easier to remember things that happened more recently than things that happened a long time ago. And after hippocampal time cells, with their sequential firing patterns, were described in 2011, Howard, by then at Boston University, was gratified to see that they seemed to possess many of the properties he and Shankar had predicted for their so-called timing cells.

But the first piece of the puzzle was still missing. No one had identified the gradually evolving set of temporal context neurons needed to produce the time signal in the first place, Howard says. We waited a long time for somebody to do the experimentreally just moving the electrodes over to the LEC and looking for it.

After graduating from Harvey Mudd in 2009, Tsao returned to the Kavli Institute for a PhD. Although he mostly worked on other projects, by the end of his program hed convinced himself, and the Mosers, that the rat experiments from his summer internship were worth another look. Tsao was an exceptional student, May-Britt Moser says, and the Kavli team trusted that his data were correct, but we didnt know what we were seeing. The neurons in the LEC seemed to be behaving so unpredictably.

Digging back into his old work after he graduated from his PhD program, Tsao began thinking about better ways to analyze the dataset. We had always looked at activity at the level of individual neurons, he says. At some point, we decided to look at it at the entire population level. In doing so, Tsao revealed that LEC activity was, in fact, changinggradually, within and between trials.

IKUMI KAYAMA, STUDIO KAYAMA

Its unclear how the brain keeps track of the timing of events within a memory. One theory posits that, as memories are formed, temporal information about the experience is represented by gradual changes in activity in a particular population of neurons situated in the brains lateral entorhinal cortex (LEC, yellow region). These neurons, called temporal context cells, become active at the beginning of an experienceas a rat explores an arena, for exampleand then relax gradually, at different rates. Other brain cells (not shown) may also become more active throughout an experience, or change their activity on a slower time scale, spanning multiple experiences. This information is fed into the hippocampus (pink region), which generates time cells. These cells become active sequentially at specific moments during an experience to mark the passage of time.

ikumi kayama, studio kayama

Some researchers hypothesize that, because the signal provided by the LEC is unique at any one time point, activity in this brain area could help timestamp memories themselves to allow temporal organization of individual episodes, in addition to marking time within experiences. Together, these records of time may help create the brains sense of when and in what order events happened, and could potentially aid the recall of memories later on by reinstating past patterns of activity.

IKUMI KAYAMA, STUDIO KAYAMA

Data from further experiments, carried out by Kavli researchers after Tsao moved to Stanford University for a postdoc in 2015, showed that a whole cluster of cells within the LEC became active at the beginning of trials, and then that activity decayed as individual neurons relaxed at various rates. Other cells in the LEC, meanwhile, seemed to become gradually less (or sometimes more) active over the course of the entire experiment. Looking at the data this way, the team was able to distinguish individual trials not just according to wall color but, far more intriguingly, by the order in which the rat had done them, explains May-Britt Moser. Together, [these cells] coded for time.

Publishing the findings in late 2018, the team cited Howards and Shankars work, highlighting how the sort of activity patterns Tsao had seen in the LEC neuronal population matched up with the pairs theoretical predictions. The Norwegian group also noted that this evolving signal seemed able to track passing time over multiple timescaleschanging fast enough to distinguish between individual moments on the scale of seconds within a single episode, as well as to distinguish whole episodes from one another over the scale of minutes or hours. On reading the teams findings, I was ecstatic, Howard says. It was really a big deal for me.

The paper was exciting for many in the neuroscience community, and its publication was followed by a burst of theoretical work from several groups, not just Howards. Edmund Rolls, a computational neuroscientist at the University of Warwick, incorporated the findings from the Kavli groups 2018 paper into a model that explored how interacting networks in the brain might convert gradually changing LEC activity into a sequence of hippocampal time cells, based on a framework hed developed more than a decade earlier to explain how grid cells might lead to the generation of place cells.

Additional experimental data started flowing in, too. Howard and colleagues, for example, analyzed recordings from monkeys entorhinal cortexan area containing the MEC and LECand found activity similar to that observed in Tsaos rats, according to a preprint published last summer on bioRxiv. Specifically, a cluster of neurons in the entorhinal cortex spiked after a monkey was presented with an image, and then returned to baseline, with different neurons relaxing at different rates. Just a couple of months later, researchers in Germany reported that activity recorded from the human LEC could be used to reconstruct the timeline of events people experienced during a learning task.

The gradual change in LEC activity wasnt the only novel result from Tsaos paper. Several groups picked up on a related finding that the rate of change in the LECand indeed in many areas of the brainmay depend on the sort of experience an animal is having. That phenomenon might help explain why the passage of time within episodic memories seems so subjective.

As a follow-up to his original experiments with the rat arena, Tsao had done a couple of additional trials during his Kavli internship with a figure-eight maze. In each of those trials, instead of freely exploring an arena, the rat would run around the maze, following the track left, then right, then left, and so on. After discovering patterns in rats LEC neuronal firing during arena trials, Tsao hoped to see something similar in data from the figure-eight mazessomething that would distinguish trials from one another according to when they took place. But . . . it turned out we couldnt tell them apart very well, says Tsao. For a while this was very disappointingthis was basically the opposite conclusion that we had reached from the [arena] experiment.

It wasnt until Tsao dug into the literature on episodic memory that he came to realize what might be going on. Maybe its not so much about physical time, as you measure in clocks, but more about subjective time, as you perceive it, he says. Running in a twisted loop was a repetitive, boring task compared to exploring an arena, and the rats LEC seemed to reflect that by changing its activity less substantially during the figure-eight experiment than it had during the arena experiment. It seemed as though the rats brain wasnt really experiencing individual figure-eight trials as distinct events, at least not to the extent it had for arena trials, Tsao says.

This link between the type of experience and the way time is represented in neurons touches on a well-known quirk of episodic memory. Its easier to pick out memories from a week of exciting and varied activities than from a week filled with normal, uninteresting tasks, and the former feels much longer than the latter when its recalled. (This is different from the sensation of time dragging when doing something boringan effect of consciously counting time as it passes rather than representing it in a memory of the event, notes Buonomano.) Tsaos study hinted that part of this subjective effect might arise because the LEC, which receives neural input from areas involved in processing sensory information, changes its activity to a greater degree during more complex experiences than during ones that require little processing. It implies, Tsao speculates, that time in memory might be entirely drawn from the content of your experiences, as opposed to being coded as an explicit thing.

Although neural recordings are challenging to carry out in humans, functional MRI (fMRI) data from other research groups has helped flesh out the link between the rate of activity changes in the cortex and the representation of time in memory. Kareem Zaghloul, a neurosurgeon and neuroscientist at the National Institute of Neurological Disorders and Stroke and a big fan of Marc Howards work and his model, had been running an experiment on the effects of brain stimulation on human memory around the time Tsaos paper came out. As part of their project, Zaghloul and his colleagues decided to use their dataset to look at how temporal context might influence memory formation. We hypothesized that perhaps the extent to which these signals of time change, maybe that affects your ability to distinguish memories from one another, Zaghloul says.

Participants in his groups study had been asked to learn pairs of words, such as pencil and barn, and then remember these pairs later while avoiding confusing them with other pairs theyd learned, such as orange and horse. Measuring activity using electro-encephalography across broad regions of participants brains while they learned the word pairs, the researchers found that the faster a persons neural activity changed during the learning task, the better they performed on memory recall later on.11 Electrical stimulation of participants brains during the learning task didnt have a consistent effect on the rate of activity change, Zaghloul adds, but when it made it faster, people tended to do better at remembering the word pairs, and when it made it slower . . . people tended to do worse, he says. The findings, published last year, suggest that this representation of time does play a role in your ability to lump or distinguish memories, he says.

That the sense of time in episodic memory might be dependent on neural activity rather than on a traditional clock reinforces some researchers belief that the brain perceives time rather differently from how people imagine it to. Buonomano and New York University neuroscientist Gyrgy Buzski have independently argued before and since Tsaos work that neuroscientists should rely less on preconceived notions of time and instead think more about how time-related information might be used by the brain. The sole function of memory is to allow animals to better prepare for the future, says Buonomano. Sometimes the field forgets that detail.

Tsao is still studying the brains of rats as a postdoc at Stanford University, although his focus has shifted to other topics in neuroscience. But for other researchers studying the representation of time in episodic memory, the work has only just begun.

May-Britt Moser says her group is continuing the line of research Tsao started, exploring how the hippocampus in rats integrates temporal and spatial information from the LEC and MEC during memory formation. The ideas been around for a while. Several years ago, Eichenbaum and colleagues reported that rats time cells seem sensitive to spatial as well as temporal information. More-recent research has complicated the story further, identifying time cells outside the hippocampus, and finding that some place cells seem to respond to time-related signals from the LEC, leading some neuroscientists to propose that the hippocampus possesses different time-tracking systems for different timescales.

To Howard, one of several theoreticians who has modeled how the brain might combine signals encoding the when and where of episodic memories, the blurred boundary between space and time is intuitive. Having originally trained in physics, he says, I was pretty sure that the brains representation of space and the brains representation of time ought to obey the same equations, whatever the scale. He and many other neuroscientists are now working under the assumption that the brain uses a unified representation of space and time in remembered experiences. And at least for some aspects of memory, Howard says, I think thats the story thats starting to unfold now.

While Tsaos work focused on how time is encoded during memory formation, some groups are working on the other side of the coin: what happens during the process of memory retrieval. Researchers at the University of California, Irvine, recently reported that people who showed higher LEC activity during a memory retrieval task were better at recalling when specific events in a sequence happened, supporting a role for the LEC in a sense of time during memory retrieval as well as formation. Zaghloul, Howard, and others, meanwhile, have independently published work showing that when people successfully recall memories, they seem to reinstate the activity patterns in the medial temporal lobea region that includes the hippocampus and the entorhinal cortexthat were present when that memory was formed. Its an effect, notes Zaghloul, thats thought to allow a sort of jump back in time on recalling a memory.

Such an ability to reinstate past activity patterns could have applications to the brains representation of events that havent yet happened, too, Howard says. It occurred to us quite a while ago that if the brain has equations of the past, you could construct an estimate of the future with the same types of properties. Empirical data to test the idea are lacking for now. One of the first things to do will be to figure out how the brain could skip back or forward to different activity states, because we dont currently have algorithms that can do that, Howard notes. Were actively working on . . . figuring out a set of equations to describe the how of jumping back in time. Actually, Im looking at my chalkboard right now, and Im pretty optimistic.

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How Time Is Encoded in Memories - The Scientist