• Time flows, time flies, time stands still.

Time flows, time flies, time stands still. (Photo : @GilCosta)

A team of neuroscientists at the Champalimaud Center for the Unknown in Lisbon, Portugal has discovered the activity of certain neurons in a deep region of the mouse brain can be manipulated to induce the animal to under- or overestimate the duration of a fixed time interval.

This is the first time scientists have identified neural circuitry that modulates judgments of elapsed time -- at least in the mouse brain.

Like Us on Facebook

These results offer a neurobiological answer to the long-standing question of how the brain produces such variable estimates of time. They may also help to explain why time seems to fly when people are having fun, or why time seems endless we're bored.

The study published in the journal Science was authored by Joe Paton, principal investigator of the Learning Lab, PhD student Sofia Soares and post-doc Bassam Atallah.

The team has been studying the neuroscience of how duration is judged for a number of years as part of a larger interest in understanding how the brain learns to link causes with effects even over extended over time periods.

The passing of time seems such an elusive concept that studying it from the neurobiological point of view might appear short of impossible.

Unlike vision or audition, time judgment can't be traced back to a sense organ like the eye or the ear. Paton said this makes time's neural underpinnings all the more difficult to pinpoint.

But the challenge with time goes deeper. The objective existence of time itself and its flow, which unequivocally exists for each and every one of us, has actually been questioned by some theoretical physicists.

And yet, the ability to estimate duration is obviously crucial for any animal's survival.

"Timing is important for extracting information from the environment and deciding when to expect something to happen or when to engage or disengage from an action", said Paton.

The question remains: What part of the brain could be generating this vital, subjective experience called time?

To unravel the neurobiology of this inner and universal perception, the team had an idea of where to look. Specifically, they were interested in studying certain dopamine-releasing neurons in structure deep in the brain, called the "substantia nigra pars compacta" known to play a role in temporal processing.

Dopamine is one of the brain's chemical "messengers" or neurotransmitters. It's involved in many of the psychological factors and disorders associated with changes in time estimation

"Give a fearful stimulus to a rat, and his dopamine release hits the ceiling," said Paton.

In humans, the destruction of the substantia nigra causes Parkinson's disease, which is also known to impair the perception of time.

An additional reason for choosing to look more closely at these neurons was that they project onto another brain structure called the striatum, which Paton's group had thoroughly previously studied and found to carry the information to support timing behavior.

They knew that removing the input of these dopamine neurons to the striatum "can cause a selective deficit in timing."

The scientists started by training mice to perform a task that involved timing. Such an approach has even been used to study timing.

"However, when we first set out to train mice to report their judgment of time, there was real doubt whether it could even be done!" said Atallah.

To achieve this, the authors used modern molecular and genetic tools that allowed both measuring and manipulating dopamine neurons on a fast timescale.

"Nobody had managed to do this with respect to the passage of time<' according to Soares. "Up to now, there were many contradictory results regarding dopamine's role in time perception."

What they did was to train the mice to estimate whether the duration of the interval between two tones was shorter or longer than 1.5 seconds.

Mice indicated their choice but placing their snout at either a right (shorter) or left (longer) port. During the task, the interval between the tones was made to vary, and if the mice chose the right answer (they correctly estimated time), they were rewarded.

"After months of training, they became pretty good at it."

The second part of the work consisted in passively measuring signals that reflect the electrical activity of dopamine neurons in the substantia nigra pars compacta using a technique called fiber photometry while mice performed the task.

The team used genetic tools to make the neurons fluoresce when active and measured the intensity of the emitted light.

Since the fluorescence "is an indicator of the electrical activity of a number of these neurons around the optical fiber tip, this allowed us to indirectly monitor the variation of those neurons' activity during the task", said Paton.

Using this technique, the scientists observed an increase in the neurons' activity at the onset of both the first and the second tones. This suggested that the neurons might be effectively involved in the task.

But more important, the team discovered the increase of neural activity itself did not always have the same amplitude -- and this was the clue they needed.

"What we saw was that the bigger the increase in neural activity (at the first and the second tone), the more the animals tended to underestimate the duration of the interval", said Soares.

"And the smaller the increase, the more the animal overestimated duration."

The conditions under which the dopamine neuron response predicted judgments suggested electrical activity in these cells was actually strongly correlated with the animals' judgment of the passage of time.

At this point, the team wanted to know whether they had found a mere correlation between these neurons' activity and the way the brain keeps track of time, or a causal link between the two. Could the neurons' activity actually induce the alterations in judgment of elapsed time observed in the mice?

The neurons seemed to reflect information about the estimation of duration by the animals. But might they actually be controlling their sense of time?

To address this, researchers performed a third round of experiments. They took advantage of a technique called optogenetics, where they used light to manipulate (stimulate or silence) these neurons in a specific and fast way to see the impact on the animals' behavior during the task.

"We found that if we stimulated the neurons, the mice tended to underestimate duration, and if we silenced them, they tended to overestimate it," paton noted.

"This result, together with the naturally occurring signals we observed in the previous experiments, demonstrate that the activity of these neurons was sufficient to alter the way the animals judged the passage of time. This was the major result of our study."

Can the results be extrapolated to humans?

The team believes it's very likely that a similar circuit is at work in the human brain. But the problem is that what they measured in mice can't be said to have been a percept because the animals can't tell us what they felt.

"When we study animals, the only thing we can measure is the animal's behavior. But we are never sure of what they perceive," said Paton.

"We interpret this as 'a subjective experience of the animal', but it's no more than an interpretation. And that's the best we can do."