When it comes to how we experience, interact with, and navigate the world, timing is everything. And new research in mice suggests that a specific set of cells is critical to how we learn complex behaviors that depend on timing.
The discovery by the team from the University of Utah in the US could eventually help reveal the onset of neurodegenerative diseases that affect the perception of time, such as Alzheimer’s disease.
To create a memory of your own personal archives, your brain must encode the timing and sequence of events as you experience them. It creates this timeline using circuits in the medial temporal lobe (MTL), one of which is the medial entorhinal cortex (MEC).
This MEC circuit has “time cells” that fire at specific moments during tasks, on a scale of seconds and minutes, a kind of organic internal metronome that helps us keep track of time in the moment.
Scientists believe that this “timer” can leave traces in episodic memories, so that the “frames” of our experience are played back in sequence with a built-in rhythm. However, to do so, these temporal cells would need learning dynamics that allow them to encode different temporal contexts.
We know that “spatial cells” within the MTL can reorganize their “fields of fire” according to spatial contexts as the animal moves through different and changing environments.
The researchers wanted to investigate whether temporal cells have a similar ability to “remap” to different temporal contexts. They combined a complex time-based learning task with brain imaging to observe patterns of temporal cell activity.
If temporal cells are as flexible as their spatial relatives, the team hypothesized that “(1) different sequences of temporal cells become active as animals learn to identify a new temporal context, creating a unique map or ‘timeline’ of each time zone.” context, and (2) such dynamics support the learning of timing behavior.”
The first trial involved mice completing a task in which the timing of events was crucial, discriminating between an odor stimulus and a variable timing to receive a reward.
Patterns of cell activity over time were consistent regardless of the pattern of odor stimuli, but became more complex as the mice learned, developing unique “time scales” corresponding to each stimulus.
And when the mice messed up, the researchers noticed that their time cells also fired in the wrong order.
“The time cells are supposed to be active at specific moments during the test,” says neurobiologist Hyunwoo Lee. “But when the mice made mistakes, this selective activity became messy.”
When the researchers chemically blocked the MECs, knocking out the mice’s timing cells, the animals were still able to perceive and predict the timing of an event, but it was impossible for them to learn the time-based task from scratch.
“Time cells play a surprisingly more complicated role than just keeping track of time,” says the study’s first author, neurobiologist Erin Bigus.
“The MEC doesn’t act like a really simple stopwatch that’s necessary to keep track of time in any simple circumstances. Its role seems to be to actually learn these more complex temporal relationships.”
This research could lead to a better understanding of psychological conditions where people experience time very differently, such as Alzheimer’s disease, which we already know affects the MEC early in its development.
“We are interested in investigating whether complex timing tasks could be a useful way to detect early onset Alzheimer’s disease,” says the study’s lead author, neurobiologist James Heys.
There is also growing interest in how “time blindness” – a symptom of ADHD and autism – arises. Understanding how time is mapped and recorded in the brain could also help with investigations there.
The researchers note that while they found that the MEC has a clear role in timing, there are other areas in the MTL, such as the hippocampus and lateral entorhinal cortex, that also encode time.
“A clear future direction will include testing the necessity of additional MTL regions,” the team writes.
This research was published in Nature Neuroscience.