How the cerebellum is involved in our sense of timing

In a recent issue of Neuron, the research team of Mark Wagner (National Institutes of Health, USA) has illustrated how the cerebellum helps us to keep track of timing in the order of seconds. In their Preview article, researchers at the Netherlands Institute for Neuroscience and Erasmus University Medical Centre reflect on these findings and offer directions for future research in the field.

Timing is of the essence in a myriad of tasks, whether it’s estimating when to cross a busy road, starting a sentence in a flowing conversation, or being able to return a ball in a tennis match. The passage of time often needs to be tracked over multiple seconds, relying on patterns of neuronal activity to do so. However, for such an important skill used so frequently, surprisingly little is known about the role of the cerebellum (‘little brain’) in seconds-long time tracking. New evidence from the Wagner group sheds light on how the cerebellum is involved in our ability to track long time intervals.

Exactly how the cerebellum is involved in time tracking remains a complicated puzzle as Robin Broersen, first author of the Preview article and neuroscientist at Chris de Zeeuw’s lab, explains: “There is a long-standing consensus that the cerebellum plays a role in the timing of very short intervals (in the order of milliseconds). This allows the cerebellum to perform rapid and timely adjustments to ongoing movements and learn to make well-timed movements during conditioning tasks. Long-interval time tracking, where we’re consciously waiting over a few seconds, was thought to rely mainly on other brain areas. The fact that cells in the cerebellum track the passage of time during intervals lasting multiple seconds is a new and interesting finding.”

Unravelling the puzzle

To better understand the cerebellum’s role in timing, researchers from the Wagner group taught mice a behavioural task with a delayed water reward. Mice learned to grasp a robotic arm and push it forward, triggering a delay timer. After 1 or 2 seconds a water droplet was released, which the mice could drink by licking the nozzle. After many repetitions, the mice learned to predict when the water would be released and only started licking after the waiting period, when the reward was expected.

While the mice performed the task, the group used new fluorescence imaging techniques to observe neuronal activity in two cerebellar cell-types simultaneously. The cerebellum receives information from two main inputs: mossy fibres and climbing fibres. By simultaneously measuring two cell-types, the Wagner group was able to study how input from the mossy fibres and climbing fibres shape the activity of neurons in the cerebellum during the delay period.

Ramping is the key

The Wagner group researchers found that while the mice waited for their water reward, granule cells, which are directly connected by mossy fibres, started firing according to a specific pattern known as ‘ramping activity’, during which activity of neurons steadily goes up or down as time progresses. Once the mice received their water, the other input (from climbing fibres) became active.

This interaction can be compared to a stopwatch: the granule cells connected by mossy fibres represent the progressing time through ramping activity, while the climbing fibres stop the timer again by becoming active.

Fine-tuning timing to perfection

So how do mice improve their timing with practice in this task? This depends on a well-known concept within neuroscience: plasticity. The connections between the cells in the cerebellum are fine-tuned according to earlier experiences but can also change if the waiting duration changes.

This concept is reflected in the Wagner group findings: most granule cells that showed ramping activity after training, only showed activity during reward delivery before training. When they trained a computer model to predict changes in connections based on the ramping activity in granule cells and the activity in climbing fibres, they could accurately predict the activity of other cells inside the cerebellum during the task.

Placing the research in a broader context

Broersen: “A growing body of evidence links the cerebellum to various cognitive processes, thereby moving away from the view that the cerebellum is simply a motor control structure. This article, exploring the neuronal workings of timing over a longer timespan (seconds rather than milliseconds), underlines this.”

“In our Preview article, we highlight that many brain areas provide information to the cerebellum both through mossy fibre and climbing fibre inputs, either directly or indirectly. This is true for information representing a range of functions (such as movement, posture and reward learning). Information from one common source thus arrives at the cerebellum via multiple routes.”

While the Wagner group findings are incredibly fundamental, they also help to better understand what happens to the timing abilities of patients with cerebellar disorders.  Patients with cerebellar defects exhibit deficits related to timing, such as disturbed speech, gait, balance, predictive motor timing and even impairments in the perception of actions made by others.

Future studies could investigate how activity in the cerebellum matches with other connecting brain areas, those that send information to the cerebellum, and those that receive. Another interesting avenue would be to dive further into the interactions between the two inputs to the cerebellum. How much time can there be between the activity in those inputs for plasticity to happen?

Broersen: “In the long term, these fundamental insights could help to better understand cerebellar disorders and to help patients with cerebellar defects, but there is still a lot of research to be done before we get there”.

Source: Neuron