“On your marks. Get set. Go!” Mapping delayed responses in the brain

In some ways, we can think of the brain as an input/output machine; it receives signals from the environment and the body through peripheral and sends back appropriate responses. And although this is an oversimplified view of the world’s most complex computer, it is nonetheless the basis of an enormous amount of behavioral research.

For example, a group of researchers led by Professor Carl Petersen at EPFL’s School of Life Sciences has published a paper in Neuron where they explore what neuroscientists refer to as a “delayed motor response”. The importance of the study is self-evident: reacting to stimuli in a timely manner – not too early, not too late – can be critical, not only for biological, but also social survival.

“Our behavior is dominated by internal appetites like ‘want to eat’ or ‘want to touch’, which come up in our mind as we explore the sensory world,” says Vahid Esmaeili, one of the study’s lead authors. “However, it is often critical to wait until appropriate moment before starting an action; for instance, in a sprint race, you get ready with the ‘Get Set’ signal, but must not move before the ‘Go’, regardless of how eager you are.”

The researchers explored the mechanism behind delayed motor responses by training mice to perform a behavioral task simulating this process: the mice would first receive a small vibration to their whisker, which acted as a “Get Set” signal. After a delay, the mice would hear a sound, which acted as a “Go” signal. If they licked a nozzle soon after “Go”, the mice would get a drop of sugar water; if they licked it before the sound, they wouldn’t. The idea was to train the mice to wait until the “Go” tone regardless of how eager they were to lick the nozzle after receiving the “Get set” whisker vibration which predicts the sugar water.

Tracking this delayed response with sophisticated techniques like wide-field calcium imaging, multi-region high-density electrophysiology, and time-resolved optogenetics (activating genes with light), the scientists were able to precisely track the exact circuit of activity in the brain’s cortex involved in it.

The study showed that, while mice received the ‘Get set’ signal and waited for the ‘Go’ sound, their motor-preparation area became active while their motor-execution area was suppressed. “By inactivating the motor-preparation area, mice could not lick the nozzle after the ‘Go’ sound,” explains Keita Tamura, the study’s other lead author. “In contrast, by activating the motor-execution area, mice prematurely licked the nozzle, failing to wait until the ‘Go’ sound.”

The findings indicate that the “Get set” cue triggers both the preparation of movement and suppression of its premature execution in distinct brain regions, which enables timely reaction to the “Go” signal. More specifically, a part of the mouse’s brain called the “secondary whisker motor cortex” likely plays a significant role in linking sensations from the whisker to actual planning of a motor response.

“Building on the present finding, we can study circuit mechanisms for how different brain areas suppress or activate each other,” says Carl Petersen. “This can lead us to further elucidate how we can make quick accurate movements, and how we can suppress internal impulses by cognitive control.”

The authors conclude: “Our results therefore point to task-epoch-specific contributions of distinct cortical regions to whisker-triggered planning of goal-directed licking and timely execution of planned lick responses.”