Overview: Researchers identified a brain region responsible for directing action, and another that suppresses action. The study reports that impulsive behavior can be activated or suppressed by activating these areas.
Source: Champalimaud Center for the Unknown
It’s the last race. Eight athletes are lined up on the track, their feet tense against the starting blocks. They hear the countdown: “On Your Marks!”, “Get Set”, and then, a split second before the shot, a runner leaps forward and disqualifies himself from the competition. At such times, an often overlooked aspect of behavior—the suppression of actions—is painfully exposed.
A study published today in the journal Nature reveals how the brain keeps us from brawling.
“We discovered one area of the brain that is responsible for directing action and another for suppressing that drive. We can also elicit impulsive behavior by manipulating neurons in these areas,” said study senior author Joe Paton, director. of the Champalimaud Neuroscience Program in Portugal.
Solve a riddle
Paton’s team set out to solve a puzzle that stemmed in part from Parkinson’s and Huntington’s disease. These conditions manifest as movement disorders with broadly opposite symptoms. While Huntington’s patients suffer from uncontrolled, involuntary movements, Parkinson’s patients struggle with initiating action. Curiously, both conditions arise from dysfunction of the same brain region: the basal ganglia. How can the same structure support conflicting functions?
According to Paton, a valuable hint emerged from previous studies, which identified two important circuits in the basal ganglia: the direct and indirect pathways. It is thought that while the activity of the direct pathway promotes movement, the indirect pathway suppresses it. However, the precise manner in which this interplay is performed was largely unknown.
A timing task with a twist
Paton took an original approach to the problem. While previous studies examined the basal ganglia during movement, Paton’s team focused instead on suppressing active action.
The team designed a task in which mice had to determine whether an interval between two tones was longer or shorter than 1.5 seconds. If it was shorter, a reward would be given on the left side of the box, and if it was longer, it would be available on the right.
“The key was that the mouse had to remain perfectly still in the period between the two tones,” said Bruno Cruz, a PhD student in the lab. “So even if the animal was sure that the 1.5-second mark had passed, it had to suppress the urge to move until after the second tone sounded, then go for the reward.”
The researchers monitored the neural activity of both pathways as the mouse performed the task. As in previous studies, activity levels were similar when the mouse moved. During the action-suppression period, however, things changed.
Interestingly, in contrast to the co-activation we and others observed during movement, the activity patterns across the two pathways were markedly different during the action-suppression period. The activity of the indirect pathway was generally higher and it increased continuously. while the mouse waited for the second tone,” Cruz said.
According to the authors, this observation suggests that the indirect pathway flexibly supports the animal’s behavioral goals. “As time goes by, the mouse becomes more confident that it is in a ‘long interval’ trial. And so his urge to move becomes increasingly difficult to control. It is likely that this continued increase in activity reflects this internal struggle,” Cruz explains.
Inspired by this idea, Cruz tested the effect of braking the indirect route. This manipulation caused the mice to behave more impulsively, significantly increasing the number of trials where they fired prematurely into the reward gate. With this innovative approach, the team effectively discovered an ‘impulsivity switch’.
“This discovery has broad implications,” Paton thought. “In addition to its clear relevance to Parkinson’s disease and Huntington’s disease, it also provides a unique opportunity to investigate impulse control disorders such as addiction and obsessive-compulsive disorder.”
Looking for the drive to act
The team identified a brain region that actively suppresses the urge to act, but where does that urge come from? Since the direct route is believed to promote action, the direct suspect was the direct route from the same region. However, the mouse’s behavior was virtually unaffected when the researchers inhibited it.
“We knew that the mice experienced a strong urge to act, as removing suppression promoted impulsive action. But it wasn’t immediately clear where else the action promotion site might be. To answer this question, we decided to move on.” to computational modelling,” Paton recalls.
“Mathematical models are extremely useful for understanding complex systems like this,” added Gonçalo Guiomar, a doctoral student in the lab.
“We gathered knowledge about the basal ganglia, formulated it mathematically and tested how the system processes information. We then combined the model’s prediction with evidence from previous studies and identified a promising new candidate: the dorsomedial striatum.”
The team’s hypothesis was correct. Inhibiting direct pathway neurons in this new region was sufficient to alter mouse behavior. “Both regions of which we have included are located in a part of the basal ganglia called the striatum. The first region is responsible for so-called ‘low-level’ motor-sensory functions and the second is devoted to ‘high-level’ functions such as decision-making,” Guiomar explains.
From action to temptation and beyond
The authors state that their findings contradict the general perception of how the basal ganglia work, which is more centralized, and that their model offers a new perspective on how the basal ganglia work.
“Our study indicates that there may be multiple neural circuits in the brain that are constantly competing over which action to perform next. This insight is important to better understand how this system works, which is imperative for the treatment of certain movement disorders, but it goes even further,” said Paton.
“Observations from neuroscience are at the heart of many machine learning and AI techniques. The idea that decision-making can take place through the interaction of numerous parallel circuits within the same system could be useful for designing new types of intelligent systems,” he added.
Finally, Paton suggests that perhaps one of the most unique aspects of the research is its ability to access inner cognitive experiences.
“Impulsivity, seduction… These internal processes are some of the most fascinating things the brain does because they reflect our inner life. But they are also the hardest to study because they don’t have many outward signs that we can measure.
“Setting up this new method has been challenging, but now we have a powerful tool to investigate internal mechanisms, such as those involved in resisting and succumbing to temptation,” Paton concluded.
About this neuroscience research news
Original research: Closed access.
†Action Suppression reveals parallel control of the opponent through striatal circuits” by Joseph Paton et al. Nature
Action Suppression reveals parallel control of the opponent through striatal circuits
The direct and indirect pathways of the basal ganglia are classically thought to promote and suppress action, respectively. The observed co-activation of striatal direct and indirect medium spiny neurons (dMSNs and iMSNs, respectively) has challenged this view.
Here we study these circuits in mice performing an interval categorization task that requires a series of self-initiated and cued actions and, critically, a sustained period of dynamic action suppression.
Although movement produced the co-activation of iMSNs and dMSNs in the sensorimotor, dorsolateral striatum (DLS), fiber photometry and photo-identified electrophysiological recordings, signatures of functional contradiction between the two pathways revealed during action suppression.
Notably, optogenetic inhibition showed that DLS circuitry was largely turned on to suppress — not promote — action. In particular, iMSNs in a given hemisphere were dynamically turned on to suppress seductive contralateral action.
To understand how such a regionally specific circuit function arose, we constructed a computational reinforcement learning model that reproduced key features of behavior, neural activity and optogenetic inhibition.
The model predicted that parallel striatal circuits outside the DLS learned the action-promoting functions, creating the temptation to act. Consistent with this, optogenetic inhibition experiments revealed that dMSNs in the associative, dorsomedial striatum, unlike those in the DLS, promote contralateral actions.
These data demonstrate how adversary interactions between multiple circuit- and region-specific basal ganglia processes can lead to behavioral control, and play a critical role for the sensorimotor indirect pathway in the proactive suppression of seductive actions.