Part of growing up, we’ve come to learn that patience is a virtue. Whether it’s a matter of being caught on the highway on the way home after finishing a long workday — or eagerly counting down the days until an exciting new movie, book, or film finally releases, patience is something we all have to embrace at some time or other. The ability to harness it and the rewards are something we all learn over time, but neuroscientists have yet to fully understand what this learning process looks like in the human brain.
A recent study on mice conducted by the Neural Computation Unit at the Okinawa Institute of Science and Technology Graduate University may offer an answer. The paper’s authors, Drs. Katsuhiko and Kayoko Miyazaki, have been able to isolate specific locations within the rodents’ brain that use the movement of serotonin to encourage patience. Their study was published in the journal Science Advances. “Serotonin is one of the most famous neuromodulators of behavior, helping to regulate mood, sleep-wake cycles, and appetite,” says Miyazaki. “Our research shows that release of this chemical messenger also plays a crucial role in promoting patience, increasing the time that mice are willing to wait for a food reward.”
Their team’s latest effort builds heavily from previous research — when the unit began making use of a powerful and minimally invasive technique called “optogenetics” — the use of light to stimulate specific neurons in the brain — in its search for a direct causal link between the neurochemical serotonin and patience. The researchers began by breeding genetically engineered mice that contained serotonin-releasing neurons expressing a single light-sensitive protein.
Once they had their mice, the researchers were then able to stimulate these neurons to produce serotonin at specific times with a light signal that triggered an optical fiber in the rodents’ brains. They realized that by stimulating these neurons as the mice were waiting to be fed increased the time they waited patiently for their pellets. The mice seemed to be the most agreeable and patient when the probability of a food reward was high but the precise timing of when they received their reward was less predictable.
“In other words, for the serotonin to promote patience, the mice had to be confident that a reward would come but uncertain about when it would arrive,” says Miyazaki.
In their prior research, Miyazaki and colleagues looked at a region of the brain known as the dorsal raphe nucleus — the center hub for serotonin-releasing neurons. Neurons from this chamber then spread out into other portions of the forebrain and now the team has been able to uncover which other areas of the brain are critical to processing patience.
The team narrowed their list down to three areas of the brain that contributed to a hike in impulsive behaviors when damaged — a deep brain structure known as the nucleus accumbens, a central part of the reward circuit that responds to both serotonin and dopamine, as well as two parts of the frontal lobe — both the orbitofrontal cortex (involved in emotion and memory) and also the medial prefrontal cortex (which retrieves long-term memory.)
“Impulse behaviors are intrinsically linked to patience — the more impulsive an individual is, the less patient — so these brain areas were prime candidates,” explains Miyazaki.
Do Good Things Really Come to Those Who Wait?
For their study, the research team inserted optical fibers into the dorsal raphe nucleus and then into either the nucleus accumbens, the orbitofrontal cortex, or the medial prefrontal cortex of each rodent.
The researchers began by training their mice to carry out a simple waiting task. Each of the mice learned to stay in place, with their snout inside a hole, or a “nose poke,” just until they received a food pellet. In two-thirds of the trials the researchers performed, the mice were given their reward. Not all the reward times were constant, however. In some of the tests, these pellets were awarded to the mice at six seconds, or sometimes 10 seconds after they began the nose poke. In other trials, the timing of the reward was completely randomized.
In the other 25% of tests, the experiment’s omission trials, no reward pellets were given to the mice. The researchers instead took note of how long the mice continued to do the nose poke in omission trials, expecting a reward to be given. They sought to determine how eager the mice were when no serotonin was acting on their neurons.
Whenever the research team stimulated serotonin-releasing neural fibers that affected the nucleus accumbens, they discovered there was no increase in the time the mice waited, indicating that serotonin in this region of the brain does not regulate an individual’s degree of patience. The researchers found more promising results when they targeted the release of serotonin in both the orbitofrontal cortex and the medial prefrontal cortex when the mice stayed in position. They waited longer. The release of serotonin in both the orbitofrontal cortex and dorsal raphe nucleus promoted patience, with more effective results on the latter — perhaps because of the role it plays in processing memory.
In the medial prefrontal cortex, however, the researchers observed that the increase in patience only occurred when the timing intervals for the reward varied. Whenever timing was fixed, it had no effect. “The differences seen in how each area of the brain responded to serotonin suggests that each brain area contributes to the overall waiting behavior of the mice in separate ways,” says Miyazaki.
What Does Patience Look Like?
In order to explore deeper, the researchers put together a computational model to show a fuller picture of why the mice waited. Miyazaki’s model is based on an understanding that the lab mice have their own mental stopwatch that accounts for the timing of reward delivery and routinely estimates the probability that within a short time, another reward will be delivered. Over continuous gaps of time, the mice develop an ability to determine whether or not they are experiencing a reward or non-reward trial and accordingly, they choose whether or not they will continue to wait.
The model also assumes that the orbitofrontal cortex and the medial prefrontal cortex regions each have different internal models of reward timing, and that the latter region is more sensitive to timing variations, individually calculating the odds of a reward in each situation. The researchers found that an increase of serotonin was linked to an increase in the rodent’s belief that they were part of a reward trial. Therefore, they waited longer.
Most significantly, the research team’s model revealed that by stimulating of the dorsal raphe nucleus, they increased that probability from 75% all the way to 94% in both the orbital frontal cortex and the medial prefrontal cortex, while stimulation of the brain areas separately only increased the probability in that particular area.
“This confirmed the idea that these two brain areas are calculating the probability of a reward independently from each other, and that these independent calculations are then combined to ultimately determine how long the mice will wait,” explains Miyazaki. “This sort of complementary system allows animals to behave more flexibly to changing environments.”
By expanding our current knowledge of how the different parts of the brain are either more or less impacted by their response to serotonin will be critical to developing future pharmaceuticals. Right now, psychiatrists prescribe selective serotonin reuptake inhibitors (SSRIs), which raise levels of serotonin in the brain in order to treat depression. While this has a beneficial effect for most patients who take it, the dosage varies from person to person, and the treatments could be made more precise. They have some ways to go, even before their research is applied to human test subjects in the not too far future.
“This is an area we are keen to explore in the future, by using depression models of mice,” says Miyazaki. “We may find under certain genetic or environmental conditions that some of these identified brain areas have altered functions.”
Once researchers have a stronger command about what’s happening in these regions, they can change their focus accordingly when it comes to treatments in the future — fine tuning treatments that will hit affected areas of the brain rather than the entire brain. Not only will there be significantly fewer side effects that make people wary of the medications that treat psychological conditions like depression — the insights of modern-day neuroscience could soon show us what these long-held virtues, like patience, actually look like when actively at work.
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