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We’ve all been there. Whether we’re stuck in traffic at the end of a long day or eagerly awaiting the release of a new book, movie or album, there are times when we need to be patient. Learning to suppress the urge for instant gratification is often vital to future success, but how patience is regulated in the brain remains poorly understood.
Now, in a study in mice conducted by the Neural Computation Unit at the Okinawa Institute of Science and Technology Graduate University (OIST), the authors, Dr Katsuhiko Miyazaki and Dr Kayoko Miyazaki, pinpoint specific areas of the brain that individually promote patience. through the action of serotonin. Their results were published on November 27 in Advances in science.
“Serotonin is one of the most famous neuromodulators of behavior, it helps regulate mood, sleep-wake cycles and appetite,” said Dr. Katsuhiko Miyazaki. “Our research shows that the release of this chemical messenger also plays a crucial role in promoting patience by increasing the time that mice are willing to wait for a food reward.”
Their most recent work builds heavily on previous research, in which the unit used a powerful technique called optogenetics – using light to stimulate specific neurons in the brain – to establish a causal link between serotonin and patience.
The scientists bred genetically engineered mice with serotonin-releasing neurons that expressed a light-sensitive protein. This meant that the researchers could stimulate these neurons to release serotonin at precise times by shining the light, using an optical fiber implanted in the brain.
The researchers found that stimulating these neurons while the mice waited for food increased their waiting time, with the maximum effect seen when the likelihood of receiving a reward was high but when the timing of the reward was uncertain.
“In other words, for serotonin to foster patience, the mice had to be sure that a reward would come, but unsure when it would come,” said Dr. Miyazaki.
In the previous study, the scientists focused on an area of the brain called the dorsal raphe nucleus, the central hub of neurons that release serotonin. Neurons in the dorsal raphe nucleus extend into other areas of the forebrain, and in their most recent study, scientists specifically explored which of these other areas of the brain helped regulate patience.
The team focused on three areas of the brain that had been shown to increase impulsive behaviors when damaged: a deep brain structure called the nucleus accumbens and two parts of the frontal lobe called the orbitofrontal cortex and the medial prefrontal cortex.
“Impulsive behaviors are inherently related to patience – the more impulsive an individual is, the less patient – so these areas of the brain were prime candidates,” explained Dr Miyazaki.
Good things come to those who know how to wait (or not …)
In the study, the scientists implanted optical fibers into the dorsal raphe nucleus and also into one of the nucleus accumbens, the orbitofrontal cortex or the medial prefrontal cortex.
The researchers trained the mice to perform a waiting task in which the mice held their noses inside a hole, called a “nose poke”, until a food pellet was delivered. Scientists rewarded the mice in 75% of the tests. In some test conditions, the timing of the reward was set at six or ten seconds after the mice started poking their noses, and in other test conditions, the timing of the reward varied.
In the remaining 25% of the trials, called omission trials, the scientists did not provide a food reward to the mice. They measured how long the mice continued to puncture their nose during the omission tests – in other words, how patient they were – when the serotonin-releasing neurons were and weren’t stimulated.
When the researchers stimulated the serotonin-releasing neural fibers that reached the nucleus accumbens, they found no increase in waiting time, suggesting that serotonin in this area of the brain plays no role in regulating patience.
But when the scientists stimulated the release of serotonin in the orbitofrontal cortex and medial prefrontal cortex while the mice were holding their noses, they found that the mice waited longer, with some crucial differences.
In the orbitofrontal cortex, the release of serotonin promoted patience as effectively as the activation of serotonin in the dorsal raphe nucleus; both when the timing of the reward was fixed and when the timing of the reward was uncertain, with stronger effects in the latter.
But in the medial prefrontal cortex, scientists only saw an increase in patience when the timing of the reward was varied, with no effect observed when the timing was set.
“The observed differences in how each area of the brain responded to serotonin suggests that each area of the brain contributes to the overall waiting behavior of the mice in separate ways,” said Dr Miyazaki.
Modeling patience
To investigate further, the scientists built a computational model to explain the waiting behavior of the mice.
The model assumes that mice have an internal model of reward delivery times and continue to estimate the likelihood of a reward being delivered. They can then judge over time whether they are in a rewarded or unrewarded process and decide whether or not to continue waiting. The model also assumes that the orbitofrontal cortex and the medial prefrontal cortex use different internal reward timing models, the latter more sensitive to timing changes, to calculate the probabilities of reward individually.
The researchers found that the model fit better with the experimental wait time data by increasing the likelihood of expected reward from 75% to 94% under stimulation of serotonin. Put simply, serotonin increased the mice’s belief that they were in a reward test, so they waited longer.
Importantly, the model showed that stimulation of the dorsal raphe nucleus increased the probability by 75% 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 of each other and that these independent calculations are then combined to ultimately determine how long the mice will wait,” explained Dr. Miyazaki. “This type of complementary system allows animals to behave more flexibly to changing environments.”
Ultimately, increasing our knowledge of how different areas of the brain are more or less affected by serotonin could have vital implications for future drug development. For example, selective serotonin reuptake inhibitors (SSRIs) are drugs that increase serotonin levels in the brain and are used to treat depression.
“This is an area we wish to explore in the future using models of mice with depression,” said Dr Miyazaki. ‘Under certain genetic or environmental conditions we may find that some of these identified brain areas have altered function. By identifying these regions, this could open avenues to deliver more targeted treatments that target specific areas of the brain rather than the entire brain.’
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