A study by Japanese scientists at the Okinawa Institute of Science and Technology (OIST) has found that serotonergic neural projections to the brain's orbitofrontal and medial prefrontal cortices differentially modulate patience, as assessed by the time spent awaiting future rewards in mice.

Despite its importance to survival, the regulation of patience has been poorly understood, but the new study identifies specific brain areas that individually promote patience via serotonin, the authors reported in the November 27, 2020, edition of Science Advances.

Knowing how serotonin affects different brain areas could have important implications for the future development of targeted antidepressants increasing brain serotonin levels, such as selective serotonin reuptake inhibitors (SSRIs).


"Serotonin modulates mood, sleep cycles and appetite, but our research shows that its release also plays a crucial role in promoting patience, increasing the time mice will wait for a food reward," said study leader Katsuhiko Miyazaki, senior staff scientist in the Neural Computation Unit at OIST.

"SSRIs are widely used to treat psychiatric disorders, notably depression, by increasing the serotonergic tone in the whole brain," Miyazaki told BioWorld Science.

"However, SSRI remission rates are high, for example almost 40% for treatment with [the SSRI] citalopram, and SSRIs increase extracellular serotonin concentrations throughout the brain and do not selectively target a specific brain area."

This lack of selectivity may contribute to the high incidence of adverse effects and reduced efficacy associated with SSRIs.

"There may be side effects or reduced efficacy when SSRIs target the whole brain, suggesting that targeted antidepressants would reduce side effects and enhance the effectiveness of these drugs," said Miyazaki.

However, developing such treatments requires a thorough understanding of serotonin's activity in the brain, which was investigated using optogenetics in specially bred mice with serotonergic neurons expressing a light-sensitive protein, with light used to stimulate neurons to release serotonin.

Stimulating neurons while mice were awaiting food was found to increase their waiting time, with the maximum effect being seen when the probability of a reward was high but the timing uncertain.

"For serotonin to promote patience, the mice had to be confident that a reward would come, but be uncertain about when it would arrive," said Miyazaki.

In previous research, the OIST researchers had focused on the dorsal raphe nucleus (DRN), from which serotonergic neurons extend into other forebrain areas.

In their new study, they investigated which brain areas help regulate patience, including the nucleus accumbens (NA), orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) and implanted optical fibers into the DRN and one of either the NA, OFC or mPFC to monitor serotonin release.

"We focused on the OFC, mPFC and NA, because damage to these areas has been shown to increase impulsive behaviors, which are intrinsically related to patience," explained Miyazaki.

In mice trained to wait with their nose in a hole until food was delivered, the animals were rewarded in 75% of cases, but the reward's timing varied from 6-10 seconds in other tests, while mice received no reward in the remaining 25% of cases, known as omission trials.

The researchers then measured how long mice waited during omission trials, when serotonergic neurons were or were not stimulated.

When serotonergic neurons extending into the NA were stimulated, no increase was seen in waiting time, but when serotonin release was stimulated in the OFC and mPFC, mice waited longer for their reward.

In the OFC, serotonin release was found to promote patience as effectively as serotonin activation in the DRN, during both fixed and uncertain reward timing, with stronger effects in the latter, but increased patience was seen in the mPFC only when the reward timing was varied.

"These differences in serotonin response suggest that each brain area contributes to mouse waiting behavior in separate ways," noted Miyazaki.

To investigate this further, the researchers constructed a Bayesian decision-making computer model of waiting that assumed the OFC and mFC calculate the probability of reward separately.

The model showed that stimulation of the DRN with serotonin increased the probability of waiting from 75% to 94% in both the OFC and the mPFC, whereas stimulating areas separately only increased the probability in that particular area.

"This confirms that the two brain areas calculate the reward probability independently and that calculations are then combined to determine how long the mice will wait, allowing them to behave more flexibly to changing environmental conditions," said Miyazaki.

"We are now keen to explore this possibility further in mouse models of depression, including both SSRI-responsive and nonresponsive mice, between which dysfunction of the serotonergic system would differ," he said.

"Our Bayesian decision model of waiting could evaluate which parameters are affected by serotonergic neuron activation in the DRN and serotonergic projections into brain areas in depression model mice.

"These data may reveal which neural circuits are impaired in each depression model and could open up new avenues by which to provide targeted treatments that act on specific areas of the brain, rather than the whole brain."