Increased serotonin prevents compulsion in addiction.

Extracellular serotonin decreases cocaine taking in mice.

Serotonergic projections to the orbitofrontal and medial prefrontal cortices differentially modulate waiting for future rewards.

Optogenetic activation of serotonergic neurons in the dorsal raphe nucleus (DRN) enhances patience when waiting for future rewards, and this effect is maximized by both high probability and high timing uncertainty of reward. Here, we explored which serotonin projection areas contribute to these effects using optogenetic axon terminal stimulation. We found that serotonin stimulation in the orbitofrontal cortex (OFC) is nearly as effective as that in the DRN for promoting waiting, while in the nucleus accumbens, it does not promote waiting. We also found that serotonin stimulation in the medial prefrontal cortex (mPFC) promotes waiting only when the timing of future rewards is uncertain. Our Bayesian decision model of waiting assumed that the OFC and mPFC calculate the posterior probability of reward delivery separately. These results suggest that serotonin in the mPFC affects evaluation of time committed, while serotonin in the OFC is responsible for overall valuation of delayed rewards.

Reward probability and timing uncertainty alter the effect of dorsal raphe serotonin neurons on patience.

Recent experiments have shown that optogenetic activation of serotonin neurons in the dorsal raphe nucleus (DRN) in mice enhances patience in waiting for future rewards. Here, we show that serotonin effect in promoting waiting is maximized by both high probability and high timing uncertainty of reward. Optogenetic activation of serotonergic neurons prolongs waiting time in no-reward trials in a task with 75% food reward probability, but not with 50 or 25% reward probabilities. Serotonin effect in promoting waiting increases when the timing of reward presentation becomes unpredictable. To coherently explain the experimental data, we propose a Bayesian decision model of waiting that assumes that serotonin neuron activation increases the prior probability or subjective confidence of reward delivery. The present data and modeling point to the possibility of a generalized role of serotonin in resolving trade-offs, not only between immediate and delayed rewards, but also between sensory evidence and subjective confidence.

Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards.

Serotonin is a neuromodulator that is involved extensively in behavioral, affective, and cognitive functions in the brain. Previous recording studies of the midbrain dorsal raphe nucleus (DRN) revealed that the activation of putative serotonin neurons correlates with the levels of behavioral arousal [1], rhythmic motor outputs [2], salient sensory stimuli [3-6], reward, and conditioned cues [5-8]. The classic theory on serotonin states that it opposes dopamine and inhibits behaviors when aversive events are predicted [9-14]. However, the therapeutic effects of serotonin signal-enhancing medications have been difficult to reconcile with this theory [15, 16]. In contrast, a more recent theory states that serotonin facilitates long-term optimal behaviors and suppresses impulsive behaviors [17-21]. To test these theories, we developed optogenetic mice that selectively express channelrhodopsin in serotonin neurons and tested how the activation of serotonergic neurons in the DRN affects animal behavior during a delayed reward task. The activation of serotonin neurons reduced the premature cessation of waiting for conditioned cues and food rewards. In reward omission trials, serotonin neuron stimulation prolonged the time animals spent waiting. This effect was observed specifically when the animal was engaged in deciding whether to keep waiting and was not due to motor inhibition. Control experiments showed that the prolonged waiting times observed with optogenetic stimulation were not due to behavioral inhibition or the reinforcing effects of serotonergic activation. These results show, for the first time, that the timed activation of serotonin neurons during waiting promotes animals' patience to wait for a delayed reward.

Activation of dorsal raphe serotonin neurons is necessary for waiting for delayed rewards.

The forebrain serotonergic system is a crucial component in the control of impulsive behaviors. We previously reported that the activity of serotonin neurons in the midbrain dorsal raphe nucleus increased when rats performed a task that required them to wait for delayed rewards. However, the causal relationship between serotonin neural activity and the tolerance for the delayed reward remained unclear. Here, we test whether the inhibition of serotonin neural activity by the local application of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin in the dorsal raphe nucleus impairs rats' tolerance for delayed rewards. Rats performed a sequential food-water navigation task that required them to visit food and water sites alternately via a tone site to get rewards at both sites after delays. During the short (2 s) delayed reward condition, the inhibition of serotonin neural activity did not significantly influence the numbers of reward choice errors (nosepoke at an incorrect reward site following a conditioned reinforcer tone), reward wait errors (failure to wait for the delayed rewards), or total trials (sum of reward choice errors, reward wait errors, and acquired rewards). By contrast, during the long (7-11 s) delayed reward condition, the number of wait errors significantly increased while the numbers of total trials and choice errors did not significantly change. These results indicate that the activation of dorsal raphe serotonin neurons is necessary for waiting for long delayed rewards and suggest that elevated serotonin activity facilitates waiting behavior when there is the prospect of forthcoming rewards.

The role of serotonin in the regulation of patience and impulsivity.

Classic theories suggest that central serotonergic neurons are involved in the behavioral inhibition that is associated with the prediction of negative rewards or punishment. Failed behavioral inhibition can cause impulsive behaviors. However, the behavioral inhibition that results from predicting punishment is not sufficient to explain some forms of impulsive behavior. In this article, we propose that the forebrain serotonergic system is involved in "waiting to avoid punishment" for future punishments and "waiting to obtain reward" for future rewards. Recently, we have found that serotonergic neurons increase their tonic firing rate when rats await food and water rewards and conditioned reinforcer tones. The rate of tonic firing during the delay period was significantly higher when rats were waiting for rewards than for tones, and rats were unable to wait as long for tones as for rewards. These results suggest that increased serotonergic neuronal firing facilitates waiting behavior when there is the prospect of a forthcoming reward and that serotonergic activation contributes to the patience that allows rats to wait longer. We propose a working hypothesis to explain how the serotonergic system regulates patience while waiting for future rewards.

Activation of dorsal raphe serotonin neurons underlies waiting for delayed rewards.

The serotonergic system plays a key role in the control of impulsive behaviors. Forebrain serotonin depletion leads to premature actions and steepens discounting of delayed rewards. However, there has been no direct evidence for serotonin neuron activity in relation to actions for delayed rewards. Here we show that serotonin neurons increase their tonic firing while rats wait for food and water rewards and conditioned reinforcement tones. The rate of tonic firing during the delay period was significantly higher for rewards than for tones, for which rats could not wait as long. When the delay was extended, tonic firing persisted until reward or tone delivery. When rats gave up waiting because of extended delay or reward omission, serotonin neuron firing dropped preceding the exit from reward sites. Serotonin neurons did not show significant response when an expected reward was omitted, which was predicted by the theory that serotonin signals negative reward prediction errors. These results suggest that increased serotonin neuron firing facilitates a rat's waiting behavior in prospect of forthcoming rewards and that higher serotonin activation enables longer waiting.

Activation of the central serotonergic system in response to delayed but not omitted rewards.

The forebrain serotonergic system is a crucial component in the control of impulsive behaviours. However, there is no direct evidence for natural serotonin activity during behaviours for delayed rewards as opposed to immediate rewards. Herein we show that serotonin efflux is enhanced while rats perform a task that requires waiting for a delayed reward. We simultaneously measured the levels of serotonin and dopamine in the dorsal raphe nucleus using in vivo microdialysis. Rats performed a sequential food-water navigation task under three reward conditions: immediate, delayed and intermittent. During the delayed reward condition, in which the rat had to wait for up to 4 s at the reward sites, the level of serotonin was significantly higher than that during the immediate reward condition, whereas the level of dopamine did not change significantly. By contrast, during the intermittent reward condition, in which food was given on only about one-third of the site visits, the level of dopamine was lower than that during the immediate reward condition, whereas the level of serotonin did not change significantly. Dopamine efflux, but not serotonin efflux, was positively correlated with reward consumption during the task. There was no reciprocal relationship between serotonin and dopamine. This is the first direct evidence that activation of the serotonergic system occurs specifically in relation to waiting for a delayed reward.

Different representation of forthcoming reward in nucleus accumbens and medial prefrontal cortex.

We recorded single units in the rat nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) to investigate activity related to reward mediation and anticipation during execution of an alternating reward task. NAcc and mPFC neurons showed increased activity differently during an interposed delay preceding reward delivery. Some NAcc neurons increased their activity specifically during the delay period before reward presentation, discriminating forthcoming food or water presentation. A subset of neurons in the mPFC similarly discriminated between food and water reward during the delay; however, about half did not discriminate reward qualities. These results show that the NAcc and the mPFC contribute differently to the organization and execution of goal-directed behavior.