The neuromodulator serotonin (5-HT) has been implicated in a variety of functions that involve patience or impulse control. Many of these effects are consistent with a long-standing theory that 5-HT promotes behavioral inhibition, a motivational bias favoring passive over active behaviors. To further test this idea, we studied the impact of 5-HT in a probabilistic foraging task, in which mice must learn the statistics of the environment and infer when to leave a depleted foraging site for the next. Critically, mice were required to actively nose-poke in order to exploit a given site. We show that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus increases the willingness of mice to actively attempt to exploit a reward site before giving up. These results indicate that behavioral inhibition is not an adequate description of 5-HT function and suggest that a unified account must be based on a higher-order function.

Essential features of the world are often hidden and must be inferred by constructing internal models based on indirect evidence. Here, to study the mechanisms of inference, we establish a foraging task that is naturalistic and easily learned yet can distinguish inference from simpler strategies such as the direct integration of sensory data. We show that both mice and humans learn a strategy consistent with optimal inference of a hidden state. However, humans acquire this strategy more than an order of magnitude faster than mice. Using optogenetics in mice, we show that orbitofrontal and anterior cingulate cortex inactivation impacts task performance, but only orbitofrontal inactivation reverts mice from an inference-based to a stimulus-bound decision strategy. These results establish a cross-species paradigm for studying the problem of inferencebased decision making and begins to dissect the network of brain regions crucial for its performance.

Essential features of the world are often hidden and must be inferred by constructing internal models based on indirect evidence. Here, to study the mechanisms of inference we established a foraging task that is naturalistic and easily learned, yet can distinguish inference from simpler strategies such as the direct integration of sensory data. We show that both mice and humans learn a strategy consistent with optimal inference of a hidden state. However, humans acquire this strategy more than an order of magnitude faster than mice. Using optogenetics in mice we show that orbitofrontal and anterior cingulate cortex inactivation impact task performance, but only orbitofrontal inactivation reverts mice from an inference-based to a stimulus-bound decision strategy. These results establish a cross-species paradigm for studying the problem of inference-based decision-making and begin to dissect the network of brain regions crucial for its performance.

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The neuromodulator serotonin (5-HT) has been implicated in a variety of functions that involve patience or impulse control. For example, activation of 5-HT neurons promotes waiting for delayed rewards. Many of these effects are consistent with a long-standing theory that 5-HT promotes behavioral inhibition, a motivational bias favoring passive over active behaviors. To further test this idea, we studied the impact of 5-HT in a probabilistic foraging task, in which mice must learn the statistics of the environment and infer when to leave a depleted foraging site for the next.Critically, mice were required to actively nose poke in order to exploit a given site. We found that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus increased the willingness of mice to actively attempt to exploit a reward site before giving up. These results indicate that behavioral inhibition is not an adequate description of 5-HT function and suggest that a unified account must be based on a higher-order function.Serotonin (5-HT) is a central neuromodulator that is implicated in the regulation of many processes and is one of the most important targets of psychoactive drugs 1,2 . As a unifying concept for 5-HT's manifold effects, Soubrié 3 put forward the hypothesis that a major function of 5-HT is to promote behavioral inhibition. Building on work showing that blockade of serotonin transmission results in continued responses to stimuli that are no longer rewarding 4-7 , he argued that in situations wherein animals face a decision between active response and passivity, higher levels of 5-HT would bias the decision in favor of the latter.3 More recently, the study of 5-HT and behavioral inhibition has concentrated chiefly on impulse control 8-10 . One of the most common tasks used to study impulsive behavior is the five-choice serial reaction time task (5-CSRTT), in which rodents are required to respond to visual stimuli to obtain rewards 11 . Although this task was not specifically designed to measure impulsivity, animals sometimes respond prematurely (i.e. before stimulus presentation), a behavior indicative of impulsivity. Consistent with the idea that 5-HT promotes patience, alterations such as brain-wide 5-HT depletion increase impulsivity in this task 12 .Another line of experiments focuses on animals' ability to wait in order to obtain reward 13 .Electrophysiological recordings from the dorsal raphe nucleus (DRN; the major source of serotonin to the forebrain) in rats trained to wait for delayed rewards have found that most of these neurons increase their firing rates during waiting 14 . Moreover, pharmacological blocking of these neurons by the local application of the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) locally into the DRN promotes premature leaving 14 , whereas optogenetic activation of the same neurons promotes patience 15,16 .All of these results are still broadly consistent with the Soubrié theory of behavioral inhibition. By reducing the motivation to act, increased se...