These results provide strong evidence that the efficacy of DRN 5-HT neurons in promoting waiting for delayed reward is independent of appetitive or aversive effects and support the importance of 5-HT in behavioral persistence and impulse control.

Serotonin has widespread, but computationally obscure, modulatory effects on learning and cognition. Here, we studied the impact of optogenetic stimulation of dorsal raphe serotonin neurons in mice performing a non-stationary, reward-driven decision-making task. Animals showed two distinct choice strategies. Choices after short inter-trial-intervals (ITIs) depended only on the last trial outcome and followed a win-stay-lose-switch pattern. In contrast, choices after long ITIs reflected outcome history over multiple trials, as described by reinforcement learning models. We found that optogenetic stimulation during a trial significantly boosted the rate of learning that occurred due to the outcome of that trial, but these effects were only exhibited on choices after long ITIs. This suggests that serotonin neurons modulate reinforcement learning rates, and that this influence is masked by alternate, unaffected, decision mechanisms. These results provide insight into the role of serotonin in treating psychiatric disorders, particularly its modulation of neural plasticity and learning.

Although we understand how serotonin receptors function at the single-cell level, what role different serotonin receptors play in regulating brain-wide activity and, in turn, human behavior, remains unknown. Here, we developed transcriptomic–neuroimaging mapping to characterize brain-wide functional signatures associated with specific serotonin receptors: serotonin receptor networks (SRNs). Probing SRNs with optogenetics–functional magnetic resonance imaging (MRI) and pharmacology in mice, we show that activation of dorsal raphe serotonin neurons differentially modulates the amplitude and functional connectivity of different SRNs, showing that receptors’ spatial distributions can confer specificity not only at the local, but also at the brain-wide, network level. In humans, using resting-state functional MRI, SRNs replicate established divisions of serotonin effects on impulsivity and negative biases. These results provide compelling evidence that heterogeneous brain-wide distributions of different serotonin receptor types may underpin behaviorally distinct modes of serotonin regulation. This suggests that serotonin neurons may regulate multiple aspects of human behavior via modulation of large-scale receptor networks.

The central neuromodulator serotonin (5-HT) has been implicated in a wide range of behaviors and affective disorders, but the principles underlying its function remain elusive. One influential line of research has implicated 5-HT in response inhibition and impulse control. Another has suggested a role in affective processing. However, whether and how these effects relate to each other is still unclear. Here, we report that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DRN) produces a dose-dependent increase in mice's ability to withhold premature responding in a task that requires them to wait several seconds for a randomly delayed tone. The 5-HT effect had a rapid onset and was maintained throughout the stimulation period. In addition, movement speed was slowed but stimulation did not affect reaction time or time spent at the reward port. Using similar stimulation protocols in place preference and value-based choice tests, we found no evidence of either appetitive or aversive effects of DRN 5-HT neuron activation. These results provide strong evidence that the efficacy of DRN 5-HT neurons in promoting waiting for delayed rewards is independent of appetitive or aversive effects and support the importance of 5-HT in behavioral persistence and impulse control. 3 !

Although we understand how serotonin receptors function at the single-cell level, what role different serotonin receptors play in regulating brain-wide activity and, in turn, human behaviour, remains unknown. Here, we developed transcriptomic-neuroimaging mapping to characterise brain-wide functional signatures associated with specific serotonin receptors: serotonin receptor networks (SRNs). Probing SRNs with optogenetics-fMRI and pharmacology in mice, we show that activation of dorsal raphe serotonin neurons differentially modulates the amplitude and functional connectivity of different SRNs, showing that receptors’ spatial distributions can confer specificity not only at the local, but also at the brain-wide, network-level. In humans, using resting state fMRI, different sets of SRNs are linked to different behavioural phenotypes. These results provide compelling evidence that heterogeneous brain-wide distributions of different serotonin receptor types may underpin behaviourally-distinct modes of serotonin regulation. This suggests that dorsal raphe serotonin neurons may regulate multiple aspects of human behaviour via modulation of large-scale receptor networks.

Behaviour involves complex dynamic interactions across many brain regions.Detecting whole-brain activity in mice performing sophisticated behavioural tasks could facilitate insights into distributed processing underlying behaviour, guide local targeting, and help bridge the disparate spatial scales between rodent and human studies. Here, we present a comprehensive approach for recording brain-wide activity with functional magnetic resonance imaging (fMRI) compatible with a wide range of behavioural paradigms and neuroscience questions. We introduce hardware and procedural advances to allow multi-sensory, multi-action behavioural paradigms in the scanner. We identify signal artifacts arising from task-related body movements and propose novel strategies to suppress them. We validate and explore our approach in a 4-odour classical conditioning and a visually-guided operant task, illustrating how it can be used to extract information insofar intangible to rodent behaviour studies.Our work paves the way for future studies combining fMRI and local circuit techniques during complex behaviour to tackle multi-scale behavioural neuroscience questions.