Sub-second Dopamine and Serotonin Signaling in Human Striatum during Perceptual Decision-Making

Open Access

Published:October 12, 2020in Neuron

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  • Dopamine and serotonin are measured in human striatum during awake decision-making
  • Serotonin tracks sensory uncertainty in caudate nucleus
  • Dopamine and serotonin track sensory statistics in caudate nucleus
  • Dopamine and serotonin track decision times in putamen


Recent animal research indicates that dopamine and serotonin, neuromodulators traditionally linked to appetitive and aversive processes, are also involved in sensory inference and decisions based on such inference. We tested this hypothesis in humans by monitoring sub-second striatal dopamine and serotonin signaling during a visual motion discrimination task that separates sensory uncertainty from decision difficulty in a factorial design. Caudate nucleus recordings (n = 4) revealed multi-scale encoding: in three participants, serotonin tracked sensory uncertainty, and, in one participant, both dopamine and serotonin tracked deviations from expected trial transitions within our factorial design. Putamen recordings (n = 1) supported a cognition-action separation between caudate nucleus and putamena striatal sub-division unique to primates—with both dopamine and serotonin tracking decision times. These first-of-their-kind observations in the human brain reveal a role for sub-second dopamine and serotonin signaling in non-reward-based aspects of cognition and action.


Neuromodulatory systems that deliver dopamine and serotonin to widespread brain structures affect basic physiological processes, including synaptic plasticity and stabilization of neural circuits (Marder, 2012). These neuromodulatory systems also participate in a variety of cognitive processes, such as motivation, mood, and learning (Cools et al., 2011Dayan, 2012). Consistent with this broad impact on healthy function, disturbance in dopamine and serotonin signaling has been linked to diverse clinical conditions, including Parkinson’s disease (Lotharius and Brundin, 2002), anorexia nervosa (Kaye et al., 1998), obsessive compulsive disorder (Hu et al., 2006), and mood disorders such as depression (Risch et al., 2009). Yet, there are profound difficulties associated with studying neuromodulator signaling in humans (Bucher and Wightman, 2015). As a result, we have a rudimentary understanding of how neuromodulatory systems support human cognition and behavior and thereby how their dysfunction contributes to clinical conditions.Over the last decade, this situation has begun to change, and pioneering efforts have recorded directly from human dopaminergic neurons during reward-based choice tasks (Patel et al., 2012Zaghloul et al., 2009), although recordings from serotonergic neurons have not yet been made. Such recordings are necessary to understand how dopaminergic and serotonergic function relates to human cognition and behavior, but they will only be part of the story (Dayan, 2012). It is also necessary to measure the release-and-action of dopamine and serotonin at downstream neural targets to understand the computations that are supported by these systems and how the action of neurotransmitter agonists, antagonists, and reuptake inhibitors—drugs already in widespread use—impact human cognition and behavior (Montague and Kishida, 2018). While anatomically and chemically specific methods such as positron emission tomography (Volkow et al., 1996) and microdialysis (Meyerson et al., 1990) are available for use in humans, the recordings are on the timescale of minutes and cannot resolve the sub-second computations believed to be supported by fast neuromodulation (Dayan, 2012).It is now possible to detect sub-second fluctuations in both dopamine and serotonin in deep structures of the human brain during conscious behavior (Kishida et al., 20112016Montague and Kishida, 2018Moran et al., 2018). This approach involves fast scan cyclic voltammetry adapted for use in patients undergoing deep brain stimulation (DBS) surgery for disease management (e.g., Parkinson’s disease and essential tremor). To date, striatal dopamine and serotonin have been measured during a sequential investment task with variable gains and losses (Kishida et al., 2016Moran et al., 2018). This work has produced two first-of-their-kind observations in human striatum: (1) sub-second dopamine fluctuations encode reward prediction errors, and (2) sub-second serotonin fluctuations are opponent to dopamine, showing positive transients to negative reward prediction errors and negative transients to positive reward prediction errors. However, the task is a low-dimensional probe of the dopaminergic and serotonergic systems—involving a single valence axis ranging from punishment to reward—and it is unclear how these systems function in more complex settings, such as perceptual decision-making, where variables relating to sensation, action, and learning are simultaneously at play.Pharmacological manipulations in humans (Crockett et al., 2012Guitart-Masip et al., 2012) and recordings or perturbations of neuronal activity in animals (Fonseca et al., 2015da Silva et al., 2018) already indicate that the dopaminergic and serotonergic systems support not only valence processing but also behavioral control—with dopamine invigorating and serotonin inhibiting responses. Further, recent animal research suggests that these systems support an even broader set of computations. For example, dopamine may track an animal’s strength of belief about sensory states (Lak et al., 2017) and surprise about non-reward-related features of sensory stimuli (Takahashi et al., 2017), whereas serotonin may track an animal’s uncertainty about task rules (Iigaya et al., 2018) and promote behavioral persistence in the face of short-term negative outcomes (Lottem et al., 2018). These developments promise to help advance our understanding of how the dopaminergic and serotonergic systems support healthy function in humans, but they also raise the issue of how to generalize insights from model organisms to humans (Montague and Kishida, 2018). There is an urgent need for similarly rigorous work in the conscious human brain where experimental paradigms can be even further refined to probe granular aspects of cognition and behavior.We deployed a visual perceptual decision task while recording sub-second changes in dopamine and serotonin delivery to human striatum (caudate nucleus and putamen). The task, adapted from the standard random dot motion paradigm (Newsome et al., 1989), requires participants to judge the average direction of dot motion relative to a reference direction, which only appears at the offset of the motion stimulus (Figure 1A). In addition to this temporal dissociation of sensory inference and decision formation, sensory uncertainty can be separated from decision difficulty by independently varying the fraction of coherently moving dots and the distance between the average motion direction and the reference direction (Figure 1B) (Bang and Fleming, 2018). For example, a participant may have low uncertainty about the average direction of dot motion (high coherence) but find it hard to judge their motion percept against the reference direction (low distance). The task thus allowed us to study the joint contribution of dopamine and serotonin at both the input and the output level of decision-making and within highly integrative neural structures. Critically, the striatum is believed to support perceptual decision-making (Cox and Witten, 2019Hanks and Summerfield, 2017), and the random dot motion task has been shown to activate the striatum in both non-human primates and humans (Bang and Fleming, 2018Ding and Gold, 2010Doi et al., 2020). To anticipate our results, we show that dopamine and serotonin track within-trial variables relating to uncertainty and action as well as cross-trial variables relating to task statistics.

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About S. R. Zelenz 102 Articles
S.R. Zelenz has worked in education for 20 years. Working with students from all walks of life, cultures, races, and social diversity, Zelenz’s research in Educational Leadership led to finding a better way to approach learning for students with trauma histories. Many were juvenile offenders, gang members, diagnosed with varying behavioral disorders, or had family histories of violence, murder, or narcissistic parenting. This research could not be effectively accomplished without further understanding: how epigenetic trauma inheritance may be impacting these students; how brain development from trauma may be impacting their behavioral and emotional development; as well as deep understanding of psychology and its varying classifications for behavioral and personality disorders. The goal is to find solutions for changing the conversation and making a real difference for these students. She has also worked with nonprofits of varying focus areas for the last 25 years. Her undergraduate degree in Arts Administration and Music prepared her for managing nonprofits of any size as well as procuring funding so that they can achieve their goals. Pairing her nonprofit background with her education background, she has been able to make a difference for over 200 nonprofits worldwide, written curriculum for schools across the globe, and assisted many arts organizations through performance and management.