Dopamine is thought to be a key regulator of learning from appetitive as well as aversive events. It has been proposed that dopamine neurons signal value prediction error (VPE, often referred to as reward prediction error), or the difference between the values of actual and predicted outcomes. Although accumulating evidence supports this idea for reward, how dopamine neurons integrate information about aversive events remains highly controversial. Some studies have shown that aversive stimuli inhibit dopamine neurons, while others have suggested that aversive events activate at least some dopamine neurons. Others have argued that dopamine neurons largely ignore aversive events. In order to resolve the above controversy, this project aims to examine how dopamine neurons in the ventral tegmental area (VTA) convey information about aversive events . Our main hypothesis is that dopamine neurons alter the way they respond to rewarding and aversive stimuli depending on reward contexts. More specifically, we hypothesize that in low reward contexts, dopamine neurons faithfully signal value prediction errors by combining the value of both reward and aversion. In high reward contexts, we hypothesize that dopamine neurons acquire short-latency excitatory response to aversive stimuli and decrease their inhibitory responses to aversive stimuli, thereby diminishing their ability to signal value prediction errors.
Aim 1 will test the specific hypothesis that dopamine neurons in VTA represent a combined value for reward and aversion along a one-dimensional value axis in a low reward context.
Aim 2 will test the hypothesis that VTA dopamine neurons signal value prediction error in low but not high reward contexts.
Aim 3 will test the hypothesis that expectation of an aversive stimulus reduces aversive stimulus- induced inhibition in a subtractive fashion in low reward contexts. Malfunction of the midbrain dopamine system is associated with a variety of pathological conditions including depression, anhedonia, apathy, schizophrenia, addiction, eating disorders and Parkinson's disease. In particular, aberrant dopamine responses to salient events have been implicated in addiction, schizophrenia and other mental disorders. This study will allow us to better understand situations in which dopamine neurons are activated by aversive events, and will serve as a foundation to understand dopamine signaling in health and disease.

Public Health Relevance

Malfunction of the midbrain dopamine system is associated with a variety of pathological conditions including depression, schizophrenia and addiction. Understanding neural circuits that regulate dopamine neurons will deepen our understanding of the etiology of these diseases and aid in the design of preventive and therapeutic approaches.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Rossi, Andrew
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Harvard University
Schools of Arts and Sciences
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Menegas, William; Akiti, Korleki; Amo, Ryunosuke et al. (2018) Dopamine neurons projecting to the posterior striatum reinforce avoidance of threatening stimuli. Nat Neurosci 21:1421-1430
Watabe-Uchida, Mitsuko; Eshel, Neir; Uchida, Naoshige (2017) Neural Circuitry of Reward Prediction Error. Annu Rev Neurosci 40:373-394
Menegas, William; Babayan, Benedicte M; Uchida, Naoshige et al. (2017) Opposite initialization to novel cues in dopamine signaling in ventral and posterior striatum in mice. Elife 6:
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Matsumoto, Hideyuki; Tian, Ju; Uchida, Naoshige et al. (2016) Midbrain dopamine neurons signal aversion in a reward-context-dependent manner. Elife 5: