Dopamine neurons in the ventral tegmental area (VTA) play central roles in learning and motivation. In tasks involving rewards, they respond in a stereotyped fashion. They are activated by unpredicted rewards. But when a sensory cue predicts reward, they instead start responding to the cue, while their response to reward attenuates. Moreover, when a predicted reward is omitted, their activity is transiently suppressed. From these observations, it has been postulated that dopamine neurons signal discrepancies between expected and actual reward, i.e., they compute the reward prediction error (RPE). However, it remains unknown how dopamine neurons compute RPE. To understand this question, it is important to know (1) what mechanisms suppress dopamine neurons' responses to reward when the reward is expected, and (2) what mechanisms are responsible for generating the response of dopamine neurons to reward-predicting cues. A previous study in our laboratory has shown that VTA GABA neurons exhibit sustained activations during the delay between a reward-predictive cue and reward. This result suggests that VTA GABA neurons suppress dopamine neurons' responses to reward when the reward is expected. In this proposal, to test this idea experimentally, the sustained activity of VTA GABA neurons will be optogenetically manipulated, and how this manipulation affects dopamine neurons' responses to reward will be examined electrophysiologically. Second, although previous studies have shown that the nucleus accumbens (NAc) and the ventral pallidum(VP) provide large numbers of inhibitory inputs to dopamine neurons, and NAc neurons project to VP, the exact roles of these connections in regulating the activity of dopamine neurons remain unclear. In a preliminary experiment, inactivation of unilateral NAc was found to greatly reduce dopamine neurons' responses to reward-predictive cues. We will experimentally test the hypothesis that a disynaptic, inhibitory pathway from NAc to VP to dopamine neurons is responsible in generating dopamine neurons' responses to reward-predictive cues. In total, this project aims to experimentally test the aforementioned specific hypotheses using integrative approaches in mice. Malfunctions of the dopamine system are associated with a variety of pathological conditions including depression, schizophrenia and addiction. By providing a detailed, circuit-level analysis of dopamine neuron firing, we will provide a framework for understanding how the brain learns from rewards, and how this system can be disrupted in 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
4R01MH101207-04
Application #
9070769
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Rossi, Andrew
Project Start
2013-08-01
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
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
Starkweather, Clara Kwon; Gershman, Samuel J; Uchida, Naoshige (2018) The Medial Prefrontal Cortex Shapes Dopamine Reward Prediction Errors under State Uncertainty. Neuron 98:616-629.e6
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:
Starkweather, Clara Kwon; Babayan, Benedicte M; Uchida, Naoshige et al. (2017) Dopamine reward prediction errors reflect hidden-state inference across time. Nat Neurosci 20:581-589
Mathis, Mackenzie Weygandt; Mathis, Alexander; Uchida, Naoshige (2017) Somatosensory Cortex Plays an Essential Role in Forelimb Motor Adaptation in Mice. Neuron 93:1493-1503.e6
Tian, Ju; Huang, Ryan; Cohen, Jeremiah Y et al. (2016) Distributed and Mixed Information in Monosynaptic Inputs to Dopamine Neurons. Neuron 91:1374-1389
Eshel, Neir; Tian, Ju; Bukwich, Michael et al. (2016) Dopamine neurons share common response function for reward prediction error. Nat Neurosci 19:479-86
Matsumoto, Hideyuki; Tian, Ju; Uchida, Naoshige et al. (2016) Midbrain dopamine neurons signal aversion in a reward-context-dependent manner. Elife 5:
Cohen, Jeremiah Y; Amoroso, Mackenzie W; Uchida, Naoshige (2015) Serotonergic neurons signal reward and punishment on multiple timescales. Elife 4:
Tian, Ju; Uchida, Naoshige (2015) Habenula Lesions Reveal that Multiple Mechanisms Underlie Dopamine Prediction Errors. Neuron 87:1304-1316

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