Dopamine is a key modulator of motivated behavior. Dopamine is also a key modulator of reinforcement- driven learning. Yet the relationship between these critical functions is unclear. Based on seminal recordings of dopamine cells in head-fixed animals, the dominant theory is that dopamine signals reward prediction errors - i.e. a learning signal. However, the actual release of dopamine has been repeatedly found to escalate as freely-moving animals approach rewards, in a manner more consistent with reward prediction than reward prediction errors. Furthermore, optogenetic stimulation of dopamine immediately invigorates behavior, as if boosting reward predictions. This project seeks to resolve this apparent discrepancy, and gain a new understanding of dopamine signaling and regulation. Prior studies in brain slices have established that dopamine release is strongly influenced by local mechanisms, especially nicotinic acetylcholine receptors on dopamine terminals.
Aim 1 will directly test whether there is a dissociation between dopamine firing and dopamine release. VTA dopamine cell body activity will be assessed using both optogenetic identification of single neurons, and fiber photometry, and dopamine terminal activity in accumbens core and shell will be measured using both fast-scan cyclic voltammetry and fiber photometry. These measures will be taken as rats perform multiple behavioral tasks, including a trial-and-error reinforcement learning task and a more passive Pavlovian task for better comparison to prior studies.
Aim 2 will monitor and manipulate accumbens cholinergic interneurons during the same behavioral tasks, while examining dopamine terminal activity. The hypothesis is that these interneurons can both shape the motivational message conveyed by dopamine release, and rapidly switch this message to a reinforcement learning signal. Finally, Aim 3 will use variably-timed local optogenetic manipulations of dopamine and accumbens spiny neuron subpopulations (direct vs indirect) to investigate the exact timing requirements for dopamine to serve as a reinforcement learning signal. The long-term goal of this research program is to understand circuit mechanisms of adaptive decision- making, and how drugs such as nicotine perturb these mechanisms to produce addictive behavior. By using state-of-the-art techniques and carefully-designed behavioral tasks to test novel hypotheses, this project may transform our understanding of the neurobiology of motivated behavior.

Public Health Relevance

The neurotransmitter dopamine is critically involved in both normal learning and motivation, and in the maladaptive decisions that characterize drug addiction. The proposed project aims to better understand the control of dopamine activity and dopamine release, though mechanisms affected by the addictive drug nicotine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA045783-01
Application #
9499645
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Berton, Olivier Roland
Project Start
2018-04-15
Project End
2023-03-31
Budget Start
2018-04-15
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118