Diseases and disorders directly affected by dopamine systems (e.g., drug addiction and Parkinson's disease) highlight the importance of these systems in motivated human behavior and cognition. The dopamine system is known to be a critical component of normal learning, reward processing, and decision-making (reviewed in Montague et al., 2004). Unfortunately, our present knowledge of dopamine systems in human brains is relatively sparse compared to the wealth of experimentation and computational modeling on these systems in rodents and non-human primates. Previously, technological constraints have limited direct experimentation in human brains. This proposal capitalizes on our group's recent technological innovation, which was supported by the NIH R21 mechanism - CEBRA: R21DA024140 - and resulted in the successful completion of the first sub-second measurements of dopamine release in a human brain. Furthermore, these measurements took place during an active decision-making task that was framed by computational models of learning and reward processing (Kishida et al., 2011 and Kishida et al., under review). We propose to pursue three specific aims, which combine our technological advance with active learning tasks designed to probe the role of dopamine in human behavior.
Our aims i ncorporate three learning signals, where actual and counterfactual experience will each be examined in human striatal responses. The proposed work will inform on the controversial role for dopamine in reward/movement interactions. The experiments proposed will yield unprecedented insight into the function of the dopamine system in the humans afflicted with Parkinson's disease and Essential Tremor. With the support of the NIH (R21DA024140), our team successfully developed a complete prototype system for making electrochemical measurements of dopamine delivery in the human brain. Feasibility has been demonstrated by obtaining the first dopamine measurements in the striata of subjects with Parkinson's during a decision-making task. This substantial preliminary work is now ready for a larger scale with specific hypothesis testing about the role of dopamine systems in Parkinson's disease, Essential tremor, and human decision-making and behavior.

Public Health Relevance

Experiments and computational models (primarily investigated in rodents and non-human primates) suggest dopamine systems in the brain are essential for normal learning, reward-processing, and ongoing decision- making. This proposal builds upon our group's innovative work, which - for the first time - recorded sub- second measurements of dopamine in human subjects and amalgamated these measurements with computational models of dopamine function. Herein we propose to use this newly developed technology to generate unprecedented insight into the function of dopamine systems directly in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS092701-01A1
Application #
9029452
Study Section
Special Emphasis Panel (SPC)
Program Officer
Gwinn, Katrina
Project Start
2015-09-01
Project End
2020-07-31
Budget Start
2015-09-01
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$507,375
Indirect Cost
$174,310
Name
Virginia Polytechnic Institute and State University
Department
Type
Organized Research Units
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24060
Moran, Rosalyn J; Kishida, Kenneth T; Lohrenz, Terry et al. (2018) The Protective Action Encoding of Serotonin Transients in the Human Brain. Neuropsychopharmacology 43:1425-1435
Hétu, Sébastien; Luo, Yi; Saez, Ignacio et al. (2016) Asymmetry in functional connectivity of the human habenula revealed by high-resolution cardiac-gated resting state imaging. Hum Brain Mapp 37:2602-15
Kishida, Kenneth T; Saez, Ignacio; Lohrenz, Terry et al. (2016) Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward. Proc Natl Acad Sci U S A 113:200-5
Lohrenz, Terry; Kishida, Kenneth T; Montague, P Read (2016) BOLD and its connection to dopamine release in human striatum: a cross-cohort comparison. Philos Trans R Soc Lond B Biol Sci 371:
Montague, P Read; Kishida, Kenneth T; Moran, Rosalyn J et al. (2016) An efficiency framework for valence processing systems inspired by soft cross-wiring. Curr Opin Behav Sci 11:121-129