The dopaminergic neurons of the substantia nigra pars compacta, located within the ventral mesencephalon, encode perhaps one of the most important signals for reinforcement learning in the brain: reward prediction error. This signal is encoded by the firing pattern of dopaminergic neurons, which controls the release of dopamine at target regions. Specifically, transient, impulse-dependent release of dopamine, driven by bursts of action potentials, is critical for natural processing in the brain. Disruptions of dopamie function result in many of the symptoms of a wide range of psychiatric diseases, drug addiction, and in the extreme case of the degeneration of these cells, to Parkinson's disease, including many of its cognitive aspects. Identification of the mechanism responsible for bursts is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive. This is largely due to the difficulty in accurately duplicating bursts under controlled experimenta conditions such as those attainable during in vitro experiments. A second difficulty has been the inability to selectively activate identified dopaminergic neuron afferents that can activate distint components of the burst mechanism during in vitro and in vivo experiments.
The specific aims i n this proposal are designed to investigate the cellular mechanisms by which afferents induce bursts in dopaminergic neurons. To achieve this, we will use selective in vitro and in vivo manipulation of identified afferents following prior viral infection in vivo with light-sensitive osins (ChR2, eNpHR3.0, Chrimson, Chronos). This strategy provides a clear advantage over simultaneous activation of all afferents by electrical stimulation since optogenetic manipulation of distinct identified inputs gives us a unique opportunity to dissect and individually examine all the mechanistic components necessary for bursting.

Public Health Relevance

The dopaminergic neurons located within the ventral mesencephalon encode perhaps one of the most important signals for reinforcement learning in the brain: reward prediction error. This signal is encoded by the firing pattern of dopaminergic neurons, which controls the release of dopamine at target regions, and this signal connects disruptions of dopamine function to many of the symptoms of a wide range of psychiatric diseases, drug addiction, and in the extreme case of the degeneration of these cells, to Parkinson's disease. This proposal aims to investigate the synaptic and cellular mechanisms by which identified inputs to dopaminergic neurons trigger bursts of electrical activity in dopaminergic neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH107229-03
Application #
9392200
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ferrante, Michele
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
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Grow, Douglas A; Simmons, DeNard V; Gomez, Jorge A et al. (2016) Differentiation and Characterization of Dopaminergic Neurons From Baboon Induced Pluripotent Stem Cells. Stem Cells Transl Med 5:1133-44
Gaval-Cruz, Meriem; Goertz, Richard B; Puttick, Daniel J et al. (2016) Chronic loss of noradrenergic tone produces ?-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens. Addict Biol 21:35-48