Mesolimbic dopamine neurons play a central role in reward-based reinforcement learning. Recent evidence indicates that a pathological form of reward-based learning contributes to the development of drug addiction. This proposal seeks to define the role of specific calcium signals in regulating the functional output and plasticity of dopamine neurons. It is known that action potential firing of dopamine neurons transitions from tonic single-spike activity to phasic bursts upon presentation of reward-related stimuli. This firing mode transition is thought to be triggered by excitatory glutamatergic inputs predominantly activating NMDA (N-methyl-D-aspartate)-type glutamate receptors. The phasic dopamine release resulting from dopamine neuron bursts acts to promote synaptic plasticity in target brain areas, thereby mediating reinforcement learning and the development of drug addiction. However, recent evidence indicates that plasticity of synapses on dopamine neurons themselves may also be essential for these learning processes. Calcium signals triggered by postsynaptic action potentials are known to play a critical role in the plasticity of synapses in the brain. Therefore, the overarching hypothesis of this proposal is that large calcium transients accompanying bursts of action potentials mediate the induction of long-term potentiation (LTP) of NMDA receptor-mediated transmission onto dopamine neurons. Electrophysiological recording combined with confocal imaging of intracellular calcium and flash photolysis of caged compounds will be performed in acutely prepared brain slices from rats.
The first aim i s to determine the influence of metabotropic neurotransmitter inputs and acute psychostimulant exposure on burst- induced calcium signals.
The second aim i s to test the hypothesis that LTP of NMDA receptor- mediated transmission can be induced in a manner dependent on burst-induced calcium signals boosted by preceding metabotropic neurotransmitter inputs.
The third aim i s to test the hypothesis that repeated psychostimulant exposure in vivo enhances burst-induced calcium signals and the plasticity of NMDA receptor-mediated transmission, which may promote the learning of environmental stimuli associated with drug experience. The results obtained from this project will provide novel information to advance our understanding of the neural mechanisms underlying the development of drug addiction. Experience-dependent changes in the strength of connections between neurons in the brain reward circuit is thought to be one of the key neural mechanisms underlying drug addiction, which can be viewed as a maladaptive form of reward learning. Therefore, understanding the cellular machinery responsible for these changes would help to develop therapeutic strategies for drug addiction. The goal of this project is to determine the critical cellular signals mediating these changes and their regulation by addictive drugs.

Public Health Relevance

Experience-dependent changes in the strength of connections between neurons in the brain reward circuit is thought to be one of the key neural mechanisms underlying drug addiction, which can be viewed as a maladaptive form of reward learning. Therefore, understanding the cellular machinery responsible for these changes would help to develop therapeutic strategies for drug addiction. The goal of this project is to determine the critical cellular signals mediating these changes and their regulation by addictive drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015687-09
Application #
8263422
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Sorensen, Roger
Project Start
2002-12-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$251,445
Indirect Cost
$83,392
Name
University of Texas Austin
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
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Clements, Michael A; Swapna, Immani; Morikawa, Hitoshi (2013) Inositol 1,4,5-triphosphate drives glutamatergic and cholinergic inhibition selectively in spiny projection neurons in the striatum. J Neurosci 33:2697-708
Whitaker, Leslie R; Degoulet, Mickael; Morikawa, Hitoshi (2013) Social deprivation enhances VTA synaptic plasticity and drug-induced contextual learning. Neuron 77:335-45
Morikawa, H; Paladini, C A (2011) Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms. Neuroscience 198:95-111
Ahn, Kee-Chan; Bernier, Brian E; Harnett, Mark T et al. (2010) IP3 receptor sensitization during in vivo amphetamine experience enhances NMDA receptor plasticity in dopamine neurons of the ventral tegmental area. J Neurosci 30:6689-99
Harnett, Mark T; Bernier, Brian E; Ahn, Kee-Chan et al. (2009) Burst-timing-dependent plasticity of NMDA receptor-mediated transmission in midbrain dopamine neurons. Neuron 62:826-38
Sullivan, Matthew A; Chen, Huanmian; Morikawa, Hitoshi (2008) Recurrent inhibitory network among striatal cholinergic interneurons. J Neurosci 28:8682-90
Cui, Guohong; Bernier, Brian E; Harnett, Mark T et al. (2007) Differential regulation of action potential- and metabotropic glutamate receptor-induced Ca2+ signals by inositol 1,4,5-trisphosphate in dopaminergic neurons. J Neurosci 27:4776-85
Ponomarev, Igor; Maiya, Rajani; Harnett, Mark T et al. (2006) Transcriptional signatures of cellular plasticity in mice lacking the alpha1 subunit of GABAA receptors. J Neurosci 26:5673-83
Okamoto, Takashi; Harnett, Mark T; Morikawa, Hitoshi (2006) Hyperpolarization-activated cation current (Ih) is an ethanol target in midbrain dopamine neurons of mice. J Neurophysiol 95:619-26

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