Timing-dependent dopamine (DA) release in the nucleus accumbens (NAc) has been critically implicated in emotion-cognition interaction as well as reward-associated learning. A shift in the timing of DA release in the NAc has been shown to accompany different stages of reward conditioning. However, despite its apparent physiological significance, the cellular mechanisms by which timing-contingent DA release regulates NAc synaptic transmission have not been directly assessed. To address this knowledge gap, this application focuses on the excitatory synaptic input from the ventral medial prefrontal cortex (mPFC) to the nucleus accumbens shell (NAcSh), a key brain site involved in the integration and expression of emotional and motivational behaviors. Our preliminary results show that mPFC-to-NAcSh synaptic transmission undergoes long-term potentiation (LTP) by synchronized dopamine signaling from the ventral tegmental area (VTA). Our central hypothesis is that this LTP is DA timing-dependent and glutamate pathway-specific;it is achieved by augmented presynaptic glutamate release, and is regulated by co-activation of presynaptic dopamine and GABA receptors. To test this hypothesis, we will use whole-cell patch-clamp techniques combined with pharmacological, optogenetic, and viral-mediated gene transfer to determine the molecular and cellular mechanisms that underlie this novel form of LTP. Results from the proposed experiments will advance our knowledge of timing-dependent DA action in regulating synaptic plasticity, provide a mechanistic understanding of the mPFC-VTA-NAcSh circuitry mechanisms underlying emotion-cognition interactions, and identify molecular targets for the clinical corrections of certain cognitive, psychological, and psychiatric disorders.

Public Health Relevance

Timing-dependent dopamine signaling in the nucleus accumbens has profound implications from basic reward seeking to the pathophysiology in psychiatric disorders. The proposed work attempts to characterize a novel form of accumbal plasticity which is selectively dependent on temporally contingent DA signaling. The expected outcomes will define a novel cellular and circuitry mechanism underlying emotion-cognition interactions, and identify molecular targets for the clinical corrections of certain cognitive, psychological, and psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH101147-01A1
Application #
8649346
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Asanuma, Chiiko
Project Start
2014-04-03
Project End
2019-03-31
Budget Start
2014-04-03
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$384,063
Indirect Cost
$134,063
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213