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.
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.
Logan, Ryan W; Hasler, Brant P; Forbes, Erika E et al. (2018) Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents. Biol Psychiatry 83:987-996 |
Parekh, Puja K; Becker-Krail, Darius; Sundaravelu, Poornima et al. (2018) Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the Clock?19 Model of Bipolar Mania. Biol Psychiatry 84:817-826 |
Parekh, Puja K; Sidor, Michelle M; Gillman, Andrea et al. (2018) Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator. Neuropsychopharmacology 43:435-444 |
Wang, Junshi; Ishikawa, Masago; Yang, Yue et al. (2018) Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving. J Neurosci 38:4316-4328 |
Ozburn, Angela R; Kern, Joseph; Parekh, Puja K et al. (2017) NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors. Front Mol Neurosci 10:360 |
Yu, Jun; Yan, Yijin; Li, King-Lun et al. (2017) Nucleus accumbens feedforward inhibition circuit promotes cocaine self-administration. Proc Natl Acad Sci U S A 114:E8750-E8759 |
Graziane, Nicholas M; Sun, Shichao; Wright, William J et al. (2016) Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. Nat Neurosci 19:915-25 |
Liu, Zheng; Wang, Yao; Cai, Li et al. (2016) Prefrontal Cortex to Accumbens Projections in Sleep Regulation of Reward. J Neurosci 36:7897-910 |
Ma, Yao-Ying; Wang, Xiusong; Huang, Yanhua et al. (2016) Re-silencing of silent synapses unmasks anti-relapse effects of environmental enrichment. Proc Natl Acad Sci U S A 113:5089-94 |
Neumann, Peter A; Wang, Yicun; Yan, Yijin et al. (2016) Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection. Neuropsychopharmacology 41:2399-410 |
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