Dopamine Signaling and Synaptic Plasticity in the Nucleus Accumbens

描述（由申请人提供）：中脑核（NAc）中的时间依赖性多巴胺（DA）释放与情感-认知相互作用以及奖励相关学习密切相关。NAc中DA释放时间的转变已被证明伴随着奖励条件反射的不同阶段。然而，尽管它的明显的生理意义，定时相依DA释放调节NAc突触传递的细胞机制尚未直接评估。为了解决这一知识差距，本应用程序的重点是兴奋性突触输入从腹内侧前额叶皮层（mPFC）的核壳（NAcSh），一个关键的大脑部位参与整合和表达的情绪和动机行为。我们的初步研究结果表明，mPFC到NAcSh突触传递经历长时程增强（LTP）的同步多巴胺信号从腹侧被盖区（VTA）。我们的中心假设是，这种LTP是DA时间依赖性和谷氨酸途径特异性的，它是通过增强突触前谷氨酸释放来实现的，并通过突触前多巴胺和GABA受体的共激活来调节。为了验证这一假设，我们将使用全细胞膜片钳技术结合药理学，光遗传学和病毒介导的基因转移，以确定这种新形式的LTP的分子和细胞机制。从拟议的实验结果将推进我们的知识的时间依赖性DA行动在调节突触可塑性，提供一个机械的理解mPFC-VTA-NAcSh电路机制的情感认知相互作用，并确定某些认知，心理和精神疾病的临床纠正的分子靶点。

DESCRIPTION (provided by applicant): 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.