Dopamine Signaling and Synaptic Plasticity in the Nucleus Accumbens

描述（由申请人提供）：伏隔核（NAc）中时间依赖性多巴胺（DA）的释放与情绪-认知相互作用以及奖励相关学习有重要关系。在奖赏条件作用的不同阶段，NAc释放DA的时间会发生变化。然而，尽管具有明显的生理意义，但时间条件下DA释放调节NAc突触传递的细胞机制尚未得到直接评估。为了解决这一知识差距，本应用程序将重点放在从腹侧内侧前额叶皮层（mPFC）到伏隔核壳（NAcSh）的兴奋性突触输入上，伏隔核壳是参与情绪和动机行为整合和表达的关键大脑部位。我们的初步结果表明，mpfc - nacsh突触传递通过腹侧被皮层（VTA）同步多巴胺信号进行长期增强（LTP）。我们的中心假设是，这种LTP是DA时间依赖性和谷氨酸通路特异性的；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受体的共同激活来调节。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来确定这种新型LTP的分子和细胞机制。这些实验的结果将进一步加深我们对DA在调节突触可塑性中的时间依赖性作用的认识，为mPFC-VTA-NAcSh回路机制在情绪-认知相互作用中的作用提供机制理解，并为某些认知、心理和精神疾病的临床纠正确定分子靶点。

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.