Factors that govern the role of dopamine in striatal AMPAR plasticity

描述(申请人提供)：多巴胺(DA)是神经回路中的关键神经调节剂，用于运动控制、认知和奖励。DA调节的一个主要目标是兴奋性神经递质谷氨酸的信号传递。DA调节谷氨酸能信号和可塑性的基本原理是什么？解决这个问题的数据复杂得令人抓狂。这种复杂性在很大程度上可能是由于细胞类型和研究DA的电路之间的差异造成的。还有什么其他因素可能导致这种异质性？使用伏隔核(NAC)的体外脑片制备--神经回报回路的中心组成部分--我们的初步研究提供了两个额外因素的证据：1)体内暴露于新刺激和2)DA信号的时间与长时程增强(LTP)诱导有关。我们发现，短暂的接触新奇事物使DA能够在NAC AMPAR突触强度中诱导长期的抑制。我们还发现，先前的DA信号增强了强直刺激诱导健壮LTP的能力。使用直接和灵敏的电生理方法，我们将研究新颖性和时序在NAC AMPAR的DA调节中的作用。我们希望我们的研究能为多巴胺在健康和疾病中的调节提供新的指导原则。

DESCRIPTION (provided by applicant): Dopamine (DA) is a critical neuromodulator in neural circuits for motor control, cognition and reward. A chief target of DA modulation is signaling of the excitatory neurotransmitter, glutamate. What are the basic principles for DA modulation of glutamatergic signaling and plasticity? Data addressing this question are maddeningly complex. Much of this complexity may be due to variations between cell types and circuits in which DA has been studied. What other factors might contribute to the heterogeneity? Using an ex vivo brain slice preparation of the nucleus accumbens (NAc)-a central component of the neural reward circuit-our pilot studies provide evidence for two additional factors: 1) in vivo exposure t novel stimuli and 2) the timing of DA signaling in relation to long-term potentiation (LTP) induction. We find that a brief exposure to novelty enables DA to induce a long-lasting depression in NAc AMPAR synaptic strength. We also find that prior DA signaling boosts the ability of tetanic stimulation to induce robust LTP. Using direct and sensitive electrophysiologica measures, we will investigate the roles for novelty and timing in DA modulation of NAc AMPARs. We expect our studies to inform new guiding principles for dopamine modulation in health and disease.