Factors that govern the role of dopamine in striatal AMPAR plasticity

描述（由申请人提供）：多巴胺（DA）是神经回路中用于运动控制、认知和奖励的关键神经调质。DA调节的主要目标是兴奋性神经递质谷氨酸的信号传导。DA调节多巴胺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。这种复杂性的大部分可能是由于细胞类型和电路之间的变化，其中DA已被研究。还有哪些因素可能导致异质性？使用离体脑片制备的神经核（NAc）-神经奖励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）在体内暴露于新的刺激和2）DA信号传导的时间与长时程增强（LTP）诱导。我们发现，一个短暂的接触新奇，使DA诱导NAc AMPAR突触强度的持久的抑郁症。我们还发现，事先DA信号增强强直刺激诱导强大的LTP的能力。使用直接和敏感的电生理措施，我们将调查的作用，新奇和时机的DA调制NAc AMPAR。我们希望我们的研究能够为健康和疾病中的多巴胺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.