Epigenetic Control of Reward Learning

形成和维持环境线索、行动和奖励刺激之间联系的能力是生存所必需的习得行为的一个基本而又基本的方面。多项研究已经确定，这种与奖励相关的学习是由以伏隔核为中心的分布式脑核网络和位于中脑的多巴胺神经元的神经支配来调节的。多巴胺和伏隔核神经元都编码刺激-奖励关系，这两个区域的处理受损会抑制奖励学习。在伏隔核内，多巴胺通过几个明确的细胞内信号级联来指导突触可塑性和改变神经元输出。最近的研究表明，多巴胺在伏隔核内的传递诱导表观遗传重塑，这与基因表达的短暂和长期变化有关。然而，表观遗传变化在奖励学习中所起的作用尚不清楚。本研究将探讨两种不同类型的表观遗传改变（组蛋白修饰和DNA甲基化）是否由经典刺激-奖励条件作用诱导。这些变化将使用各种尖端技术进行研究，包括染色质免疫沉淀，DNA直接亚硫酸盐测序和定量RT-PCR。这些实验将使我们不仅能够确定奖励学习是否与伏隔核的表观遗传修饰有关，而且还将揭示这种变化正在影响哪些基因。此外，表观遗传变化对学习功能调节的能力将通过在调节过程中阻断伏隔核中的特定组蛋白修饰或DNA甲基化来研究。该结果将为奖励学习的表观遗传控制提供新的见解，并增强我们对调节动机行为的分子途径的理解。

The ability to form and maintain associations between environmental cues, actions, and rewarding stimuli is an elementary yet fundamental aspect of learned behavior that is necessary for survival. Multiple lines of research have identified that such reward-related learning is mediated by a distributed network of brain nuclei centered upon the nucleus accumbens and its innervation from dopamine neurons located in the midbrain. Both dopamine and nucleus accumbens neurons encode stimulus-reward relationships, and impaired processing in either area inhibits reward learning. Within the nucleus accumbens, dopamine operates through several well- defined intracellular signaling cascades to direct synaptic plasticity and alter neuronal output. Recent studies indicate that dopamine transmission within the nucleus accumbens induces epigenetic remodeling that is associated with both brief and prolonged changes in gene expression. However, the role that epigenetic changes play in reward learning is unclear. This proposal will examine whether two different types of epigenetic alteration (histone modification and DNA methylation) are induced by classical stimulus-reward conditioning. These changes will be investigated using a variety of cutting-edge techniques, including chromatin immunoprecipitation, direct bisulfite sequencing of DNA, and quantitative RT-PCR. These assays will allow us to determine not only whether reward learning is associated with epigenetic modification in the nucleus accumbens, but will also reveal which genes such changes are affecting. Furthermore, the ability of epigenetic changes to functionally modulate learning will be examined by blocking specific histone modifications or DNA methylation in the nucleus accumbens during conditioning. The results will provide novel insight into the epigenetic control of reward learning and enhance our understanding of the molecular pathways that regulate motivated behavior.