Epigenetic Control of Reward Learning

在环境提示、行动和奖励刺激之间形成和保持联系的能力是习得行为的一个基本但基本的方面，这是生存所必需的。多项研究证实，这种与奖赏相关的学习是由以伏隔核为中心的大脑核团及其位于中脑的多巴胺神经元的神经支配所组成的分布式网络。多巴胺和伏隔核神经元都编码刺激-奖赏关系，而这两个区域的加工障碍都会抑制奖赏学习。在伏隔核内，多巴胺通过几个定义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，伏隔核内的多巴胺传递诱导了表观遗传重塑，这与基因表达的短暂和长期变化有关。然而，表观遗传变化在奖赏学习中扮演的角色尚不清楚。这项提议将检验两种不同类型的表观遗传改变(组蛋白修饰和DNA甲基化)是否由经典的刺激-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直接亚硫酸氢盐测序和定量RT-PCR。这些分析将使我们不仅能够确定奖赏学习是否与伏隔核中的表观遗传修饰有关，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的功能调节能力将通过在条件作用过程中阻断伏隔核中特定的组蛋白修饰或DNA甲基化来检测。这些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.