Epigenetic Control of Reward Learning

描述（由申请人提供）： 在环境线索、行为和奖励刺激之间形成和维持关联的能力是生存所必需的习得行为的基本方面。多条研究线已经确定，这种奖励相关的学习是由以中脑多巴胺神经元为中心的脑核团及其神经支配的分布式网络介导的。多巴胺和丘脑核神经元都编码刺激-奖赏关系，任何一个区域的受损处理都会抑制奖赏学习。在丘脑核内，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并改变神经元输出。最近的研究表明，多巴胺在丘脑核内的传递诱导了与基因表达的短暂和长期变化相关的表观遗传重构。然而，表观遗传变化在奖励学习中的作用尚不清楚。该提案将研究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-奖励条件反射诱导。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的直接亚硫酸氢盐测序和定量RT-PCR。这些分析不仅可以让我们确定奖励学习是否与核内的表观遗传修饰有关，还可以揭示这些变化影响了哪些基因。此外，将通过在条件反射期间阻断特定组蛋白修饰或核内的DNA甲基化来检查表观遗传变化在功能上调节学习的能力。这些结果将为奖赏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。 公共卫生相关性： 奖励相关学习对于适应性和适应不良动机行为都是至关重要的，调节这种自然和药物奖励学习的神经过程在系统和分子水平上都具有相当大的特征。因此，虽然这项研究将阐明有助于奖励相关行为的正常形成和维持的分子机制，但它也将更好地理解这些机制如何有助于药物成瘾。从长远来看，这种更好的理解将使我们能够制定更有效的药物成瘾治疗和预防策略，提高成瘾者的生活质量，并将导致更好地理解适应性学习。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Reward-related learning is critical to adaptive as well as maladaptive motivated behavior, and the neural processes that regulate such learning for natural and drug rewards share considerable features, both at the systems and molecular level. Therefore, while this study will elucidate the molecular mechanisms that contribute to normal formation and maintenance of reward-related behaviors, it will also provide a better understanding of how such mechanisms may contribute to drug addiction. In the long term, this improved understanding will equip us to develop more effective treatment and prevention strategies for drug addiction and improve quality of life for addicted individuals, and will also lead to a better understanding of adaptive learning in general.