Epigenetic Control of Brain Reward Systems

 描述(申请人提供)：毒瘾是一种慢性、复发性疾病，在戒毒很长一段时间后，与毒品有关的协会能够对行为施加巨大的控制。中枢神经系统中的表观遗传修饰对长期的行为和神经元可塑性至关重要，并与动机行为、药物相关学习和成瘾的许多特征有关。然而，在成瘾的背景下，我们利用表观遗传操作的治疗潜力的能力受到了限制，因为缺乏对药物经历后表观遗传动态的详细洞察，以及无法 实时定位特定的表观遗传改变，以询问它们的分子和行为功能。这项建议寻求利用单细胞全表基因组测序方法来定义特定神经元群体中药物经验的表观遗传学特征。除了揭示新的候选治疗方法外，这些信息还将直接应用于基于CRISPR技术的有针对性的表观遗传编辑策略，这将允许操纵特定药物调控基因的表观遗传状态。这一新的方法将证明对药物相关行为的特定基因进行独特的表观遗传修饰的必要性，并使首次研究表观遗传修饰是否足以实现Alte奖励功能。最后，我们将把这些工具与个体遗传学方法相结合，以实现对自由移动动物的表观遗传状态的光驱动操纵。因此，除了揭示药物经验后表观遗传状态的确切性质和范围外，这项提案将首次研究这些修饰如何影响奖赏回路的功能，并最终总体上影响奖赏寻求行为。

 DESCRIPTION (provided by applicant): Drug addiction is a chronic, relapsing disorder in which drug-related associations are capable of exerting tremendous control over behavior long after drug taking has ceased. Epigenetic modifications in the central nervous system are critical for long-term behavioral and neuronal plasticity, and have been implicated in numerous features of motivated behavior, drug-related learning, and addiction. However, our ability to harness the therapeutic potential of epigenetic manipulations in the context of addiction has been limited by the lack of detailed insight into epigenetic dynamics following drug experiences, and the inability to target specific epigenetic alterations in real time to interrogate their molecular and behaviora function. This proposal seeks to utilize single-cell whole-epigenome sequencing approaches to define epigenetic signatures of drug experience in specific neuronal populations. In addition to revealing new therapeutic candidates, this information will be directly applied to targeted epigenetic editing strategies based on CRISPR technology, which will allow manipulation of epigenetic states at specific drug-regulated genes. This novel approach will demonstrate the necessity of unique epigenetic modifications at specific genes for drug-associated behaviors, and also enable the first investigation of whether an epigenetic modification is sufficient to alte reward function. Finally, we will integrate these tools with ontogenetic approaches to enable light-driven manipulation of epigenetic states in freely moving animals. Thus, in addition to revealing the exact nature and scope of epigenetic states following drug experience, this proposal will be the first to investigate how these modifications contribute to the function of reward circuits and ultimately to reward seeking behavior in general.