Epigenetic Reprogramming of Behaviors with Sensory Experience

通过感官体验对行为进行表观遗传重编程

• 批准号: 10398163
• 负责人: Corbin D Jones
• 金额: $ 38.3万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398163
• 关键词: Adult; Afferent Neurons; Anatomy; Animal Model; Anxiety; Behavior; Behavioral; Binding; Calcium; Calcium Signaling; Chemicals; Chromatin; Co-Immunoprecipitations; Cognition Disorders; Complex; Courtship; Cues; DNA Methylation; Disease; Drosophila genus; EP300 gene; Environment; Epigenetic Process; Food; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Histones; Hormone Receptor; Housing; Human; Immunoprecipitation; Juvenile Hormones; Lead; Ligands; Link; Maintenance; Mediating; Modeling; Modification; Molecular; Nervous system structure; Neurons; Odorant Receptors; Odors; Olfactory Receptor Neurons; Pheromone; Physiology; Property; Publishing; Receptor Signaling; Reporting; Role; Sensory; System; Testing; Therapeutic; Transferase; Work; autism spectrum disorder; base; chromatin immunoprecipitation; chromatin modification; epigenetic regulation; experience; experimental study; fly; hormonal signals; male; mating behavior; men' s group; mutant; neural circuit; neurophysiology; neuropsychiatric disorder; novel therapeutic intervention; olfactory receptor; palmitoleic acid; programs; promoter; relating to nervous system; response; sex; social; social deficits; transcription factor

Epigenetic regulation of gene expression is associated with long-lasting behavioral changes in animal models and humans. In response to environmental cues, epigenetic programs regulate gene expression in matured neurons via chromatin modifications and DNA methylation resulting in enduring neurophysiological changes. There is mounting evidence to implicate the involvement of dysfunctional epigenetic programs in many cognitive and neuropsychiatric disorders. However, establishing a causal link between epigenetic mechanism and neuronal properties that underlie behavioral adaptation in complex nervous systems has been difficult, mainly due to the paucity of behaviorally relevant neural and genetic substrates that are targeted by epigenetic regulation. Our goal is to determine the epigenetic basis of sensory experience-dependent changes in neurophysiology and behavior. We take advantage of the anatomical simplicity and the powerful genetic toolkit of the Drosophila olfactory receptor neurons (ORNs) involved in courtship behaviors, and the well- established Drosophila male courtship behavior, a robust ritualistic behavior governed by a single gene, fruitlessM (fruM) expressed in approximately 2000 interconnected neurons. Our pilot experiments and recent studies show that olfactory experience enhances the response of the Or47b and Ir84a ORNs in males and male courtship behavior. We also have linked olfactory receptor (OR) signaling through calcium, and histone acetyl transferase p300 to the expression of the transcriptional factor fruM as a molecular mechanism by which olfactory experience regulates neurophysiology and behavior. We hypothesize that fly and food odors in the environment lead to chromatin dependent changes in fruM transcription in sensory neurons to modify neurophysiology and courtship behavior with olfactory experience. To test this, we will first determine the effect of chromatin modulation by p300 on reprogramming neurophysiology and behavior. Next, we will characterize the molecular mechanisms by which olfactory experience and chromatin modulates fruM expression. Finally, we will determine the transcriptional and chromatin changes in ORNs with olfactory experience. .

基因表达的表观遗传调控与持久的行为有关 动物模型和人类的变化。作为对环境线索的回应，表观遗传 程序通过染色质修饰和DNA调节成熟神经元的基因表达 甲基化导致持久的神经生理变化。有越来越多的证据表明 暗示功能失调的表观遗传程序参与了许多认知和 神经精神障碍。然而，在表观遗传之间建立因果联系 复杂神经行为适应的机制和神经元特性 系统一直很困难，主要是由于缺乏与行为相关的神经和 以表观遗传调控为目标的遗传底物。我们的目标是确定 感觉经验依赖的神经生理学和行为变化的表观遗传学基础。 我们利用了解剖的简单性和强大的遗传工具包 果蝇嗅觉感受器神经元(ONs)参与了求偶行为，而良好的嗅觉感受器神经元与交配行为密切相关。 已建立的果蝇雄性求爱行为，这是一种由 单基因，无果M(Frum)在大约2000个相互连接的神经元中表达。我们的 初步实验和最近的研究表明，嗅觉体验增强了反应 Or47b和Ir84a角在雄性和雄性求偶行为中的作用。我们还链接了 嗅觉受体(OR)通过钙和组蛋白乙酰转移酶p300信号传导到 转录因子Frum的表达作为嗅觉的分子机制 经验调节神经生理学和行为。我们假设苍蝇和食物的气味 在环境中导致感觉中染色质依赖的Frum转录变化 神经元通过嗅觉经验改变神经生理学和求爱行为。为了测试 为此，我们将首先确定p300对染色质调制对重新编程的影响 神经生理学和行为。接下来，我们将描述分子机制，通过它 嗅觉体验和染色质调节Frum的表达。最后，我们将确定 有嗅觉经验的Orns的转录和染色质变化。 。