Epigenetic reprogramming of behaviors with sensory experience

感官体验行为的表观遗传重编程

• 批准号: 9923762
• 负责人: Corbin D Jones
• 金额: $ 39.18万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923762
• 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 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 therapeutics; 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节与持久行为有关 动物模型和人类的变化。响应环境线索，表观遗传学 程序通过染色质修饰和DNA调节成熟神经元中的基因表达 甲基化导致持久的神经生理变化。有越来越多的证据 暗示功能失调的表观遗传程序参与许多认知和 神经精神疾病。但是，建立表观遗传学之间的因果关系 复杂神经行为适应的机制和神经元特性 系统很困难，主要是由于行为相关的神经和 由表观遗传调节靶向的遗传底物。我们的目标是确定 感官经验依赖神经生理学和行为变化的表观遗传基础。 我们利用解剖学简单和强大的遗传工具包 参与求爱行为的果蝇嗅觉受体神经元（ORNS） 建立的果蝇男性求爱行为，是一种由一个强大的仪式行为 单个基因，果实（FRUM）在大约2000个相互连接的神经元中表达。我们的 试点实验和最近的研究表明，嗅觉经验增强了反应 在男性和男性求爱行为中的OR47B和IR84A ORN。我们也有链接 嗅觉受体（OR）通过钙信号传导，组蛋白乙酰基转移酶P300向 转录因子FRUM作为嗅觉的分子机制的表达 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FRUM转录的染色质依赖性变化 神经元以嗅觉经验来修饰神经生理学和求爱行为。测试 这，我们将首先确定p300调制染色质对重编程的影响 神经生理学和行为。接下来，我们将表征分子机制 嗅觉经验和染色质调节FRUM表达。最后，我们将确定 具有嗅觉经验的ORN的转录和染色质变化。 。