Social experience dependent modification of gene regulation and circuit function

基因调控和回路功能的社会经验依赖性修饰

• 批准号: 10421192
• 负责人: Corbin D Jones
• 金额: $ 31.52万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10421192
• 关键词: Affect; Alternative Splicing; Animals; Anxiety; Anxiety Disorders; Automobile Driving; Behavior; Behavior Therapy; Behavioral; Binding; Biological Models; Brain; Calcium; Chromatin; Chromatin Remodeling Factor; Courtship; Cues; Data; Decision Making; Defect; Depressive disorder; Detection; Drosophila melanogaster; Environment; Epigenetic Process; Female; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene-Modified; Genes; Genetic Transcription; Housing; Image; Individual; Insecta; Knowledge; Lead; Learning; Link; Mammals; Maps; Mediating; Mental disorders; Modeling; Modification; Molecular; Neurons; Organ; Output; Pattern; Peripheral; Pheromone; Pheromone Receptors; Publishing; RNA Splicing; Regulation; Regulator Genes; Reporting; Role; Sensory; Signal Transduction; Site-Directed Mutagenesis; Smell Perception; Social Behavior; Social Environment; Social isolation; Stereotyped Behavior; Stereotyping; Switch Genes; Testing; Therapeutic; Transcript; autism spectrum disorder; base; behavior change; chromatin modification; court; experience; experimental study; fitness; flexibility; fly; male; men' s group; mutant; neural circuit; neuron development; neurophysiology; neuropsychiatric disorder; neuroregulation; novel; promoter; response; sex; social; transcription factor

SUMMARY: Animals modulate their behaviors with social experience to increase fitness. The molecular and neural circuit-based mechanisms underlying social experience-dependent behavioral modulation remains unclear. Emerging evidence indicates the intimate connection among sensory experience, chromatin and behavioral modifications. Defects in chromatin modulation are associated with many neuropsychiatric disorders. Understanding the role of chromatin in regulating behaviors requires model systems with identified genes and neural circuits with clear causal links to stereotyped behaviors. The Drosophila melanogaster is an excellent model where these links were well elucidated for courtship behaviors. In D. melanogaster, Fruitless (Fru) and Doublesex (Dsx) are master transcriptional regulators that control innate and learned sex-specific courtship behaviors, respectively. fru is expressed in 2000 interconnected neurons marking courtship circuits. Socially isolated wild type males show elevated courtship compared to grouped males. Conversely, socially isolated fruM mutant males do not court, however, if grouped, they use olfaction to learn to court either males or females. This learning requires the gene dsx, which is co-expressed with fru in decision-making neurons of courtship circuits. How social experience regulates fru and dsx expression in the courtship circuits to modify circuit function remains unknown. In published and preliminary data, we demonstrated that social experience and pheromone signaling induces chromatin-based reprogramming of fru and dsx expression in the peripheral and central courtship circuits. We also found that social cues change Fru target neuromodulatory gene expression in the peripheral neurons, which alter neuronal sensitivity and circuit function. We hypothesize that detection of social signals reprograms chromatin around behavioral switch genes such as Fru and Dsx in the central brain, which in turn modulate circuit function and behaviors. To test this, we propose to identify social experience and pheromone signaling-dependent changes in chromatin around fru and dsx genes, their effects on downstream target gene expression, circuit function and behavioral outputs.

总结： 动物通过社会经验调整自己的行为，以增加健康。分子和神经 基于电路的机制，社会经验依赖的行为调制仍然不清楚。 新出现的证据表明，感觉经验，染色质和行为之间的密切联系， 修改.染色质调节的缺陷与许多神经精神疾病有关。 了解染色质在调节行为中的作用需要具有已识别基因的模型系统， 与刻板行为有着明确因果关系的神经回路。黑腹果蝇是一种很好的 模型中，这些联系很好地阐明了求爱行为。In D. melanogaster，Fruitless（Fru）和 Dsx是调控先天性和习得性求偶的主要转录调节因子 行为，分别。Fru在2000个标记求偶回路的互连神经元中表达。社会 与分组的雄性相比，分离的野生型雄性表现出更高的求偶性。相反，社会孤立的fruM 突变的雄性不会求爱，但是，如果聚集在一起，它们会用嗅觉来学习向雄性或雌性求爱。这 学习需要基因dsx，该基因在求偶回路的决策神经元中与fru共表达。 社会经验如何调节fru和dsx在求偶回路中的表达，从而改变回路功能， 未知在已发表的和初步的数据中，我们证明了社会经验和信息素信号 诱导外周和中枢求偶中基于染色质的fru和dsx表达重编程 电路.我们还发现，社会线索改变Fru靶神经调节基因表达的外周 神经元，改变神经元的敏感性和电路功能。我们假设社会信号的检测 围绕行为开关基因（如Fru和Dsx）对染色质进行重新编程， 进而调节电路功能和行为。为了验证这一点，我们建议确定社会经验， 信息素信号依赖的变化，染色质周围的fru和dsx基因，其影响下游 靶基因表达、电路功能和行为输出。