Genetic factors controlling the intensity of social behavior

控制社会行为强度的遗传因素

• 批准号: 9330873
• 负责人: KENTA ASAHINA
• 金额: $ 48.5万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330873
• 关键词: Affect; Aggressive behavior; Agonistic Behavior; Animal Model; Animals; Arousal; Autistic Disorder; Behavior; Behavior Control; Behavioral; Carbon Dioxide; Complex; Conflict (Psychology); Cyclic AMP-Dependent Protein Kinases; Disease; Disease model; Drosophila genus; Drosophila melanogaster; Elements; Endocrine system; Environment; Etiology; Exhibits; FMRFamide; Foundations; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Variation; Goals; Human; Hunger; Individual; Knowledge; Label; Light; Mental disorders; Molecular; Mutation; Neurodegenerative Disorders; Neuromodulator; Neurons; Neuropeptides; Output; Patients; Phenotype; Physiological; Population; Post-Traumatic Stress Disorders; Process; RNA interference screen; Reaction; Research; Research Personnel; Schizophrenia; Signal Transduction; Sleep; Social Behavior; Social Environment; Social Interaction; Study models; System; Tachykinin; Text; Transcription Repressor/Corepressor; Tweens; Violence; Work; base; cell type; feeding; fly; genetic element; genome wide association study; nervous system disorder; neural circuit; promoter; receptor; relating to nervous system; response; vinegar fly

PROJECT SUMMARY To engage in productive social interactions, an animal must modulate its behavior based on the current situa- tion. Neural and genetic factors regulating homeostatic behaviors (e.g., feeding and sleeping) have been well studied, but the genetic mechanisms by which social behaviors are adjusted remain largely unexplored. Social behaviors are intrinsically more complex than homeostatic behaviors, because in a social context an animal must take into account its own internal state (e.g., hunger, arousal), as well as the reactions and perceived in- tentions of the other individual. Understanding how behavior-related neural circuits are modulated in these con- texts may shed light on human neural disorders that compromise patients' ability to interact with others (e.g., schizophrenia and autism). To identify genetic elements that correlate with behavioral phenotypes, genome- wide association studies have been performed involving patients with psychiatric disorders or animal models. Results from these approaches have been difficult to interpret, however, because: (1) most identified mutations had a small effect, 2) causality between mutation and behavioral phenotype often could not be established, and 3) mutations generally did not involve neuromodulators and neurohormonal systems known to control these processes. To develop more direct approaches for tackling this problem, researchers have turned to Drosophila melanogaster, which exhibits a rich repertoire of stereotypical social behaviors. The Drosophila sys- tem allows for precise genetic alterations, and the labeling and functional manipulation of specific cell types, making it an attractive model for studying how genes control behavioral choice by affecting specific neuronal populations. Research into fly agonistic behavior has been particularly informative, as specific neurons ex- pressing the neuropeptide tachykinin, which functions as a neuromodulator, have been shown to promote ag- gression. However, elements that dampen aggression levels have not been found. Using an RNAi screening approach, five genes that negatively regulate aggression were identified. Proposed research aims to elucidate the molecular mechanisms by which these genes control the intensity of agonistic interactions. These genes encode: (1) the neuropeptide FMRFamide, which may function as a neuromodulator to suppress agonistic be- havior, (2 and 3) PKA-R2 and nervy, which act downstream of G-protein coupled receptors and therefore may regulate signaling of aggression-promoting neuromodulators such as tachykinin, (4) TBPH, a transcriptional repressor implicated in neurodegenerative diseases, and (5) Gr21a, a CO2 co-receptor. Finally, interplay be- tween these negative regulators of aggression and known aggression promoters will be studied. As previous work on the genetics of Drosophila aggression has consistently identified genes that regulate mammalian ag- gression, the proposed project promises to illuminate genetic and neuronal networks that dynamically regulate agonistic interaction across animal phyla. Such knowledge will fill critical gap in our understanding about how genes influence social behaviors through specific neurons and circuits.

项目概要 为了进行富有成效的社会互动，动物必须根据当前情况调整其行为 。调节体内平衡行为（例如进食和睡眠）的神经和遗传因素一直很好 已进行了研究，但调节社会行为的遗传机制在很大程度上仍未得到探索。社会的 行为本质上比稳态行为更复杂，因为在社会环境中，动物 必须考虑其自身的内部状态（例如饥饿、觉醒）以及反应和感知 另一个人的意图。了解行为相关的神经回路是如何在这些条件下被调节的 文本可能会揭示损害患者与他人互动能力的人类神经疾病（例如， 精神分裂症和自闭症）。为了识别与行为表型相关的遗传元件，基因组 已经对患有精神疾病的患者或动物模型进行了广泛的关联研究。 然而，这些方法的结果很难解释，因为：（1）大多数已识别的突变 影响很小，2）突变和行为表型之间的因果关系通常无法确定， 3）突变通常不涉及已知控制的神经调节剂和神经激素系统 这些过程。为了开发更直接的方法来解决这个问题，研究人员转向 黑腹果蝇，表现出丰富的刻板社会行为。果蝇系统 tem 允许精确的遗传改变，以及特定细胞类型的标记和功能操作， 使其成为研究基因如何通过影响特定神经元来控制行为选择的有吸引力的模型 人口。对果蝇竞争行为的研究特别丰富，因为特定的神经元前体 按压神经肽速激肽（其作为神经调节剂）已被证明可以促进 ag- 侵略。然而，尚未发现抑制攻击性水平的元素。使用 RNAi 筛选 通过这种方法，我们鉴定出了五个对攻击性负向调节的基因。拟议的研究旨在阐明 这些基因控制激动相互作用强度的分子机制。这些基因 编码：（1）神经肽 FMRFamide，它可以作为神经调节剂来抑制激动性行为 havior、（2 和 3）PKA-R2 和 nervy，它们作用于 G 蛋白偶联受体的下游，因此可能 调节促进攻击性神经调节剂的信号传导，例如速激肽 (4) TBPH（一种转录因子） 与神经退行性疾病有关的阻遏蛋白，以及 (5) Gr21a，一种 CO2 共受体。最后，相互作用是 将研究这些攻击行为的负调节因子和已知的攻击促进因子之间的关系。如前所述 对果蝇攻击性遗传学的研究一致发现了调节哺乳动物攻击性的基因 进化，拟议的项目有望阐明动态调节的遗传和神经元网络 跨动物门的竞争性相互作用。这些知识将填补我们理解的关键空白 基因通过特定的神经元和回路影响社会行为。