Genetic factors controlling the intensity of social behavior

项目摘要 为了参与富有成效的社会互动，动物必须根据当前的情况调整自己的行为， 是的。调节稳态行为的神经和遗传因素（例如，饮食和睡眠）都很好 研究，但遗传机制，社会行为的调整仍然在很大程度上未被探索。社会 行为本质上比稳态行为更复杂，因为在社会背景下， 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- 另一个人的情绪。了解行为相关的神经回路是如何在这些条件下调制的， 文本可以揭示损害患者与他人互动的能力的人类神经障碍（例如， 精神分裂症和自闭症）。为了确定与行为表型相关的遗传因素，基因组- 已经进行了涉及精神障碍患者或动物模型的广泛关联研究。 然而，这些方法的结果很难解释，因为：（1）大多数鉴定的突变 影响很小，2）突变和行为表型之间的因果关系往往不能建立， 和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，研究人员已经转向 黑腹果蝇（Drosophila melanogaster），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， 这使得它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。对苍蝇争斗行为的研究特别有启发性，因为特定的神经元可以表达， 已经证明，按压作为神经调节剂的神经肽速激肽可以促进Ag- 格雷辛。然而，抑制攻击性水平的因素还没有被发现。 通过这种方法，确定了五个负调控攻击性的基因。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，其可作为神经调节剂抑制激动性β-内酰胺酶。 激酶，（2和3）PKA-R2和神经，其作用于G蛋白偶联受体的下游，因此可以 调节攻击促进神经调质的信号传导，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物，和（5）Gr 21 a，CO2共受体。最后，互动是- 将研究这些攻击性负调节因子和已知的攻击性促进因子之间的关系。与先前 关于果蝇攻击性遗传学的研究一直在确定调节哺乳动物攻击性的基因， gression，拟议的项目有望照亮遗传和神经网络，动态调节 动物门之间的竞争性相互作用。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。

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.