Resource development for a new model of social threat response

社会威胁应对新模式的资源开发

• 批准号: 8771140
• 负责人: DONNA L MANEY
• 金额: $ 23.76万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771140
• 关键词: Affect; Aggressive behavior; American; Amygdaloid structure; Anger; Animal Model; Animals; Anxiety; Attention deficit hyperactivity disorder; Autistic Disorder; Behavior; Behavior Control; Behavioral; Behavioral Mechanisms; Biological Models; Bipolar Disorder; Birds; Borderline Personality Disorder; Brain; Brain region; Candidate Disease Gene; Cataloging; Catalogs; Chromosomal Rearrangement; Chromosomes; Chromosomes, Human, Pair 2; Code; Complex; DNA Sequence Rearrangement; Environment; Etiology; Evolution; Face; Female; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Drift; Genetic Polymorphism; Genome; Genomics; Goals; Habitats; Haplotypes; Health; Homozygote; Human; Hypothalamic structure; Impulsivity; Individual; Knowledge; Lead; Link; Mammals; Maps; Medial; Mental Depression; Mental disorders; Messenger RNA; Modeling; Molecular; Molecular Genetics; Neuroendocrinology; Pathway Analysis; Pathway interactions; Phenotype; Population; Postdoctoral Fellow; Public Health; Reading; Research; Resource Development; Resources; Risk-Taking; Schizophrenia; Sexually Transmitted Diseases; Single Nucleotide Polymorphism; Social Behavior; Songbirds; Sparrows; Stimulus; Substance abuse problem; System; Techniques; Testing; Tissues; Variant; Vertebrates; Weight; Work; base; behavior measurement; comparative genomics; criminal behavior; experience; innovation; interest; male; next generation; novel; programs; protein function; public health relevance; response; social; social attachment; social model; trait

DESCRIPTION (provided by applicant): The underlying genetic basis of variation in social behavior is of intense interest, yet only a handful of genes have been linked to specific social behaviors in vertebrates. Thus, there is a strong need to identify populations, human or otherwise, in which there is clear linkage between genes and social behavior. In the proposed project, resources will be developed to take advantage of a uniquely suited model, the white-throated sparrow. Males and females of this abundant North American songbird occur in two plumage morphs that differ with respect to the presence of a chromosomal rearrangement (ZAL2m) that predicts responses to social threat. Birds of the white-striped (WS) plumage morph (ZAL2m/ZAL2) respond to a territorial intrusion with high levels of vocal aggression, whereas birds of the tan-striped (TS) morph (ZAL2/ZAL2) respond with relatively little or no vocal aggression. The morphs also differ with respect to the formation of social attachments and parental provisioning rates; the phenotypes are thus characterized by a suite of correlated complex traits with a discrete genetic basis. The long-term goal of this research program is to fully exploit this unique model organism, which resembles humans with respect to many aspects of social behavior, to link gene expression and complex behavior in ways never before possible. Limited gene flow between the ZAL2 and ZAL2m haplotypes has led to the genetic differentiation of the rearranged chromosomal region, resulting in the accumulation of single nucleotide polymorphisms and other changes. The primary objective of this proposal is to assess the impact of these genetic forces on the genome and brain transcriptome, thus laying the groundwork to identify molecular mechanisms of behavioral dysregulation in future studies. We will combine the experience of two PIs: one with expertise in the behavioral neuroendocrinology of wild sparrows and the other in genome evolution. In Aim 1, we will identify and evaluate sequence differences between the two haplotypes, which will reveal a large number of potential functional polymorphisms that can then be explored experimentally. In Aim 2, we will use Next Generation techniques to sequence total mRNA from individuals for whom reactive aggression was quantified in a natural setting. We will then use weighted gene coexpression network analysis (WGCNA) of the mapped and quantified reads to identify modules of highly correlated genes associated with morph and reactive aggression. Together, the two aims will reveal candidate mechanisms underlying social strategies. This exploratory project will focus on responses to social threat, which are difficult to study in humans in a naturalistic setting. All behavioral manipulations and measurement will be conducted in the animals' natural habitat, making this project highly innovative. The project is significant because many mental disorders-including autism, depression, bipolar disorder and schizophrenia are characterized by dysregulated responses to social threat and because reactive aggression is often comorbid with risk-taking, substance abuse, and criminal behavior. Thus an understanding of the mechanisms underlying response to social threat is important for human health.

描述（由申请人提供）：社会行为变异的潜在遗传基础引起了人们的强烈兴趣，但只有少数基因与脊椎动物的特定社会行为相关。因此，迫切需要确定基因与社会行为之间存在明显联系的人群，无论是人类还是其他人群。在拟议的项目中，将开发资源以利用一种独特的模型——白喉麻雀。这种丰富的北美鸣禽的雄性和雌性有两种羽毛变形，这两种羽毛变形的不同之处在于染色体重排（ZAL2m）的存在，这种重排可以预测对社会威胁的反应。白条纹（WS）羽毛变体（ZAL2m/ZAL2）的鸟类以高水平的声音攻击性来响应领地入侵，而棕褐色条纹（TS）羽毛变体（ZAL2/ZAL2）的鸟类则以相对较少或没有声音攻击性的响应。这些变体在社会依恋的形成和父母供养率方面也有所不同。因此，表型的特征是具有离散遗传基础的一系列相关的复杂性状。该研究计划的长期目标是充分利用这种独特的模式生物，它在社会行为的许多方面与人类相似，以前所未有的方式将基因表达和复杂行为联系起来。 ZAL2和ZAL2m单倍型之间有限的基因流导致了重排染色体区域的遗传分化，导致单核苷酸多态性的积累和其他变化。该提案的主要目的是评估这些遗传力对基因组和大脑转录组的影响，从而为未来研究中确定行为失调的分子机制奠定基础。我们将结合两位 PI 的经验：一位拥有野生麻雀行为神经内分泌学方面的专业知识，另一位拥有基因组进化方面的专业知识。在目标 1 中，我们将识别并评估两个单倍型之间的序列差异，这将揭示大量潜在的功能多态性，然后可以通过实验来探索。在目标 2 中，我们将使用下一代技术对在自然环境中反应性攻击进行量化的个体的总 mRNA 进行测序。然后，我们将使用映射和量化读数的加权基因共表达网络分析（WGCNA）来识别与形态和反应性攻击相关的高度相关基因的模块。这两个目标将共同揭示社会策略背后的候选机制。这个探索性项目将重点关注对社会威胁的反应，这在自然环境下很难在人类身上进行研究。所有行为操作和测量都将在动物的自然栖息地进行，使该项目具有高度创新性。该项目意义重大，因为 许多精神障碍，包括自闭症、抑郁症、双相情感障碍和精神分裂症，其特征是对社会威胁的反应失调，因为反应性攻击往往与冒险、药物滥用和犯罪行为共存。因此，了解应对社会威胁的潜在机制对于人类健康非常重要。