Genetic and Neuroendocrine Control of Behavioral Systems

行为系统的遗传和神经内分泌控制

• 批准号: 8257554
• 负责人: Emilie F. Rissman
• 金额: $ 37.27万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257554
• 关键词: Adult; Affect; Androgen Antagonists; Androgen Receptor; Androgens; Apoptotic; Area; Autistic Disorder; Behavior; Behavior Control; Behavior Disorders; Behavioral; Boxing; Brain; Calcium-Binding Proteins; Candidate Disease Gene; Cells; Competence; Cues; Development; Female; Flutamide; Gene Expression; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genetic Translation; Genetically Engineered Mouse; Goals; Human; Knockout Mice; Ligands; Malignant Neoplasms; Maps; Medial; Mental Depression; Mental disorders; Messenger RNA; Methods; Molecular; Molecular Genetics; Mus; Nature; Neonatal; Neurosecretory Systems; Odors; Pathway interactions; Patients; Pattern; Play; Preoptic Areas; Primates; Process; Proteins; Rattus; Recycling; Regulation; Research; Role; Schizophrenia; Sex Bias; Sex Characteristics; Signaling Pathway Gene; Social Behavior; Social Interaction; Stanolone; Steroid Receptors; Symptoms; System; Techniques; Testing; Time; Tumor Cell Line; affiliative behavior; aging gene; brain behavior; brain size; calbindin; calbindin-D28K; loss of function; male; mutant; nervous system disorder; neurodevelopment; neuroprotection; novel; programs; pup; relating to nervous system; repaired; research study; response; social

The long term goal of this research program is to identify the genes and signaling pathways that control sexual differentiation of social behavior. Sex differences in neurological diseases, normal and abnormal behaviors are well documented, but the mechanisms underlying the differences are not. Many behavioral disorders (i.e. schizophrenia, depression, autism etc.) have one universal symptom; atypical social interactions. Our goal is to understand development of normal social behavior and use this information to reveal novel genetic mutations in patients with behavioral disorders. In the past few years we have established that the androgen receptor (AR) is a major component in the sexual differentiation of social affiliative behaviors in the mouse. This is exciting because the AR has been implicated in sexual differentiation of primates, including humans. We will advance this finding by studying the genetic regulation of sexual differentiation downstream of AR, and we will discover the essential AR target genes. In Aims 1-3 we will validate one potential AR target gene, Calbindin D28k. Calbindin defines a sexually dimorphic cell cluster in the medial preoptic area. In addition, this calcium binding protein has well characterized anti-apoptotic actions in brain, and for these reasons it is very likely a contributor to the sexual differentiation pathway. We will use a number of genetically engineered mice, molecular, genetic and behavioral methods to characterize the relationship between the AR and Calbindin at the level of mRNA and protein. We will also use Calbindin knockout mice to assess the behavioral ramification of the loss of function of this gene. Finally we will conduct Microarray experiments to uncover novel candidate genes that are androgen responsive. The strategy we will pursue delineates the role AR plays in regulation of a gene that is part of a neuroprotection pathway and is likely involved in sexual differentiation. This same strategy can be recycled to identify other AR target genes.

这项研究计划的长期目标是识别基因和信号 控制社会行为性别分化的途径。中国的性别差异 神经疾病、正常和异常行为都有很好的记录，但 这些差异背后的机制并非如此。许多行为障碍(即 精神分裂症、抑郁症、自闭症等)有一个普遍的症状；非典型的社会 互动。我们的目标是了解正常社会行为的发展和使用 这些信息揭示了行为障碍患者的新基因突变。在……里面 在过去的几年里，我们已经确定雄激素受体(AR)是一种主要的 在小鼠社交联系行为的性别分化中的组成部分。这 这很令人兴奋，因为AR与灵长类动物的性别分化有关， 包括人类。我们将通过研究基因调控来推进这一发现 AR下游的性别分化，我们将发现AR的关键靶点 基因。在AIMS 1-3中，我们将验证一个潜在的AR靶基因Calbindin D28k。 Calbindin定义了视前内侧区域的性二形细胞团。在……里面 此外，这种钙结合蛋白具有良好的抗细胞凋亡作用。 大脑，由于这些原因，它很可能是性别分化的贡献者 路径。我们将使用一些基因工程小鼠，分子，遗传和 用行为学方法描述AR和Calbindin之间的关系 MRNA和蛋白质水平。我们还将使用Calbindin基因敲除小鼠来评估 该基因功能丧失的行为分支。最后，我们将进行 微阵列实验，以发现对雄激素反应的新候选基因。 我们将采取的策略描述了AR在调节一种基因中所起的作用 是神经保护途径的一部分，可能与性别分化有关。这 同样的策略可以重复使用，以识别其他AR靶基因。