Hormonal and Genetic Regulation of Brain Development

大脑发育的激素和遗传调节

基本信息

批准号：
8874297
负责人：
JULI S. WADE
金额：
$ 36.94万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-19 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874297
关键词：
Address Adolescent Affinity Aromatase Aromatase Inhibition Autistic Disorder Behavioral Biological Models Birds Brain Brain region Brain-Derived Neurotrophic Factor Cell Nucleus Chromosomes Communication Data Development Endocrine Estradiol Estrogens Exhibits Exocytosis Female Forebrain Development Functional disorder Gene Dosage Gene Proteins Genes Genetic Genome Hormonal Hormones Human In Situ Hybridization Investigation Knowledge Learning Ligands Link Location Mammals Masculine Mediating Mental Depression Mental disorders Messenger RNA Microtubules Modality Modeling Molecular Molecular Chaperones Morphology National Institute of Mental Health Nature Neurotrophic Tyrosine Kinase Receptor Type 2 Play Positioning Attribute Procedures Process Production Protein Tyrosine Kinase Proteins Regulation Resources Role Schizophrenia Series Sex Characteristics Sex Chromosomes Small Interfering RNA Social Behavior Songbirds Structure System Testing Tubulin Work brain behavior gene function immunocytochemistry inhibitor/antagonist interest mRNA Expression male mental health related disorder neural circuit novel protein expression receptor relating to nervous system research study response secretory carrier membrane protein 1 sex sexual dimorphism social communication steroid hormone tool vocalization zebra finch

项目摘要

DESCRIPTION (provided by applicant): Brain and behavior differ between males and females across vertebrate species. The zebra finch song system is a particularly useful model for understanding mechanisms that regulate development of sex differences in neural structure and function for many reasons, including extremely large morphological differences between males and females in a relatively simple neural circuit in which brain regions have clearly identified functions. Recent sequencing of the zebra finch genome provides new access to molecular tools and resources. As in mammalian species, estradiol (E2) can induce some masculinization, but a variety of pieces of evidence indicate that additional molecules are critical to normal male development. I propose to test a new, unique hypothesis, that the steroid hormone E2 acts in concert with masculine levels of expression of one or more sex chromosome genes to regulate appropriate male development. This work will provide critical novel information, as data on interactions between E2 and other molecules regulating sexual differentiation are very limited across species. The experiments involve three genes that we determined exhibit increased expression in specific song control nuclei in developing males compared to females. Collectively, the studies will provide a cohesive body of information integrating hormonal and genetic factors regulating development of brain structure and a learned social behavior - vocal communication, the primary modality used by humans. Specifically, we will use combinations of molecular, cellular, anatomical and behavioral approaches to test hypotheses about the relationships among E2 and specific molecules in development of forebrain structure and function. The ideas, which are not mutually exclusive, include that: (1) E2 increases expression of secretory carrier membrane protein 1 (SCAMP1), tubulin specific chaperone A (TBCA) and/or tyrosine kinase B (TrkB, the high affinity receptor for brain derived neurotrophic factor - BDNF); (2) These genes and the BDNF ligand modulate masculinization, in part by increasing responsiveness of the developing brain to E2; and (3) E2 and the genes/proteins can have complementary effects, including that E2 increases availability of BDNF, SCAMP1 and TBCA are positioned to facilitate BDNF's release, and TBCA and TrkB are localized such that they can increase BDNF's ability to act.

描述（由申请人提供）：跨脊椎动物物种的男性和女性之间的大脑和行为不同。斑马雀科系统是一个特别有用的模型，用于理解机制，由于许多原因，在相对简单的神经回路中，男性和女性之间的形态差异极大，大脑区域清楚地识别出功能。斑马雀科基因组的最新测序为分子工具和资源提供了新的访问。与哺乳动物物种一样，雌二醇（E2）可以诱导一些男性化，但是各种证据表明，额外的分子对于正常男性发育至关重要。我建议测试一种新的独特假设，即类固醇激素E2与一个或多个性别染色体基因的男性表达水平共同起作用，以调节适当的男性发育。这项工作将提供关键的新颖信息，因为有关E2与其他调节性别分化的分子之间相互作用的数据非常有限。该实验涉及三个基因，我们确定与女性相比，在发育中的男性中表现出增加的表达。总的来说，这些研究将提供一系列凝聚力的信息体系，整合了调节大脑结构发展的激素和遗传因素和学习的社会行为 - 声音交流，这是人类使用的主要方式。具体而言，我们将使用分子，细胞，解剖学和行为方法的组合来检验有关E2和特定分子之间在前脑结构和功能发展中的关系的假设。这些想法不是相互排斥的，包括：（1）E2增加了分泌载体膜蛋白1（SCAMP1），微管蛋白特异性伴侣蛋白A（TBCA）和/或酪氨酸激酶B（TRKB）（TRKB）（TRKB）（TRKB，脑衍生生的神经营养因子的高亲和力受体-BDNF）; （2）这些基因和BDNF配体调节男性化，部分是通过增加发育中的大脑对E2的反应性；（3）E2和基因/蛋白质可以具有互补作用，包括E2增加了BDNF，SCAMP1和TBCA的可用性以促进BDNF的释放，而TBCA和TRKB则被定位，因此它们可以提高BDNF的ACT能力。