Hormonal and Genetic Regulation of Brain Development

大脑发育的激素和遗传调节

• 批准号: 8547825
• 负责人: JULI S. WADE
• 金额: $ 35.64万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547825
• 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

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）：在脊椎动物物种中，雄性和雌性之间的大脑和行为不同。斑胸草雀的鸣唱系统是一个特别有用的模型，可以用来理解调节神经结构和功能性别差异的机制，原因有很多，包括在一个相对简单的神经回路中，雄性和雌性之间存在极大的形态差异，其中大脑区域具有明确的功能。最近对斑胸草雀基因组的测序为分子工具和资源提供了新的途径。在哺乳动物中，雌二醇（E2）可以诱导一些雄性化，但各种证据表明，其他分子对正常的雄性发育至关重要。我建议测试一个新的，独特的假设，即类固醇激素E2与一个或多个性染色体基因的阳性表达水平一致，以调节适当的男性发育。这项工作将提供关键的新信息，因为关于E2和其他调节性分化的分子之间相互作用的数据在物种之间非常有限。这些实验涉及三个基因，我们确定这些基因在发育中的雄性与雌性相比，在特定的歌曲控制核中表现出增加的表达。总的来说，这些研究将提供一个有凝聚力的信息体，整合激素和遗传因素，调节大脑结构的发育，以及一种习得的社会行为--人类使用的主要方式--声音交流。具体来说，我们将使用分子，细胞，解剖和行为的方法来测试E2和特定分子之间的关系在前脑结构和功能的发展假设的组合。这些观点并不相互排斥，包括：（1）E2增加分泌性载体膜蛋白1（SCAMP 1）、微管蛋白特异性伴侣蛋白A（TBCA）和/或酪氨酸激酶B的表达（TrkB，脑源性神经营养因子- BDNF的高亲和力受体）;（2）这些基因和BDNF配体调节雄性化，部分地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BDNF的可用性，SCAMP 1和TBCA被定位以促进BDNF的释放，并且TBCA和TrkB被定位以使得它们可以增加BDNF的作用能力。