Dissecting Estrogen Control of Sexual Differentiation of the Brain

剖析雌激素对大脑性别分化的控制

基本信息

批准号：
7821418
负责人：
Jessica Tollkuhn
金额：
$ 5.22万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-20 至 2011-04-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7821418
关键词：
Adult Aggressive behavior Amygdaloid structure Androgen Receptor Animals Apoptosis Aromatase Autistic Disorder Behavior Behavioral Assay Biological Assay Boxing Brain Brain region Caring Cell Count Cell Nucleus Cells Disease Endocrine Enzymes Estrogen Receptor alpha Estrogen Receptors Estrogens Female Gene Expression Genes Genetic Genetic Programming Goals Gonadal Steroid Hormones Gray unit of radiation dose Hormones Hypothalamic structure Knockout Mice LacZ Genes Lead Life Location Mediating Mental Depression Microarray Analysis Molecular Mus Mutant Strains Mice Neonatal Neurons Ovary Partner in relationship Pattern Perinatal Phenotype Play Population Publishing Regulation Reporter Role Sex Bias Sexual Development Signal Transduction Structure Structure of terminal stria nuclei of preoptic region Testosterone Time Vertebrates brain behavior chromatin immunoprecipitation critical period dimorphism fighting hormone regulation insight loss of function male maternal aggression mutant neural circuit receptor receptor expression research study sex sexual dimorphism steroid hormone

项目摘要

DESCRIPTION (provided by applicant): In this proposal, I will investigate the cellular and molecular mechanisms utilized by steroid hormones to masculinize the bed nucleus of the stria terminalis (BNST), an important node in the neural circuits that generate sexually dimorphic behaviors such as mating and aggression. The BNST is reciprocally connected with the hypothalamus and amygdala, and its structure is sexually dimorphic, with more neurons in males. Both classic endocrine studies, and genetic loss-of-function experiments indicate that steroid hormones and their receptors are also required for male-typical behaviors. Androgen receptor (AR) is expressed in more cells in the male BNST. My findings indicate that estrogen acts in a male-specfic manner during the first few days of life to direct sexual differentiation of the BNST, in part through male-specific regulation of AR. I propose to investigate two questions relating to the role of estrogen in generating sexual dimorphism in the BNST. 1) What are the mechanisms by which estrogen generates sexual dimorphism in AR expression in the brain? 2) What is the genetic program mediated by estrogen to masculinize the BNST? By answering these questions, I hope to define the mechanisms which generate a sex-specific cell population in the brain. The goal of Aim 1 is to demonstrate a direct role for estrogen in activating a male-specific expression pattern of AR in the BNST. I will utilize the previously published AR-IPIN reporter mice, which express LacZ in all AR-positive cells, to evaluate the requirement for estrogen in AR expression. Through chromatin immunoprecipitation analysis (ChIP), I will demonstrate the direct recruitment of estrogen receptor alpha (ERa) to the AR locus in the neonatal BNST of males. These studies will reveal the mechanisms for generating sexual dimorphism in AR expression in the BNST I hypothesize that, in addition to regulating AR expression, estrogen signaling controls the sex-specific expression of many genes in the BNST. The goal of Aim 2 is to identify additional sexually dimorphic genes regulated by ERcx in the developing BNST through microarray analysis. These genes will provide important insight into the role of hormones in regulating sexual differentiation of the brain. My experiments will elucidate the fundamental mechanisms that control sexual differentiation of an important brain region, the BNST. Many psychiatric conditions such as autism and depression present with sex-biased ratios. Understanding how the brain undergoes sexual differentiation is likely to advance our understanding of the basic mechanisms that lead to many of these disorders.

描述（由申请人提供）：在此提案中，我将研究类固醇激素用于男性化的细胞和分子机制，以使Stria末端（BNST）的床核（BNST）（BNST）的床核（在神经回路中产生性行为行为的重要淋巴结（例如，结合和攻击）。 BNST与下丘脑和杏仁核相互联系，其结构是性二态性的，男性的神经元更多。经典的内分泌研究和遗传功能丧失实验都表明，男性典型行为也需要类固醇激素及其受体。雄激素受体（AR）在雄性BNST的更多细胞中表达。我的发现表明，雌激素在生命的最初几天以男性特异性分化为导向BNST的性别分化，部分通过AR的男性调节。我建议研究两个与雌激素在BNST产生性二态性中的作用有关的问题。 1）雌激素在大脑中产生性二态性的机制是什么？ 2）雌激素介导的男性化的遗传程序是什么？通过回答这些问题，我希望定义在大脑中产生性别特定细胞种群的机制。目标1的目的是证明雌激素在激活BNST中AR的男性特异性表达模式中的直接作用。我将利用先前发表的AR-IPIN报告基因小鼠，这些小鼠在所有AR阳性细胞中表达LACZ，以评估AR表达中雌激素的需求。通过染色质免疫沉淀分析（CHIP），我将直接募集雌激素受体α（ERA）到雄性新生儿BNST中的AR基因座。这些研究将揭示在BNST中AR表达产生性二态性的机制。 AIM 2的目的是通过微阵列分析确定ERCX调节的其他性二态基因。这些基因将为激素在调节大脑的性别分化中的作用提供重要的见解。我的实验将阐明控制重要大脑区域的性别分化的基本机制，即BNST。许多精神病疾病，例如自闭症和抑郁症，性别偏见的比例。了解大脑如何经历性别差异可以提高我们对导致许多疾病的基本机制的理解。