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）：在本提案中，我将研究类固醇激素用于使终纹床核（BNST）男性化的细胞和分子机制，BNST是神经回路中产生性别二态性行为的重要节点，例如交配和攻击。 BNST与下丘脑和杏仁核相互连接，其结构具有性别二态性，男性的神经元较多。经典的内分泌研究和遗传功能丧失实验都表明，类固醇激素及其受体也是男性典型行为所必需的。雄激素受体 (AR) 在雄性 BNST 的更多细胞中表达。我的研究结果表明，雌激素在生命的最初几天以男性特有的方式发挥作用，部分通过男性特有的 AR 调节来指导 BNST 的性别分化。我建议研究两个与雌激素在 BNST 性别二态性产生中的作用有关的问题。 1) 雌激素在大脑中产生 AR 表达性别二态性的机制是什么？ 2) 雌激素介导的使 BNST 男性化的遗传程序是什么？通过回答这些问题，我希望定义大脑中产生性别特异性细胞群的机制。目标 1 的目标是证明雌激素在激活 BNST 中男性特异性 AR 表达模式中的直接作用。我将利用之前发表的 AR-IPIN 报告小鼠（其在所有 AR 阳性细胞中表达 LacZ）来评估 AR 表达对雌激素的需求。通过染色质免疫沉淀分析 (ChIP)，我将证明雌激素受体 α (ERa) 直接募集到男性新生儿 BNST 中的 AR 基因座。这些研究将揭示 BNST 中 AR 表达产生性别二态性的机制。我假设，除了调节 AR 表达外，雌激素信号还控制 BNST 中许多基因的性别特异性表达。目标 2 的目标是通过微阵列分析识别发育中的 BNST 中受 ERcx 调节的其他性二态性基因。这些基因将为了解激素在调节大脑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 BNST 性别分化的基本机制。自闭症和抑郁症等许多精神疾病的比例存在性别偏见。了解大脑如何经历性别分化可能会增进我们对导致许多此类疾病的基本机制的理解。