Epigenetic regulation of sex differences in the brain

大脑性别差异的表观遗传调控

基本信息

批准号：
10087962
负责人：
Jessica Tollkuhn
金额：
$ 48万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10087962
关键词：
Acute Adult Affect Age of Onset Aggressive behavior Alleles Amygdaloid structure Anxiety Applications Grants Atlases Behavior Behavioral Birth Brain Brain region Cell Nucleus Chromatin Development Elements Enhancers Epigenetic Process Estrogen Receptor alpha Estrogen Therapy Estrogens Event Female Feminization Foundations Gene Expression Gene Expression Profile Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Transcription Goals Gonadal Steroid Hormones Hormonal Hormone Responsive Hormones Hypothalamic structure Incidence Knowledge Label Laboratories Libido Life LoxP-flanked allele Masculine Medial Mediating Mental Depression Mental disorders Molecular Mus Neonatal Neurons Nuclear Receptors Partner in relationship Pattern Perinatal Prognosis Puberty Regulatory Element Role Schizophrenia Severities Sex Bias Sex Differences Sex Differentiation Signal Transduction Social Behavior Specific qualifier value Steroid Receptors Structure Structure of terminal stria nuclei of preoptic region Territoriality Testing Testosterone Tissues Vertebrates Work autism spectrum disorder behavior influence bioinformatics tool brain behavior cell type critical developmental period critical period differential expression epigenetic regulation epigenome epigenomics experimental study genome-wide analysis hormone regulation inhibitory neuron insight male mouse model mutant neural circuit novel postnatal programs pup sex sexual dimorphism sexual identity steroid hormone transcription factor transcriptome whole genome

项目摘要

Our grant application tests the hypothesis that sex differences in the brain are regulated by epigenetic events during a perinatal critical period. In many vertebrates, including mice, sex-specific neural circuitry develops under the control of estrogen signaling during the first few days of life. Treating neonatal females with estrogen irreversibly masculinizes adult social behavior and gene expression. However, the molecular strategies used by estrogen to exert lasting effects on the brain are poorly understood. The goal of this proposal is to identify sex differences in gene expression and chromatin in two sexually dimorphic brain regions. The posterior division of the bed nucleus of the stria terminalis (BNST), and the medial amygdala (MeA) are highly interconnected brain regions that develop under the control of neonatal estrogen and regulate innate sex- specific social behaviors such as mating and aggression. We hypothesize that neonatal estrogen generates male-specific chromatin states that fundamentally alter the cellular identity of neurons and thus their function in behavioral circuitry. We will test this hypothesis through genome-wide analysis of gene expression and chromatin specifically in ERα-expressing neurons in both pups and adults. In Specific Aim 1 we will determine the sex-specific gene programs in the BNST/MeA and explore how these programs are acutely modulated by distinct adult hormonal profiles in males and females. In Specific Aim 2 we will identify cis-regulatory elements, such as enhancers, in ERα neurons from BNST/MeA, and investigate sex differences in transcription factor occupancy of these elements. In Specific Aim 3 we will test the requirement for a novel sexually dimorphic transcription factor in generating sex differences in gene expression and behavior. Taken together, our findings will reveal how estrogen signaling during early life permanently influences adult gene expression and ultimately, sex-specific behaviors. This work will provide insight into how a transient event during a critical developmental period can have significant impact on the brain and behavior in adulthood. This critical period permanently affects brain structures and function, suggesting that sex differences in psychiatric disorders, such as autism and depression, may originate during sexual differentiation of the brain.

我们的资助申请测试了大脑性别差异受表观遗传事件调节的假设在包括小鼠在内的许多脊椎动物中，在围产期的关键时期，性别特异性的神经回路会发育。在生命的最初几天内，在雌激素信号的控制下，用雌激素治疗新生女性。然而，所使用的分子策略不可逆转地使成人社会行为和基因表达男性化。人们对雌激素对大脑产生持久影响的了解还很少。该提案的目标是确定。两个性别二态性大脑区域的基因表达和染色质存在性别差异。终纹床核（BNST）和内侧杏仁核（MeA）的分裂高度在新生儿雌激素的控制下发育并调节先天性别的相互关联的大脑区域我们欺负新生儿雌激素产生的特定社会行为。男性特异性染色质状态从根本上改变神经元的细胞身份，从而改变它们的功能我们将通过基因表达的全基因组分析来检验这一假设。在具体目标 1 中，我们将确定幼犬和成体中表达 ERα 的神经元中的染色质。 BNST/MeA 中的性别特异性基因程序，并探索这些程序如何被强烈调节在特定目标 2 中，我们将确定男性和女性不同的成人荷尔蒙特征，例如来自 BNST/MeA 的 ERα 神经元中的增强子，并研究转录因子的性别差异在特定目标 3 中，我们将测试新的性别二态性的要求。转录因子在基因表达和行为方面产生性别差异。将揭示生命早期的雌激素信号如何永久影响成年基因表达和最终，这项工作将深入了解关键时期的短暂事件。发育期会对成年期的大脑和行为产生重大影响。永久性地影响大脑结构和功能，表明精神疾病中的性别差异，例如就像自闭症和抑郁症一样，可能起源于大脑的性别分化过程。