Epigenetic Regulation of Sex Differences in the Brain

大脑性别差异的表观遗传调控

• 批准号: 10668067
• 负责人: Jessica Tollkuhn
• 金额: $ 63.4万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668067
• 关键词: Acute; Adult; Affect; Age of Onset; Anxiety; Behavior; Birth; Brain; Brain region; CRISPR/Cas technology; Candidate Disease Gene; Cell Survival; Cells; Chromatin; Cre driver; Data; Development; Disease; Disease susceptibility; Enhancers; Epigenetic Process; Estradiol; Estrogen Receptor alpha; Estrogens; Estrous Cycle; Estrus; Etiology; Event; Female; Funding; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Hormonal; Hormone Receptor; Hormones; Incidence; Individual; Instinct; Interneurons; Knowledge; Label; Life; Maps; Masculine; Mediating; Mental Depression; Mental Health; Mental disorders; Modeling; Molecular; Morphology; Mus; Neonatal; Neurons; Nuclear Receptors; Perinatal; Periodicity; Phenotype; Ploidies; Population; Progesterone; Progesterone Receptors; Prognosis; Regulator Genes; Regulatory Element; Research; Resolution; Role; Schizophrenia; Severities; Sex Bias; Sex Chromosomes; Sex Differences; Sex Differentiation; Signal Transduction; Social Behavior; Specific qualifier value; Stimulus; Structure; Structure of terminal stria nuclei of preoptic region; System; Techniques; Testing; Testosterone; Time; Tissue-Specific Gene Expression; Untranslated RNA; Variant; Vertebrates; Viral; Work; autism spectrum disorder; autosome; behavioral response; cell type; critical developmental period; critical period; epigenetic regulation; epigenomic profiling; gain of function; hormonal signals; insight; loss of function; male; neonate; neural; neural circuit; neurophysiology; novel; novel strategies; postnatal; postnatal development; programs; public health relevance; recruit; resilience; response; sex; sexual dimorphism; social; success

PROJECT SUMMARY/ABSTRACT There are pronounced sex differences in the incidence and etiology of mental health conditions. However, the developmental mechanisms that give rise to sex differences in disease susceptibility or resilience remain largely unknown. In this application we will explore the developmental origins of brain sex differences. 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, neural circuitry, and gene expression. To understand the actions of estrogen on the brain, we recently identified the genomic targets of estrogen receptor alpha (ERα) and revealed that these genes are differentially invoked in the developing and adult brain of both sexes. The goal of this proposal is to determine the molecular and circuit consequences of early life ERα actions, with the long-term intent of connecting individual ERα target genes to discrete sex-variable phenotypes. The posterior division of the bed nucleus of the stria terminalis (BNSTp) is a key node in neural circuits that mediate social behaviors and is larger in males compared to females. We hypothesize that BNSTp sexual dimorphism is specified by parallel epigenetic events during a perinatal critical period: initiation of a persistent male-biased gene expression signature and establishment of sex-specific neuronal connectivity. In Aim 1 we will determine the transcriptional mechanisms that define sex differential gene regulation strategies: persistent early life gene expression in males, and fluctuations in response to estrous hormones in adult females. In Aim 2 we will map the connectivity of the two male-biased cell types we previously identified in the BNSTp, in both adults and across postnatal development. In Aim 3 we will test the causality of perinatal ERα target genes and loci in specifying BNSTp sex differences. Taken together, our findings will reveal how gonadal hormone signaling during early life permanently influences adult gene expression, neuronal connectivity, and ultimately, sex-variable 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.

项目总结/摘要 在心理健康状况的发病率和病因方面存在明显的性别差异。但 导致疾病易感性或恢复力性别差异的发育机制仍然存在， 大部分未知。在这个应用程序中，我们将探索大脑性别差异的发展起源。在许多 脊椎动物，包括小鼠，在雌激素信号的控制下， 生命的最初几天。用雌激素治疗新生儿女性不可逆转地使成人社会男性化 行为、神经回路和基因表达。为了了解雌激素对大脑的作用，我们 最近确定了雌激素受体α（ERα）的基因组靶点，并揭示这些基因是 在发育中和成年期的大脑中的差异。本提案的目的是确定 早期生命ERα作用的分子和电路后果，长期意图是连接 单个ERα靶向基因以离散的性别可变表型。床核的后分裂 终纹（BNSTp）是介导社会行为的神经回路中的关键节点，并且在男性中较大 与女性相比。我们假设BNSTp性别二型性是由平行的表观遗传 围产期关键期的事件：持续性男性偏好基因表达特征的启动， 建立性别特异性神经元连接。在目标1中，我们将确定转录机制 定义了性别差异基因调控策略：男性持续的早期基因表达， 在成年雌性中对动情激素的反应波动。在目标2中，我们将映射两个 我们先前在BNSTp中发现的雄性偏向的细胞类型，在成年人和出生后发育中。 在目标3中，我们将测试围产期ERα靶基因和位点在指定BNSTp性别差异中的因果关系。 总之，我们的研究结果将揭示如何性腺激素信号在生命早期永久 影响成年人的基因表达，神经元连接，并最终，性别可变的行为。这项工作将 深入了解关键发育期的短暂事件如何对 大脑和行为。这一关键时期会永久性地影响大脑结构和功能， 这表明，精神疾病（如自闭症和抑郁症）的性别差异可能起源于 大脑的性别分化