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.

项目概要/摘要 精神健康状况的发病率和病因学存在明显的性别差异。然而， 引起疾病易感性或恢复力性别差异的发育机制仍然存在 很大程度上不为人所知。在此应用中，我们将探讨大脑性别差异的发育起源。在许多 在包括小鼠在内的脊椎动物中，性别特异性神经回路在雌激素信号传导的控制下发育。 生命的最初几天。用雌激素治疗新生女性不可逆转地使成年社会男性化 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）的基因组靶标，并揭示这些基因 在两性的发育中和成年大脑中都有不同的调用。该提案的目标是确定 早期生命 ERα 作用的分子和电路后果，具有连接的长期意图 个体 ERα 将基因靶向离散的性别可变表型。床核后部分裂 终纹 (BNSTp) 是调节社会行为的神经回路中的关键节点，男性的终纹较大 与女性相比。我们假设 BNSTp 性二态性是由平行表观遗传指定的 围产期关键期的事件：持续的偏向男性的基因表达特征的启动和 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 定义性别差异基因调控策略：男性持续的早期生命基因表达，以及 成年女性对动情激素的反应波动。在目标 2 中，我们将绘制两者的连通性 我们之前在 BNSTp 中发现了成人和出生后发育过程中偏雄性的细胞类型。 在目标 3 中，我们将测试围产期 ERα 靶基因和基因座在指定 BNSTp 性别差异方面的因果关系。 总而言之，我们的研究结果将揭示生命早期的性腺激素信号如何永久发挥作用 影响成人基因表达、神经元连接，并最终影响性别变异行为。这项工作将 深入了解关键发育时期的短暂事件如何对 成年后的大脑和行为。这个关键时期永久影响大脑结构和功能， 表明精神疾病（例如自闭症和抑郁症）的性别差异可能起源于 大脑的性别分化。