Early Brain Serotonin and Its Lasting Impact on Neuronal Epigenetic Programming

早期大脑血清素及其对神经元表观遗传编程的持久影响

• 批准号: 8441969
• 负责人: EVAN S DENERIS
• 金额: $ 32.95万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-22 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441969
• 关键词: Address; Adolescent; Adrenal Glands; Adult; Agonist; Amygdaloid structure; Anxiety; Argipressin; Autocrine Communication; Autoreceptors; Behavior; Binding; Biochemical; Biological Assay; Brain; DNA; DNA Methylation; Development; Emotional; Enhancers; Environmental Risk Factor; Epigenetic Process; Exposure to; Feedback; GTP Cyclohydrolase; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Glucocorticoid Receptor; HDAC2 gene; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase; Histones; Homeostasis; Human; Hypothalamic structure; Knock-out; Life; Life Experience; Life Stress; Maintenance; Mental disorders; Methylation; Mus; Neonatal; Neurons; Nucleic Acid Regulatory Sequences; Pathogenesis; Pathway interactions; Pattern; Physiological; Pituitary Gland; Placenta; Program Development; Property; Prosencephalon; RNA Editing; Research; Rodent; Role; Series; Serotonin; Signal Pathway; Signal Transduction; Source; Staging; Stress; Testing; Transducers; Tryptophan 5-monooxygenase; Weaning; autocrine; biological adaptation to stress; conditioned fear; extracellular; fetal; gene function; genome-wide; hindbrain; histone deacetylase 2; hypothalamic-pituitary-adrenal axis; in vivo; maternal separation; nervous system development; nonhuman primate; novel; paraventricular nucleus; postnatal; postsynaptic; programs; promoter; receptor; response; transcription factor

Early life 5-HT signaling influences neurodevelopmental trajectories and altered 5-HT signaling has been implicated in the pathogenesis of numerous stress-related psychiatric disorders. What is not clear is how extracellular 5-HT exerts its effects on nervous system development and whether the critical synthetic source of 5-HT is the brain. In Project 1: Early Brain Serotonin and its Lasting Impact on Neuronal Epigenetic Programming, Evan Deneris seeks to determine whether 5-HT synthesized specifically in hindbrain raphe neurons and secreted during fetal and early postnatal life is an important extracellular signal required for early-life epigenetic programming of serotonergic homeostasis and hypothalamic-pituitary-adrenal (HPA) axis stress circuitry. To investigate this hypothesis, Deneris seeks to apply his recently developed temporally controlled targeting approaches to knock out the gene, tryptophan hydroxylase 2, responsible for synthesis of brain 5-HT. Tph2 will be targeted during fetal and early postnatal life to reduce brain 5-HT synthesis but not synthesis of 5-HT from exogenous sources such as the placental or gut. The targeting of Tph2 at different stages of early life enables Deneris to investigate a series of questions that have been difficult or impossible to address with previous approaches aimed at determining the developmental impact of brain 5 HT synthesis. In Specific Aim 1, Deneris will target Tph2 during fetal life and during the critical early postnatal period to investigate a potential role for 5-HT as an autocrine signal required for homeostatic maintenance of intrinsic 5-HT neuron transcriptional programs, intrinsic 5-HT neuron biochemical and physiological properties and RNA editing patterns. In Specific Aim 2, Deneris seeks to initiate a novel study of the previously unexplored serotonergic epigenome and determine how it impacts stress-related behaviors. Tph2 targeted mice will be used to determine the impact of early-life 5-HT on long lasting programming of histone acetylation/methylation marks and DNA promoter methylation patterns in serotonergic genes and serotonergic histone deacetylase (HDAC) expression. 5-HT neuron-type targeting of HDAC2, an HDAC strongly expressed in developing 5-HT neurons, will be used to determine how alterations in the serotonergic epigenome impacts 5-HT neuron function and stress-related behaviors. In Specific Aim 3, Deneris' team will utilize his powerful 5-HT neuron-type genetic strategies to directly test the long standing hypothesis that 5 HT produced in the brain is a developmental transducer of early life experience and is required to epigenetically program development of the HPA axis and protect against the effects of early life stress.

生命早期 5-HT 信号传导影响神经发育轨迹，并且 5-HT 信号传导的改变已被证实 涉及许多与压力相关的精神疾病的发病机制。不清楚的是如何 细胞外 5-HT 对神经系统发育的影响及其关键合成来源 5-HT是大脑。项目 1：早期大脑血清素及其对神经元表观遗传的持久影响 Evan Deneris 编程试图确定 5-HT 是否在后脑中缝中特异性合成 神经元在胎儿和出生后早期分泌，是重要的细胞外信号 血清素能稳态和下丘脑-垂体-肾上腺（HPA）的早期表观遗传编程 轴应力电路。为了研究这一假设，丹尼斯试图应用他最近开发的时间模型 控制靶向方法来敲除负责合成的色氨酸羟化酶 2 基因 大脑5-HT。 Tph2 将在胎儿期和产后早期以减少大脑 5-HT 合成为目标，但 不是从胎盘或肠道等外源合成 5-HT。 Tph2 的靶向 早期生活的不同阶段使丹尼斯能够调查一系列困难或困难的问题 以前旨在确定大脑发育影响的方法无法解决这个问题 5 高温合成。在具体目标 1 中，Deneris 将在胎儿生命期间和关键的产后早期以 Tph2 为目标 研究 5-HT 作为维持体内平衡所需的自分泌信号的潜在作用 内在 5-HT 神经元转录程序、内在 5-HT 神经元生化和生理学 特性和 RNA 编辑模式。在具体目标 2 中，Deneris 试图启动一项关于 以前未经探索的血清素表观基因组，并确定它如何影响压力相关行为。 Tph2 目标小鼠将用于确定生命早期 5-HT 对组蛋白持久编程的影响 血清素能基因中的乙酰化/甲基化标记和 DNA 启动子甲基化模式 血清素能组蛋白脱乙酰酶 (HDAC) 表达。 HDAC2（一种 HDAC）的 5-HT 神经元型靶向 在发育中的 5-HT 神经元中强烈表达，将用于确定血清素能的变化如何 表观基因组影响 5-HT 神经元功能和压力相关行为。在特定目标 3 中，Deneris 的团队将 利用他强大的 5-HT 神经元型遗传策略来直接测试长期存在的假设，即 5 大脑中产生的 HT 是早期生活经历的发育传感器，并且需要 表观遗传编程 HPA 轴的发育并防止早期生活压力的影响。