Early Brain Serotonin and Its Lasting Impact on Neuronal Epigenetic Programming

生命早期的5-HT信号影响神经发育轨迹，并且改变的5-HT信号已经被证实是神经发育的一部分。 与许多压力相关的精神疾病的发病机制有关。目前尚不清楚的是， 细胞外5-HT在神经系统发育中发挥作用， 5-HT是大脑。项目1：早期脑血清素及其对神经元表观遗传的持久影响 Evan Deneris试图确定5-HT是否在后脑中缝中特异性合成 在胎儿和出生后早期分泌的神经元是一个重要的细胞外信号， β-肾上腺素能稳态和下丘脑-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，Deneris试图应用他最近开发的时间 控制靶向方法敲除负责合成的基因色氨酸羟化酶2 大脑5-HT在胎儿和出生后早期，Tph 2将被靶向以减少大脑5-HT合成， 而不是从外源性来源如胎盘或肠道合成5-HT。Tph 2的靶向作用 早期生活的不同阶段使德内里斯能够调查一系列困难或 不可能解决与以前的方法，旨在确定大脑的发展影响5 HT合成。在特定目标1中，Deneris将在胎儿期和出生后关键早期靶向Tph 2 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 性质和RNA编辑模式。在具体目标2中，Deneris试图发起一项新的研究， 以前未探索的多巴胺能表观基因组，并确定它如何影响压力相关的行为。TPH2 靶向小鼠将用于确定早期生活5-HT对组蛋白的长期持续编程的影响， 乙酰化/甲基化标记和DNA启动子甲基化模式， 肾上腺素能组蛋白脱乙酰酶（HDAC）表达。HDAC 2（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，将被用于确定如何改变多巴胺能神经元， 表观基因组影响5-HT神经元功能和应激相关行为。在《特定目标3》中，德内里斯的团队将 利用他强大的5-HT神经元型遗传策略直接测试长期存在的假设，5 大脑中产生的HT是早期生活经历的发育转换器， 表观遗传学程序HPA轴的发展和保护免受早期生活压力的影响。

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.