Functional Role for H3 Serotonylation During Critical Periods of Postnatal Brain Development and Plasticity

H3 血清素化在产后大脑发育和可塑性关键时期的功能作用

基本信息

批准号：
10679672
负责人：
Ashley Cunningham
金额：
$ 4.61万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2025-12-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679672
关键词：
Adult Affect Architecture Attenuated Beds Behavior Behavioral Biochemical Brain Brain region Cell Nucleus Cell Separation Chronic stress Data Development Dopamine Dorsal Embryo Embryonic Development Environmental Impact Exposure to Female Foundations Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomics Glutamine Histone H3 Histones Homeostasis Hormones Human Image Imaging Techniques Individual Laboratories Life Ligands Lysine Mediating Mental Depression Mental disorders Mentorship Methylation Modeling Modification Molecular Mus Neonatal Neurodegenerative Disorders Neurodevelopmental Disorder Neuronal Differentiation Neuronal Plasticity Neurons Neurotransmitters Norepinephrine Nuclear Pattern Play Population Post-Translational Protein Processing Predisposition Prefrontal Cortex Process Prosencephalon Proteins Regulation Risk Factors Rodent Model Role Serotonin Sex Differences Stimulus Stress Synapses System Techniques Technology Therapeutic Time Viral Viral Vector behavioral phenotyping brain circuitry cell type combinatorial covalent bond critical period early life stress epigenetic regulation epigenomics experimental study extracellular genomic locus histone modification imaging approach in vivo insight lifetime risk male maternal separation medical schools mind control monoamine mood regulation multiple omics nerve supply nervous system disorder neurodevelopment neuropsychiatry neurotransmission novel permissiveness postnatal postnatal development postnatal period pre-clinical preclinical study receptor response sex stress reactivity transcription factor transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract The serotonergic (5HTergic) system is implicated in a wide range of neurodevelopmental and neuropsychiatric phenomena, including the regulation of mood and stress reactivity. While 5HT actions have been assumed to be mediated exclusively through 5HT receptors and their synaptic effects, recent studies have demonstrated the presence of nuclear pools of 5HT in dorsal raphe serotonergic neurons and forebrain target neurons. Our laboratory has established that 5HT forms covalent bonds with histone H3—resulting in H3 glutamine 5 serotonin (H3Q5ser)–a process known as H3 serotonylation. We have further shown that H3 serotonylation plays key regulatory roles in establishing normal embryonic and adult patterns of brain transcriptional plasticity. However, functional roles for H3 serotonylation during early post-natal brain development, time points encompassing critical periods of neural plasticity, have largely been unexplored, and the impact of environmental stimuli (aberrant or otherwise) on this modification during early life remains unknown. I hypothesize that H3 serotonylation trajectories vary – in a region-specific manner – across the post-natal brain to control critical aspects of neurodevelopmental gene expression and early life stress disrupts these patterns directly influencing vulnerability to stress-related behavioral abnormalities. Under the mentorship of Drs. Ian Maze and Eric Nestler at the Icahn School of Medicine at Mount Sinai, I will address this hypothesis with three distinct aims using a variety of approaches. In Aim 1, I will functionally assess H3 serotonylation dynamics during post-natal development, examine how early life stress disrupts these patterns, and elucidate the causal relationship of this novel histone modification on gene expression regulation using strategic integration of epigenomic and transcriptomic approaches (ie. RNA sequencing and CUT&RUN). In Aim 2, I will characterize how disruptions in post-natal serotonylation-associated gene expression directly result in alterations in brain circuitry leading to increased vulnerability to stress-related behavioral abnormalities using advanced gene-editing techniques and behavioral analyses. In Aim 3, I will characterize brain-wide patterns of H3 serotonylation across post-natal brain development and in response to early like stress using whole brain clearing and imaging techniques (ie. iDISCO+). Overall, this project will provide novel insight into the ways that h3 serotonylation controls brain development and the mechanisms by which disruptions to this posttranslational mark cause aberrant pathophysiological states.

项目概要/摘要血清素能 (5HTergic) 系统与多种神经发育和神经精神疾病有关现象，包括情绪和压力反应的调节，而 5HT 的作用被认为是。完全通过 5HT 受体及其突触效应介导，最近的研究表明中缝背侧血清素能神经元和前脑靶神经元中存在 5HT 核池。实验室已确定 5HT 与组蛋白 H3 形成共价键，从而产生 H3 谷氨酰胺 5 血清素 (H3Q5ser)——称为 H3 血清素化的过程我们进一步表明 H3 血清素化发挥着关键作用。然而，在建立正常胚胎和成人大脑转录可塑性模式中的调节作用。 H3 血清素化在产后早期大脑发育过程中的功能作用，时间点包括神经可塑性的关键时期，很大程度上尚未被探索，而环境刺激的影响（异常或其他）在早年的这种修改仍然未知，我勇敢地说H3。产后大脑中的血清素化轨迹以特定区域的方式变化，以控制关键的神经发育基因表达和早期生活压力的各个方面破坏了这些模式，直接影响在伊恩·梅兹（Ian Maze）和埃里克·内斯特勒（Eric Nestler）博士的指导下，容易出现与压力相关的行为异常。在西奈山伊坎医学院，我将通过三个不同的目标来解决这个假设在目标 1 中，我将在功能上评估产后 H3 血清素化动态。发展，检查早期生活压力如何破坏这些模式，并阐明其因果关系利用表观基因组和基因组的策略整合对基因表达调控进行新型组蛋白修饰在目标 2 中，我将描述转录组方法（即 RNA 测序和 CUT&RUN）的特征。出生后血清素化相关基因表达直接导致大脑回路的改变，从而导致使用先进的基因编辑技术增加了与压力相关的行为异常的脆弱性在目标 3 中，我将描述产后大脑中 H3 血清素化的全脑模式。使用全脑清除和成像技术（即，总体而言，该项目将为 h3 血清素化控制大脑的方式提供新颖的见解。发育以及破坏这种翻译后标记导致异常的机制病理生理状态。