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.

项目摘要/摘要血清素能（5HTERGIC）系统在各种神经发育和神经精神上实现现象，包括调节情绪和压力反应性。虽然已经假定了5HT的动作仅通过5HT接收器及其突触效应介导，最近的研究表明在背侧raphe血清素能神经元和前脑靶神经元中存在5HT的核池。我们的实验室已经确定5HT与组蛋白H3形成共价键 - 在H3谷氨酰胺5羟色胺中添加（H3Q5SER） - 一种称为H3血清素化的过程。我们进一步表明，H3详细词扮演键在建立正常的胚胎和成人脑转录可塑性模式中的调节作用。然而，在产后大脑发育期间，H3详细词的功能作用，时间点包含神经塑性的关键时期在很大程度上是意外的，并且环境刺激的影响（异常或以其他方式）在早期生活中进行这种修改仍然未知。我假设H3 血清素化轨迹以特定区域的方式变化 - 跨产后大脑，以控制关键神经发育基因表达和早期生活压力的各个方面会破坏这些模式直接影响与压力相关的行为异常的脆弱性。在博士的心态下。 Ian Maze和Eric Nestler 在西奈山的伊坎医学院，我将使用三个不同的目标来解决这一假设各种方法。在AIM 1中，我将在产后期间功能评估H3的血清素化动力学开发，检查早期生活压力如何破坏这些模式，并阐明这一因果关系新型组蛋白对基因表达调节的修饰，使用表观基因组和的策略性整合转录组方法（即RNA测序和剪切和运行）。在AIM 2中，我将表征中断产后血清素化相关的基因表达直接导致脑电路的改变，导致使用先进的基因编辑技术和行为分析。在AIM 3中，我将表征跨产后大脑的H3详细脑部模式使用整个大脑清除和成像技术来开发和应对早期压力（即。 idisco+）。总体而言，该项目将提供有关H3血子素控制大脑方式的新颖洞察力开发和对这种翻译后标记中断的机制导致异常病理生理状态。