Early life stress and differential effects on the molecular maturation of specific subtypes of brain serotonin neurons

早期生活压力和对大脑血清素神经元特定亚型分子成熟的不同影响

• 批准号: 10725411
• 负责人: Susan M. Dymecki
• 金额: $ 46.61万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-25 至 2025-08-24
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725411
• 关键词: ARHGEF5 gene; Adolescence; Adult; Affect; Affective; Behavior; Behavioral; Brain; Brain Mapping; Cell Nucleus; Cells; Censuses; Child; Childhood; Chromatin; Chronic; Clinical Research; Cognitive; DNA Methylation; Data; Development; Embryo; Epigenetic Process; Fluoxetine; Functional disorder; Genes; Histones; Human; Life; Longevity; Maps; Mediating; Mental disorders; Methylation; Modeling; Modification; Molecular; Mus; Nature; Neonatal; Neurobiology; Neurons; Outcomes Research; Pathway interactions; Phenotype; Predisposition; Prevention; Process; Property; Protocols documentation; Psychiatric therapeutic procedure; Psychopathology; Public Health; Research; Resolution; Risk; Rodent; Selective Serotonin Reuptake Inhibitor; Serotonin; Sorting; Stress; Subgroup; System; Tail; Testing; Therapeutic; Time; Writing; brain cell; brain dysfunction; brain tissue; dorsal raphe nucleus; early life exposure; early life stress; epigenome; experimental study; extracellular; genetic regulatory protein; lens; maladaptive behavior; maternal separation; molecular phenotype; multiple omics; neuron development; neurotransmission; novel; organizational structure; postnatal; postnatal development; pup; response; social; tool; transcriptome; transcriptome sequencing; transcriptomics

Project Summary/Abstract Extreme adversity and stress in early life, affecting over one in three children, can perturb critical processes in brain development that may increase risk for mental illness throughout life. Possible underlying neurobiological pathways and temporal windows of particular sensitivity are explored in this R21 study in which we focus on a newly discovered organizational structure and maturation trajectory for the many different subtypes of brain serotonin (5-HT)-producing neurons across early postnatal life in mice. Rodent studies show neurobiological modifications in response to early life stress (ELS) that include brain 5-HTergic neurons, and clinical studies implicate diminished 5-HT-mediated neurotransmission. Thus, the ‘ground state’ of brain 5-HTergic neurons may change with ELS, and by adulthood, the causal pathway may no longer be present. Little is known about which of the many brain 5-HTergic neuron subtypes are vulnerable, what molecular mechanisms and timing underlie the ELS-sensitivity, and how this relates to long-term brain and behavioral dysfunction. This is now discoverable, through precision brain cell access tools in mice, advances in single-cell (sc) ‘omics,’ and recent discoveries – many from our group – that rewrite the organizational map for the brain 5-HTergic neuronal system. We now know that the adult brain 5-HTergic system in mice is organized into over twenty neuronal subtypes that, while sharing generic 5-HTergic features, are otherwise distinct molecularly, and in many cases also shown to be distinct functionally and hodologically. Mapping the embryonic 5-HTergic neuronal system has revealed fewer subgroups. Lacking have been studies across postnatal development at a resolution sufficient to identify 5-HTergic neuron subtypes and reveal potential molecular pathways and temporal sequences by which the mature subtype organization arises. We recently generated transcriptomic (scRNA- sequencing) data across postnatal development and discovered several novel features distinguishing the various 5-HTergic neuron subtypes that may be impacted by ELS. These findings provide a high-resolution developmental map of the emergence of brain 5-HTergic neuron subtypes and their differential windows of maximal maturational change as reflected in the state of their transcriptome and epigenome. Here we apply this new 5-HTergic system ‘lens’ to reveal short- and long-term cellular, molecular, and epigenetic effects of two well-documented early life [day 2(neonatal) through 15 (childhood)] exposures in mice: transient daily maternal separation (Aim 1), and chronic daily administration of a selective serotonin reuptake inhibitor (SSRI), fluoxetine (Aim 2). Discoveries will include neurobiological pathways sensitive to early life exposures and which may have relevance to human psychopathologies that originate early in life.

项目总结/摘要 三分之一以上的儿童在生命早期受到极端逆境和压力的影响， 大脑发育可能会增加一生中患精神疾病的风险。可能的潜在神经生物学 在这项R21研究中，我们探讨了特定敏感性的通路和时间窗口， 新发现的组织结构和成熟轨迹的许多不同亚型的大脑 5-羟色胺（5-HT）产生神经元在小鼠出生后的早期生活。啮齿动物研究表明神经生物学 包括脑5-HT能神经元在内的对早期生活应激（ELS）的反应的修饰，以及临床研究 暗示5-HT介导的神经传递减少。因此，大脑5-HTergic神经元的“基态” 可能会随着ELS而改变，到成年时，因果通路可能不再存在。知之甚少 在许多脑5-HTergic神经元亚型中，哪些是脆弱的，哪些分子机制和时间 ELS敏感性的基础，以及这与长期大脑和行为功能障碍的关系。这是现在 通过精确的小鼠脑细胞访问工具，单细胞（sc）“组学”的进展，以及最近的 我们小组的许多发现改写了大脑5-HTergic神经元的组织图， 系统我们现在知道，成年小鼠脑5-HTergic系统由20多个神经元组成， 亚型，虽然共享通用的5-HTergic特征，但在分子上是不同的，并且在许多情况下 也显示出不同的功能和hodologically。胚胎5-HT能神经元系统的定位 显示出更少的亚群。缺乏对出生后发育的研究， 足以鉴定5-HTergic神经元亚型，并揭示潜在的分子途径和时间 成熟亚型组织产生的序列。我们最近生成了转录组学（scRNA- 测序）的数据，并发现了几个新的特点，区分 各种可能受ELS影响的5-HT能神经元亚型。这些发现提供了高分辨率的 脑5-HT能神经元亚型的出现及其分化窗口的发育图 最大的成熟变化，反映在他们的转录组和表观基因组的状态。在这里我们申请 这种新的5-HTergic系统“透镜”可以揭示细胞、分子和表观遗传的短期和长期影响 小鼠中两次记录充分的生命早期[第2天（新生儿）至15天（儿童期）]暴露：每日短暂暴露 母亲分离（目标1），以及长期每日给予选择性5-羟色胺再摄取抑制剂（SSRI）， 氟西汀（Aim 2）。这些发现将包括对生命早期暴露敏感的神经生物学通路， 可能与人类早期的精神病理学有关。