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

项目摘要/摘要 早期生活中的极端逆境和压力会影响超过三分之一的儿童，会扰乱儿童的关键过程 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，我们探索了具有特殊敏感性的路径和时间窗口，其中我们重点研究了 新发现的大脑许多不同亚型的组织结构和成熟轨迹 小鼠出生后早期的5-羟色胺(5-羟色胺)产生神经元。啮齿动物研究表明神经生物学 包括脑内5-羟色胺能神经元在内的对早期生活应激(ELS)反应的修改和临床研究 暗示5-羟色胺介导的神经传递功能减弱。因此，脑内5-羟色胺能神经元的“基态” 可能会随着ELS的改变而改变，到成年时，因果关系可能不再存在。人们对此知之甚少 大脑中的哪些5-羟色胺能神经元亚型是脆弱的，什么分子机制和时机 ELS敏感性的基础，以及这与长期的大脑和行为功能障碍的关系。这就是现在 通过小鼠精确的脑细胞访问工具，可以发现单细胞(Sc)组学的进展，以及最近的 许多来自我们团队的发现改写了大脑5-H能神经元的组织图 系统。我们现在知道，小鼠的成年大脑5-羟色胺能系统由20多个神经元组成 亚型，虽然共享通用的5-H能特征，但在其他方面在分子上是不同的，在许多情况下 在功能上和生理上也是截然不同的。胚胎5-H能神经元系统的定位 揭示了更少的子群。缺乏对出生后发育的研究 足以识别5-羟色胺能神经元亚型并揭示潜在的分子途径和时间 成熟的亚型组织产生的序列。我们最近产生了转录(scRNA- 测序)数据，并发现了几个新的特征来区分 ELS可能影响的各种5-羟色胺能神经元亚型。这些发现提供了一个高分辨率 脑内5-羟色胺能神经元亚型及其分化窗的发育图 最大的成熟变化反映在转录组和表观基因组的状态上。我们在这里适用 这一新的5-羟色胺能系统‘透镜’揭示了细胞、分子和表观遗传学的短期和长期影响 两次有充分记录的早期生命[第2天(新生儿)至第15天(童年)]暴露在小鼠身上：每天短暂 产妇分离(目标1)，以及每天长期服用选择性5-羟色胺再摄取抑制剂(SSRI)， 氟西汀(目标2)。这些发现将包括对早期生命暴露敏感的神经生物学途径，以及 可能与起源于生命早期的人类精神病理有关。

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.