Does neurotransmitter plasticity of para-serotonergic neurons augment autoresuscitation following perinatal stress and buffer SIDS risk?

副血清素能神经元的神经递质可塑性是否会增强围产期应激后的自动复苏并缓冲 SIDS 风险？

• 批准号: 10254240
• 负责人: Susan M. Dymecki
• 金额: $ 63.98万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10254240
• 关键词: Acute; Adult; Affect; Apnea; Area; Arousal; Automobile Driving; Autoreceptors; Binding; Birth; Brain; Brain Stem; Breathing; Cell Count; Cells; Characteristics; Childhood; Chronic; Data; Development; Disease; Dorsal; Engineering; Enzymes; Epidemiology; Exhibits; Exposure to; Failure; Functional disorder; GATA3 gene; Genes; Harvest; Heterogeneity; Human; Hypoxia; Impairment; In Situ; In Situ Hybridization; Infant; Interruption; Investigation; Label; Link; Location; Methods; Molecular; Morphology; Mus; Neonatal; Neuronal Plasticity; Neurons; Neurotransmitters; Newborn Animals; Newborn Infant; Perinatal; Phenotype; Play; Population; Pregnancy; Process; Prospective Studies; Rattus; Recovery; Reflex action; Resolution; Respiratory Center; Risk; Risk Factors; Rodent Model; Role; Serotonergic System; Serotonin; Shapes; Signal Transduction; Stress; Structure; Sudden infant death syndrome; System; TPH2; Testing; Tissues; Transcript; brain tissue; cell type; cohort; comparative; designer receptors exclusively activated by designer drugs; experience; functional plasticity; gestational hypoxia; hindbrain; hypoglossal nucleus; immunocytochemistry; insight; mind control; molecular phenotype; molecular subtypes; neonate; nerve supply; neuroadaptation; normoxia; novel; phenotypic biomarker; postnatal; postneonatal mortality; prenatal; prenatal exposure; prenatal risk factor; preventive intervention; pup; raphe nuclei; respiratory; response; reuptake; single-cell RNA sequencing; social defeat; stress management; stressor; therapeutic target; transcription factor; transcriptomics

Project Summary: A robust autoresuscitatory reflex (AR) is critical to newborn survival from birth. The transition to independent breathing and accommodation of breathing interruptions, apneas, that are common in neonates and infants, requires a coordinated cardiorespiratory response for recovery. 5-hydroxytryptamine (5- HT, serotonin) and the brainstem raphe cells that produce it, referred to as Pet1 neurons, organize and drive successful AR in newborn animals and humans. Unsuccessful AR is understood to be a major contributor to the sudden infant death syndrome (SIDS), where alterations in the brain 5-HTergic system have been described in ~half of human SIDS cases, including increased number of 5-HT neurons of differing morphology (smaller, simpler, perhaps immature), deficiencies in autoreceptor 5-HT1A binding, and decreased levels of 5- HT and tryptophan hydroxylase 2 (TPH2, the rate-limiting biosynthetic enzyme for 5-HT). We propose investigations to reveal in mice how aspects of this SIDS brain 5-HTergic phenotype develop prenatally. Our approach is informed by two recent findings. First, Pet1+ neurons in the raphe expressing high levels of 5-HT identity genes (e.g. Ddc, Vmat2, Gata3, Pet1) have been identified, smaller in size, with modest levels of autoreceptor 5-HT1A yet remarkably expressing little or no TPH2 and 5-HT. We call these novel cells para-5- HTergic neurons, signifying their partially shared molecular phenotype, shared location, and developmental emergence with 5-HT neurons. Second is the discovery of neurotransmitter switching, a noncanonical form of neuronal plasticity that occurs in response to stressors. Recent data support its role in shaping the 5-HTergic neuronal system, where stressors may drive some para-5-HT neurons to produce 5-HT as an adaptive response. Preliminary findings reveal that para-5-HT neurons derived from rhombomere (r) 4 densely and selectively innervate respiratory and arousal centers, and that gestational exposure to intermittent hypoxia results in an increased number of TPH2+ cells postnatally with as yet uncertain 5-HT levels. We propose that para-5-HT neurons are a pliant population that may be transformed when challenged prenatally by hypoxia to produce 5-HT in newborns as a compensatory mechanism to support AR. We hypothesize that in response to the major SIDS risk factor of prenatal hypoxia, certain para-5-HT neurons adaptively transform to produce 5-HT to rectify a 5-HTergic signaling imbalance that hinders the AR and, alternatively, that an insufficient transformation plays a critical role in SIDS. We will test this by exposing mice to intermittent hypoxia or normoxia during gestation, characterizing cellular and molecular phenotypes and querying neurotransmitter transformation (Aim 1); further, we will determine the effect of acute activation or inhibition of these r4-para-5-HT neurons on the AR in these mice (Aim 2), and we will examine phenotypic markers of para-5-HT neurons in human SIDS and control brain tissue (Aim 3). This novel, functionally defined, para-5-HT cell type and plasticity may be highly relevant to newborn viability.

项目概述：强大的自苏醒反射(AR)对新生儿的出生存活率至关重要。这个 过渡到独立呼吸和适应呼吸中断，呼吸暂停，这在 新生儿和婴儿，需要协调的心肺反应才能康复。5-羟色胺 羟色胺)和产生它的脑干中缝细胞，称为Pet1神经元，组织和驱动 在新生动物和人类身上成功地进行了AR。不成功的应收账款被认为是 婴儿猝死综合征(SID)，其中大脑5-羟色胺能系统的变化 在约一半的人类小儿麻痹症病例中描述，包括不同形态的5-羟色胺神经元数量增加 (更小，更简单，可能不成熟)，自身受体5-HT1a结合不足，5-HT1a水平降低 羟色胺和色氨酸羟化酶2(TPH2，5-羟色胺的生物合成限速酶)。我们建议 在小鼠身上进行研究，以揭示这种小岛屿发展中国家大脑5-羟色胺能表型的某些方面是如何在产前发育的。我们的 最近的两个发现告诉了我们这一方法。首先，中缝内Pet1+神经元表达高水平的5-羟色胺 识别基因(如DDC、VMAT2、GATA3、Pet1)已被鉴定，大小较小，具有中等水平的 自身受体5-HT1a几乎或不表达TPH2和5-羟色胺。我们称这些新细胞为Par5-5- H能神经元，表明它们部分共享的分子表型、共享的位置和发育 出现5-羟色胺神经元。第二个是神经递质转换的发现，这是一种非规范的 神经元对应激源的反应发生的可塑性。最近的数据支持它在塑造5-HTeric中的作用 神经系统，在那里应激源可能驱动一些准-5-羟色胺神经元产生5-羟色胺作为适应性 回应。初步研究结果表明，从菱形核(R)4派生的类-5-羟色胺神经元密度较高， 选择性地支配呼吸和唤醒中心，以及孕期暴露在间歇性低氧中 结果出生后TPH2+细胞数量增加，但5-羟色胺水平尚不确定。我们建议 类5-羟色胺神经元是一个柔韧的群体，当产前受到 缺氧使新生儿产生5-羟色胺作为支持AR的代偿机制。我们假设 为了应对婴儿猝死综合征的主要危险因素产前缺氧，某些类5-羟色胺神经元自适应地 转化为产生5-羟色胺，以纠正5-羟色胺能信号失衡，从而阻碍AR和， 或者，不充分的转型在小岛屿发展中国家中起着关键作用。我们将通过曝光来测试这一点 小鼠在妊娠期间对间歇性低氧或常氧的反应，细胞和分子表型的特征 和询问神经递质转化(目标1)；进一步，我们将确定急性激活的效果 或抑制这些小鼠的R4-对-5-羟色胺神经元(目标2)，我们将检测表型 人类小儿麻痹症和对照脑组织中对5-羟色胺神经元的标记(目标3)。这部小说，从功能上讲 明确的对位5-羟色胺细胞类型和可塑性可能与新生儿存活率高度相关。