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: 10460532
• 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/10460532
• 关键词: Acute; Adult; Affect; Apnea; Area; Arousal; Automobile Driving; Autoreceptors; Binding; Birth; Brain; Brain Stem; Breathing; Cell Count; Cell Size; 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; Life; 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; Transgenic Organisms; 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.

项目摘要：一个强大的自动复苏反射（AR）是至关重要的新生儿从出生存活。的 过渡到独立呼吸和适应呼吸中断，呼吸暂停，这是常见的， 新生儿和婴儿需要协调的心肺反应以恢复。5-羟色胺（5- HT，血清素）和产生它的脑干中缝细胞，称为Pet 1神经元，组织和驱动 在新生动物和人类中成功的AR。不成功的AR被认为是导致 婴儿猝死综合征（SIDS），其中大脑5-HTergic系统的改变已被发现。 在约一半的人类SIDS病例中描述，包括不同形态的5-HT神经元数量增加 （更小，更简单，可能不成熟），自身受体5-HT 1A结合缺陷，以及5-HT 1A水平降低， HT和色氨酸羟化酶2（TPH 2，5-HT的限速生物合成酶）。我们提出 在小鼠中揭示这种SIDS脑5-HTergic表型的各个方面是如何在产前发育的。我们 最近的两项研究结果为这种方法提供了信息。首先，中缝核中的Pet 1+神经元表达高水平的5-HT， 已经鉴定了一些身份基因（例如Ddc、Vmat 2、Gata 3、Pet 1），它们的大小较小，具有适度水平的 自身受体5-HT 1A显著表达很少或不表达TPH 2和5-HT。我们称这些新细胞为帕拉-5- HTergic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-HT神经元。第二个是发现神经递质转换，一种非规范的形式， 神经元对压力的可塑性。最近的数据支持其在塑造5-HTergic中的作用 神经元系统，其中应激源可以驱动一些5-HT旁神经元产生5-HT作为适应性神经元。 反应初步结果表明帕拉-HT神经元密集地起源于菱形节（r）4， 选择性地支配呼吸和唤醒中心，妊娠期暴露于间歇性缺氧 导致出生后TPH 2+细胞数量增加，5-HT水平尚不确定。我们建议 帕拉-羟色胺神经元是一个可塑的群体，当受到产前刺激时， 缺氧可使新生儿产生5-HT，作为支持AR的代偿机制。我们假设 为了应对产前缺氧这一SIDS的主要危险因素，帕拉-HT神经元自适应地 转化产生5-HT以纠正阻碍AR的5-HT能信号传导失衡， 换句话说，转型不充分在小岛屿发展中国家发挥着关键作用。我们将通过暴露 小鼠间歇性缺氧或常氧在怀孕期间，表征细胞和分子表型 和查询神经递质转化（目标1）;进一步，我们将确定急性激活的影响 或抑制这些小鼠中AR上的这些r4-帕拉-5-HT神经元（目的2），我们将检查表型 人SIDS和对照脑组织中的帕拉-5-HT神经元的标记物（目的3）。这部小说，功能上 定义，帕拉5-HT细胞类型和可塑性可能是高度相关的新生儿的生存能力。