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.

项目摘要：强大的自动反射反射（AR）对于从出生起的新生儿生存至关重要。这 过渡到独立的呼吸和呼吸中断，呼吸暂停的呼吸和适应性 新生儿和婴儿需要协调的心肺反应才能恢复。 5-羟色胺（5- HT，5-羟色胺）和产生它的脑干Raphe细胞，称为PET1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 婴儿猝死综合征（SIDS），其中大脑5个疼痛系统的改变 在〜一半的人小群体病例中描述，包括不同形态的5-HT神经元数量增加 （较小，更简单，也许不成熟），自身受体5-HT1A结合的缺陷，5--的水平降低 HT和色氨酸羟化酶2（TPH2，5-HT的限速生物合成酶）。我们建议 在小鼠中进行的调查揭示了该小径的各个方面如何在产前发育5个胸甲表型。我们的 最近的两个发现为方法提供了信息。首先，raphe中的PET1+神经元表达高水平的5-HT 已经鉴定出识别基因（例如DDC，VMAT2，GATA3，PET1），尺寸较小，水平适中 自身受体5-HT1A，但很少或没有TPH2和5-HT表达。我们称这些新细胞为para-5-- htergic神经元，表示其部分共享的分子表型，共享位置和发育 5-HT神经元的出现。第二是发现神经递质切换的发现，这是一种非规范形式 响应压力源而发生的神经元可塑性。最近的数据支持其在塑造5束束缚中的作用 神经元系统，压力源可能会驱动一些Para-5-HT神经元以产生5-HT作为自适应 回复。初步发现表明，源自菱形（r）4密度和 有选择地支配呼吸道和唤醒中心，妊娠暴露于间歇性缺氧 在产后尚不确定的5-HT水平上，导致TPH2+细胞数量增加。我们提出了这一点 Para-5-HT神经元是一个庞大的人群，当在产前挑战时可能会转化 缺氧在新生儿中产生5-HT作为支持AR的补偿机制。我们假设 为了响应产前缺氧的主要SIDS风险因素，某些Para-5-HT神经元适应 转化以产生5-HT以纠正5个腕信号传导不平衡，从而阻碍AR和， 另外，不足的转化在小岛屿发展中的作用至关重要。我们将通过暴露 在妊娠期间，小鼠到间歇性缺氧或正常氧，表征细胞和分子表型 并查询神经递质转换（AIM 1）；此外，我们将确定急性激活的影响 或抑制这些小鼠AR上的这些R4-PARA-5-HT神经元（AIM 2），我们将检查表型 人小片和对照脑组织中para-5-HT神经元的标记（AIM 3）。这本小说在功能上 定义的，Para-5-HT细胞类型和可塑性可能与新生儿的生存能力高度相关。