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：强大的自动复苏反射 (AR) 对于新生儿出生后的存活至关重要。这 过渡到独立呼吸并适应呼吸中断、呼吸暂停，这在 新生儿和婴儿需要协调的心肺反应才能恢复。 5-羟色胺（5- HT（血清素）和产生它的脑干中缝细胞（称为 Pet1 神经元）负责组织和驱动 AR 在新生动物和人类中取得了成功。不成功的 AR 被认为是导致 婴儿猝死综合症 (SIDS)，大脑 5-HTergic 系统发生改变 大约一半的人类 SIDS 病例中有描述，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-HT1A 结合缺陷，以及 5-HT1A 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 研究揭示了小鼠 SIDS 大脑 5-HTergic 表型的各个方面如何在产前发育。我们的 该方法基于最近的两项发现。首先，中缝中的 Pet1+ 神经元表达高水平的 5-HT 已鉴定出身份基因（例如 Ddc、Vmat2、Gata3、Pet1），其大小较小，且具有适度的水平 自身受体 5-HT1A 但显着表达很少或不表达 TPH2 和 5-HT。我们称这些新细胞为para-5- HTergic 神经元，表示它们部分共享的分子表型、共享位置和发育 5-HT神经元的出现。其次是神经递质转换的发现，这是神经递质转换的一种非规范形式。 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-HTergic 方面的作用 神经元系统，其中压力源可能会驱动一些 para-5-HT 神经元产生 5-HT 作为适应性 回复。初步研究结果表明，源自菱形 (r) 4 的 para-5-HT 神经元密集且分布广泛。 选择性地神经支配呼吸和唤醒中枢，并且妊娠期暴露于间歇性缺氧 导致出生后 TPH2+ 细胞数量增加，但 5-HT 水平尚不确定。我们建议 para-5-HT 神经元是一个顺从的群体，当产前受到以下因素的挑战时可能会发生转变： 新生儿缺氧会产生 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主要 SIDS 危险因素，某些 para-5-HT 神经元适应性地 转化产生 5-HT，以纠正阻碍 AR 的 5-HTergic 信号不平衡， 另一方面，转型不充分在小岛屿发展中国家中起着至关重要的作用。我们将通过暴露来测试这一点 小鼠在妊娠期间间歇性缺氧或常氧，表征细胞和分子表型 并询问神经递质转化（目标 1）；此外，我们将确定急性激活的效果 或抑制这些小鼠 AR 上的这些 r4-para-5-HT 神经元（目标 2），我们将检查表型 人类 SIDS 和对照脑组织中 para-5-HT 神经元的标记（目标 3）。这部小说，从功能上来说 根据定义，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。