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: 10672925
• 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/10672925
• 关键词: Acute; Adult; Affect; Apnea; Area; Arousal; Automobile Driving; Autoreceptors; Binding; Birth; Brain; Brain Stem; Breathing; Buffers; Cell Count; Cell Size; Cells; Characteristics; Childhood; Chronic; Data; Date of birth; 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; brain tissue; cell type; cohort; comparative; comparison control; 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; 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.

项目总结：强大的自身复苏反射（AR）对新生儿的生存至关重要。的