Impact of Early Life Experience on Vagal Neurons and Circuits

早期生活经历对迷走神经元和回路的影响

• 批准号: 10461651
• 负责人: PAT LEVITT
• 金额: $ 8.14万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-12 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461651
• 关键词: Address; Adult; Affect; Afferent Neurons; Anatomy; Animal Model; Atlases; Behavior; Behavioral; Biological; Brain; Brain Stem; Cardiovascular system; Caring; Cells; Cholecystokinin; Chronic; Chronic Disease; Chronic stress; Clinical; Cognition; Cognitive; Communication; Coupled; Data; Development; Digestion; Disease; Dorsal; Duodenum; Emotional; Event; Exposure to; Feeding behaviors; Female; Fluorescence-Activated Cell Sorting; Fluorescent in Situ Hybridization; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic Transcription; Genomics; Health Status; Hormone secretion; Human; Hypothalamic structure; Immune; Incidence; Inflammation; Inflammatory; Injections; Investigation; Label; Libraries; Life; Life Experience; Link; Long-Term Effects; Longevity; Maps; Mediating; Mental Health; Messenger RNA; Metabolic; Metabolism; Modeling; Molecular; Molecular Analysis; Motor; Motor Neurons; Mus; Nerve; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pancreas; Pathway interactions; Peripheral; Phenotype; Physiological; Physiology; Pilot Projects; Pituitary Gland; Pituitary Hormones; Prosencephalon; Publishing; Reflex action; Reporter; Reporting; Research; Resolution; Resources; Risk; Rodent; Rodent Model; Role; Route; Sensory; Sex Differences; Shapes; Signal Pathway; Signal Transduction; Spinal; Stomach; Stress; Synapses; System; Tissues; Tracer; Vagus nerve structure; Viral; Viscera; Visceral; Work; adverse childhood events; base; biological adaptation to stress; brain shape; cholecystokinin 8; connectome; differential expression; disorder risk; early life adversity; early life stress; experience; experimental study; functional adaptation; gastrointestinal; gastrointestinal system; gut dysbiosis; high risk; hypothalamic-pituitary-adrenal axis; immune function; innovation; insight; intestinal barrier; male; molecular phenotype; motility disorder; motivated behavior; motor control; motor disorder; mouse model; neural circuit; neurogenomics; neurotransmission; novel; novel strategies; physical conditioning; postnatal; pre-clinical; programs; relating to nervous system; response; sensorimotor system; sex; single-cell RNA sequencing; stimulus sensitivity; systemic inflammatory response; targeted treatment; transcriptome; transcriptomics; translational approach

Chronic stress profoundly affects physical and mental health. Evolutionarily conserved responses to early life stress (ELS), characterized in humans as adverse childhood experiences (ACEs), support their investigation using animal models. Nearly 1 in 6 adults in the U.S. experience 4 or more ACEs, resulting in increased incidence of physiological dysfunctions linked to chronic brain and multi-organ diseases. We hypothesize that the multi-system consequences of ELS are linked to as-yet undefined genomic and functional adaptations in vagal neurons and circuits. Vagal sensory neurons comprise a major communication route from viscera to brain that shapes motivated behavior, metabolism, pituitary hormone secretion, inflammation, and autonomic outflow. In concert, cortico-limbic and hypothalamic centers modulate vagal parasympathetic control over cardiovascular, digestive, and immune-related functions. ELS is linked to reductions in vagal tone that promote a variety of physiological dysfunctions, and our published and pilot preclinical findings in rodents indicate that ELS induces early and persistent transcriptional and connectional adaptations in vagal neurons and circuits. Given that vagal sensory-motor functions are integral to physiological health status, surprisingly few studies have examined developmental and adult vagal phenotypes that contribute to disease risk in the face of ELS. Our published and preliminary data provide the foundation for our working hypothesis that ELS triggers early and long-term transcriptome-level molecular adaptations in vagal neurons, coupled with functional adaptations in central vagal circuits. The proposed research begins to address this by pursuing four Specific Aims in an established mouse model of ELS: 1) determine the early developmental and long-term impact of ELS on vagal subclass molecular phenotypes using advanced transcriptomics strategies; 2) determine long-term ELS effects on the transcriptional profiles of vagal neuron subtypes innervating specific digestive viscera using molecular anatomical strategies; 3) determine early and long-term effects of ELS on the central vagal connectome using transsynaptic viral labeling; and 4) determine long-term functional effects of ELS on vago-vagal signaling. This research program addresses a high-impact preclinical problem through innovative discovery research that leverages the strengths of our multi-PI research team. We include sex as a biological variable in all experiments, based on some reported sex differences in the effects of ELS on visceral sensory-motor functions in rodents and in humans. The proposed work will provide a novel understanding of experience-driven developmental adaptations in interoceptive signaling pathways and visceral motor control in mice, with a unique focus on vagal circuits that bridge central and peripheral systems at high risk for ELS-induced dysfunction. This collaborative, multi-PI research program will provide a new platform for future mechanistic studies probing causal links between ELS, chronic disease, and experience-driven adaptations in vagal sensory and motor systems.

慢性压力深刻影响身心健康。对早期生命的进化保守反应 压力（ELS），在人类中被描述为不良童年经历（ACE），支持他们的调查 使用动物模型。在美国，近六分之一的成年人经历过 4 次或更多 ACE，导致 与慢性脑部和多器官疾病相关的生理功能障碍的发生率。我们假设 ELS 的多系统后果与尚未定义的基因组和功能适应有关 迷走神经元和回路。迷走神经感觉神经元是从内脏到内脏的主要通讯途径 大脑塑造动机行为、新陈代谢、垂体激素分泌、炎症和自主神经 外流。皮质边缘和下丘脑中心协同调节迷走神经副交感神经控制 心血管、消化和免疫相关功能。 ELS 与迷走神经张力的降低有关，从而促进 各种生理功能障碍，我们在啮齿类动物中发表的和试点的临床前研究结果表明 ELS 诱导迷走神经元和回路的早期和持续的转录和连接适应。 鉴于迷走神经感觉运动功能是生理健康状态不可或缺的一部分，令人惊讶的是很少有研究 研究人员检查了发育和成年迷走神经表型，这些表型在 ELS 时会增加疾病风险。 我们已发表的初步数据为我们的工作假设提供了基础，即 ELS 会提前触发 迷走神经元的长期转录组水平分子适应以及功能适应 在中枢迷走神经回路中。拟议的研究开始通过追求四个具体目标来解决这个问题 建立ELS小鼠模型：1）确定ELS对迷走神经的早期发育和长期影响 使用先进的转录组学策略对分子表型进行亚类； 2) 确定长期 ELS 效果 利用分子生物学研究神经支配特定消化内脏的迷走神经元亚型的转录谱 解剖策略； 3) 使用以下方法确定 ELS 对中央迷走神经连接组的早期和长期影响 跨突触病毒标记； 4) 确定 ELS 对迷走神经信号传导的长期功能影响。这 研究计划通过创新发现研究解决了一个高影响力的临床前问题 利用我们多 PI 研究团队的优势。我们将性别作为所有变量中的一个生物变量 实验，基于一些报告的 ELS 对内脏感觉运动功能影响的性别差异 在啮齿动物和人类中。拟议的工作将为经验驱动提供新的理解 小鼠内感受信号通路和内脏运动控制的发育适应 独特地关注连接中枢和外周系统的迷走神经回路，这些系统处于 ELS 诱发的高风险中 功能障碍。这个协作的、多 PI 研究项目将为未来的机械学提供一个新的平台 研究探讨 ELS、慢性疾病和迷走神经经验驱动适应之间的因果关系 感觉和运动系统。