Impact of Early Life Experience on Vagal Neurons and Circuits

慢性压力深刻地影响着身心健康。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的童年经历（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次或更多次ACE， 与慢性脑和多器官疾病有关的生理功能障碍的发病率。我们假设 ELS的多系统后果与尚未确定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包括从内脏到神经元的主要通讯途径。 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 外流皮质边缘中枢和下丘脑中枢一致地调节迷走副交感神经对 心血管、消化和免疫相关功能。ELS与迷走神经张力降低有关， 各种生理功能障碍，以及我们在啮齿动物中发表的临床前研究结果表明， ELS诱导迷走神经元和回路中的早期和持续的转录和连接适应。 考虑到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， 研究了在ELS面前导致疾病风险的发育和成人迷走神经表型。 我们发表的初步数据为我们的工作假设提供了基础，即ELS在早期触发 迷走神经元的长期转录组水平的分子适应， 中枢迷走神经回路拟议的研究开始通过追求四个具体目标来解决这个问题， 建立的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亚类分子表型; 2）确定长期ELS效应 利用分子生物学方法研究支配特定消化器官的迷走神经元亚型的转录谱 解剖学策略; 3）使用以下方法确定ELS对中枢迷走神经连接体的早期和长期影响： 跨突触病毒标记;和4）确定ELS对迷走神经-迷走神经信号传导的长期功能作用。这 研究计划通过创新的发现研究解决了高影响力的临床前问题， 利用我们多PI研究团队的优势。我们把性作为一个生物变量， 实验，基于一些报道的ELS对内脏感觉运动功能影响的性别差异 在啮齿类动物和人类中。建议的工作将提供一个新的理解经验驱动 在小鼠内感受信号通路和内脏运动控制中的发育适应， 独特的重点是迷走神经回路，桥接中枢和外周系统的高风险ELS诱导 功能障碍这种合作，多PI研究计划将提供一个新的平台，为未来的机械 探索ELS、慢性疾病和迷走神经经验驱动适应之间因果关系的研究 感觉和运动系统。

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.