Impact of Early Life Experience on Vagal Neurons and Circuits

慢性压力会对身心健康产生深远影响。进化保守的对早期生命的反应 压力(ELS)，在人类中被描述为不良童年经历(ACE)，支持他们的研究 使用动物模型。在美国，近六分之一的成年人经历过4次或更多的A级，导致 与慢性大脑和多器官疾病有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确定的基因组和功能适应有关 迷走神经和神经回路。迷走感觉神经元构成了从内脏到 形成动机行为、新陈代谢、脑下垂体激素分泌、炎症和自主神经的大脑 外流。皮质-边缘和下丘脑中枢共同调节迷走神经的副交感神经控制。 心血管、消化和免疫相关功能。ELS与迷走神经张力的减少有关，迷走神经张力促进 各种生理功能障碍，以及我们发表的和试点的啮齿动物临床前研究结果表明 ELS在迷走神经和迷走神经回路中诱导早期和持久的转录和连接适应。 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 检查了在ELS面前导致疾病风险的发育和成人迷走神经表型。 我们发表的和初步的数据为我们的工作假设提供了基础，即ELS早期触发 迷走神经中长期转录组水平的分子适应，以及功能适应 在中央迷走神经回路。这项拟议的研究通过在一个 建立ELS小鼠模型：1)测定ELS对迷走神经的早期发育和长期影响 使用高级转录组学策略对分子表型进行亚类划分；2)确定ELS的长期效应 用分子生物学方法研究支配特定消化器官的迷走神经细胞亚型的转录谱 解剖策略；3)确定ELS对中央迷走神经连接体的早期和长期影响 跨突触病毒标记；以及4)确定ELS对迷走神经信号的长期功能影响。这 研究计划通过创新的发现研究解决高影响的临床前问题 充分利用我们多元PI研究团队的优势。我们把性作为生物变量包括在所有 基于一些已报道的ELS对内脏感觉-运动功能影响的性别差异的实验 在啮齿动物和人类身上。拟议的工作将提供对经验驱动的新的理解 小鼠感觉间信号通路和内脏运动控制的发育适应 专注于连接中枢和外周系统的迷走神经回路，具有ELS诱导的高风险 功能障碍。这种协作的、多PI的研究计划将为未来的机械学提供一个新的平台 探索ELS、慢性病和迷走神经中经验驱动适应之间的因果联系的研究 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.