# Impact of Early Life Experience on Vagal Neurons and Circuits

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2023 · $689,533

## Abstract

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 fu...

## Key facts

- **NIH application ID:** 10616664
- **Project number:** 5R01DK126085-03
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** PAT LEVITT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $689,533
- **Award type:** 5
- **Project period:** 2021-04-12 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10616664

## Citation

> US National Institutes of Health, RePORTER application 10616664, Impact of Early Life Experience on Vagal Neurons and Circuits (5R01DK126085-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10616664. Licensed CC0.

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