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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

基本信息

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
项目类别：
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

项目摘要

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.

慢性压力严重影响身体和心理健康。对早期生命的进化保守反应