Leveraging vagal oxytocin receptors to understand cardiometabolic interoception

利用迷走神经催产素受体了解心脏代谢内感受

基本信息

批准号：
10698525
负责人：
Eric Gerald Krause
金额：
$ 58.8万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-26 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10698525
关键词：
Affect Baroreflex Behavior Behavioral Blood Blood Pressure Brain Cardiovascular system Cell Nucleus Clinical Trials Coupled Cre lox recombination system Disease Duodenum Eating Emotional Energy Metabolism Equilibrium Esthesia Food Energy Functional Magnetic Resonance Imaging Gastrointestinal tract structure Gene Deletion Gene Transfer Heart Rate Homeostasis Human Hypothalamic structure Image Impairment Indirect Calorimetry Intake Interoception Intranasal Administration Investigation Lead Liquid substance Mediating Mediator of activation protein Metabolic syndrome Mind-Body Intervention Mus Neurons Neuropeptides Nodose Ganglion Obesity Organ Oxytocin Oxytocin Receptor Pathway interactions Pattern Peripheral Peripheral Nervous System Pharmacology Physiological Play Population Prefrontal Cortex Process Receptor Signaling Reporting Role Shapes Signal Transduction Social Perception Stimulus Stomach Stretching Telemetry Therapeutic Tissues Viral aortic arch autism spectrum disorder behavioral response blood pressure elevation blood pressure reduction body system body-mind cardiometabolism experimental study food consumption gastrointestinal gastrointestinal system in vivo indexing insight intravital imaging multi-photon nerve supply neural circuit novel optogenetics paraventricular nucleus phenotypic biomarker preclinical study pressure response social

项目摘要

Project Summary Oxytocin is a hypothalamus-derived neuropeptide well-known for shaping the perception of social stimuli and recognized for its actions at the oxytocin receptor (Oxtr) within the brain, where it orchestrates emotional and homeostatic responses to social stimuli. As a result, oxytocin is considered a mediator of exteroception and is in clinical trials for diseases ranging from autism to obesity. While less-studied, Oxtr(s) are also expressed in the peripheral nervous system, and we propose that investigation of these Oxtr(s) is critical to unraveling the intricacies of interoception. Our preliminary studies in mice revealed that within the nodose ganglia (NDG), Oxtr(s) demarcate specific neurons innervating the aortic arch, stomach and duodenum. Fascinatingly, excitation of Oxtr-expressing neurons in the NDG (referred to as NDGOxtr) elicits a robust cardiometabolic response typified by lowered blood pressure and food intake. Our interpretation of these results is that NDGOxtr can be studied to understand how signals from the vasculature or gastrointestinal (GI) tract are relayed to the brain and could lead to novel insights for developing mind-body interventions to alleviate diseases that impact multiple organs in the cardiometabolic axis. In human fMRI studies, perturbations in blood pressure or GI distension change the activity of the prefrontal cortex (PFC), and intriguingly, we found that excitation of NDGOxtr also alters the activity of a subset of PFC neurons. These results suggest that NDGOxtr influence cortical neurons encoding interoception of the vasculature or GI tract to orient behavior toward restoring homeostasis. Finally, the presence of the Oxtr within the NDG, in conjunction with reports that oxytocin depolarizes NDG neurons, suggests that Oxtr(s) promote excitation of vagal afferents to increase the sensitivity by which the vasculature or GI tract are perceived. These observations have led to the hypothesis that distinct NDGOxtr shape interoception through separate neural circuits that relay signals from the vasculature or GI tract to the PFC. We further hypothesize that oxytocin enhances this interoception by increasing the sensitivity of vagal afferents to cardiometabolic alterations. We will pursue the following Specific Aims. Aim 1 uses neuroanatomical tracing, intravital imaging of NDG and in vivo optogenetics with physiological and behavioral recordings to determine whether separate populations of NDGOxtr respond to stimulation of the vasculature or GI tract to elicit distinct compensatory responses. Aim 2 uses intravital imaging of the PFC and in vivo optogenetics with physiological and behavioral recordings to evaluate whether NDGOxtr innervating the vasculature or GI tract affect the excitation-inhibition balance of PFC neurons to orient behavior toward rectification of homeostatic need. Aim 3 uses tissue specific gene deletion, intravital imaging and pharmacology to investigate how Oxtr(s) expressed by the NDG affect indices of cardiometabolic interoception. Collectively, our experiments will reveal, at a detailed and mechanistic level, 1) the stimuli that NDGOxtr transduce, 2) the cortical neurons that encode and orient responses to these stimuli, 3) the role that Oxtr-signaling plays in these processes.

项目概要催产素是一种源自下丘脑的神经肽，以塑造社会刺激的感知和因其对大脑内催产素受体 (Oxtr) 的作用而闻名，该受体负责协调情绪和情绪对社会刺激的稳态反应。因此，催产素被认为是外感受的介质，并且在针对从自闭症到肥胖等疾病的临床试验。虽然研究较少，但 Oxtr(s) 也表达在周围神经系统，我们建议对这些 Oxtr 的研究对于解开谜团至关重要内感受的复杂性。我们对小鼠的初步研究表明，在结状神经节（NDG）内， Oxtr 划分了支配主动脉弓、胃和十二指肠的特定神经元。令人着迷的是， NDG（称为 NDGOxtr）中表达 Oxtr 的神经元的兴奋会引发强大的心脏代谢以血压降低和食物摄入量降低为代表的反应。我们对这些结果的解释是 NDGOxtr 可以研究以了解来自脉管系统或胃肠道 (GI) 的信号如何传递到大脑，并可能为开发身心干预措施以减轻影响的疾病带来新的见解心脏代谢轴上的多个器官。在人类功能磁共振成像研究中，血压或胃肠道的扰动扩张改变了前额皮质（PFC）的活动，有趣的是，我们发现 NDGOxtr 的兴奋还改变 PFC 神经元子集的活动。这些结果表明 NDGOxtr 影响皮质神经元编码脉管系统或胃肠道的内感受，以引导行为恢复体内平衡。最后， NDG 中 Oxtr 的存在，以及催产素使 NDG 神经元去极化的报道，表明 Oxtr(s) 促进迷走神经传入的兴奋，以增加脉管系统的敏感性或胃肠道被感知。这些观察结果得出了这样的假设：不同的 NDGOxtr 形状通过单独的神经回路进行内感受，将信号从脉管系统或胃肠道传递到全氟碳化物。我们进一步假设催产素通过增加内感受的敏感性来增强这种内感受。迷走神经传入心脏代谢改变。我们将追求以下具体目标。目标 1 使用神经解剖追踪、NDG 活体成像以及生理和行为的体内光遗传学记录以确定不同的 NDGOxtr 群体是否对脉管系统或胃肠道的刺激有反应道引起不同的补偿反应。目标 2 使用 PFC 的活体成像和体内光遗传学通过生理和行为记录来评估 NDGOxtr 是否支配脉管系统或胃肠道影响 PFC 神经元的兴奋-抑制平衡，以纠正稳态行为需要。目标 3 使用组织特异性基因缺失、活体成像和药理学来研究 Oxtr(s) NDG 表达的影响心脏代谢内感受的指数。总的来说，我们的实验将揭示，在详细和机械层面上，1) NDGOxtr 转导的刺激，2) 编码和定向对这些刺激的反应，3) Oxtr 信号在这些过程中发挥的作用。