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

• 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
• 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

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.

项目摘要 催产素是一种下丘脑衍生的神经肽，以塑造社会刺激和 因其在大脑内的催产素受体（OXTR）上的作用而公认 对社会刺激的稳态反应。结果，催产素被认为是外部感受的介体，在 从自闭症到肥胖症等疾病的临床试验。虽然研究较少，但也表达了 周围神经系统，我们建议对这些oxtr的研究对于解开 互认为的复杂性。我们在小鼠的初步研究表明，在鼻子神经节（NDG）中， OXTR（S）划定特定的神经元支配主动脉弓，胃和十二指肠。有趣的是， NDG中表达OXTR的神经元的激发（称为NDGOXTR）会引起强大的心脏代谢 反应以降低血压和食物摄入为代表。我们对这些结果的解释是ndgoxtr 可以研究以了解脉管系统或胃肠道（GI）的信号如何中继到 大脑，可能导致新的见解，以制定心身干预以减轻影响影响的疾病 心脏代谢轴中的多个器官。在人类fMRI研究中，血压或GI的扰动 扩张改变了前额叶皮层（PFC）的活性，并有趣地发现了NDGOXTR的激发 还改变了PFC神经元子集的活性。这些结果表明NDGOXTR影响皮层神经元 编码脉管系统或胃肠道的互相感知到恢复体内平衡的方向行为。最后， OXTR在NDG内的存在，以及催产素去极化NDG神经元的报道， 表明OXTR（S）促进迷走神经传入的激发，以提高脉管系统的敏感性 或胃肠道被感知。这些观察结果导致了以下假设： 通过单独的神经回路的互感，这些神经回路将信号从脉管系统或胃肠道传递到 PFC。我们进一步假设催产素通过增加的灵敏度来增强这种感觉 迷走神经代谢改变的传入。我们将追求以下特定目标。 AIM 1用途 具有生理和行为的体内光遗传学的神经解剖学跟踪，NDG的浸润成像 记录以确定单独的ndgoxtr种群是否响应了脉管系统或gi的刺激 区域以引起明显的补偿性反应。 AIM 2使用PFC和体内光遗传学的浸润成像 使用生理和行为记录来评估NDGOXTR是否支配脉管系统或gi区域 影响PFC神经元对稳态的抗激发平衡 需要。 AIM 3使用组织特异性基因缺失，插入式成像和药理学来研究OXTR 由NDG表达影响心脏代谢间际观察的指标。总体而言，我们的实验将揭示， 在详细的机械水平上，1）ndgoxtr转导的刺激，2）编码和编码的皮质神经元 东方对这些刺激的反应，3）Oxtr-Signaling在这些过程中的作用。