Leveraging vagal oxytocin receptors to understand cardiometabolic interoception

项目摘要 催产素是一种来自下丘脑的神经肽，众所周知，它可以塑造对社会刺激的感知，并 因其在大脑内的催产素受体(OXTR)上的行为而被公认，在那里它协调情绪和 对社会刺激的稳态反应。因此，催产素被认为是外部感觉的媒介，并在 针对从自闭症到肥胖症的各种疾病的临床试验。虽然研究较少，但Oxtr(S)也表达在 我们认为对这些OXTR(S)的研究是解开OXTR的关键。 错综复杂的内部感觉。我们对小鼠的初步研究表明，在结状神经节(NDG)内， Oxtr(S)划分了支配主动脉弓、胃和十二指肠的特定神经元。引人入胜的是， 兴奋NDG(简称NDGOxtr)中表达OXTR的神经元可引起强大的心脏代谢 以血压和食物摄入量降低为特征的反应。我们对这些结果的解释是NDGOxtr 可以研究以了解来自血管系统或胃肠道(GI)的信号是如何传递到 并可能带来新的见解，开发身心干预措施，以减轻影响 心脏代谢轴上的多个器官。在人类功能磁共振研究中，血压或GI的扰动 扩张改变了前额叶皮质(PFC)的活动，有趣的是，我们发现NDGOxtr的兴奋 也改变了部分PFC神经元的活动。这些结果表明，NDGOxtr影响皮层神经元 编码血管系统或胃肠道的相互感觉，以引导恢复内稳态的行为。最后， NDG内OXTR的存在，以及催产素使NDG神经元去极化的报道， 提示氧化应激(S)可兴奋迷走神经传入，从而提高血管系统的敏感性。 或胃肠道被察觉。这些观察结果导致了一种假设，即不同的NDGOxtr形状 通过单独的神经回路将信号从血管系统或胃肠道传递到 一等兵。我们进一步假设，催产素通过增加神经递质的敏感性来增强这种内感觉。 迷走神经传入心脏代谢改变。我们将追求以下具体目标。AIM 1使用 神经解剖示踪、NDG活体成像及生理和行为在体光遗传学 记录以确定单独的NDGOxtr群体是否对血管系统或GI的刺激有反应 引出不同的补偿反应。AIM 2使用PFC的活体成像和活体光遗传学 通过生理和行为记录来评估NDGOxtr是否支配血管系统或胃肠道 影响PFC神经元兴奋-抑制平衡引导行为向内稳态矫正 需要。目的3利用组织特异性基因缺失、活体成像和药理学来研究OXTR(S) 以NDG表达影响心脏代谢性内感的指标。总而言之，我们的实验将揭示， 在详细和机械的水平上，1)NDGOxtr转导的刺激，2)编码和 定向对这些刺激的反应，3)OXTR信号在这些过程中所起的作用。

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.