Leveraging vagal oxytocin receptors to understand cardiometabolic interoception

项目摘要 催产素是一种下丘脑衍生的神经肽，以塑造对社会刺激的感知而闻名， 它在大脑内的催产素受体（Oxtr）上的作用得到了认可，在那里它协调了情绪和 对社会刺激的自我平衡反应因此，催产素被认为是一个调解人的外转，并在 从自闭症到肥胖症的临床试验。虽然研究较少，但Oxtr（s）也在 外周神经系统，我们建议这些Oxtr（s）的调查是至关重要的解开 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（s）划分支配主动脉弓、胃和十二指肠的特定神经元。有趣的是， NDG中表达Oxtr的神经元（称为NDGOxtr）的兴奋激发了一种强有力的心脏代谢， 以降低血压和食物摄入为特征的反应。我们对这些结果的解释是， 可以通过研究来了解来自脉管系统或胃肠道（GI）的信号是如何传递到 大脑，并可能导致新的见解，发展身心干预，以减轻疾病的影响， 心脏代谢轴中的多个器官。在人类功能磁共振成像研究中，血压或胃肠道的扰动 膨胀改变了前额叶皮层（PFC）的活动，有趣的是，我们发现NDGOxtr的兴奋 也改变了PFC神经元的一个子集的活动。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内感受以使行为朝向恢复内稳态。最后， NDG内Oxtr的存在，结合催产素使NDG神经元去极化的报道， 表明Oxtr（s）促进迷走神经传入神经的兴奋，以增加血管系统的敏感性， 或胃肠道被感知。这些观察结果导致了一种假设，即不同的NDGOxtr形状 通过分离的神经回路传递来自脉管系统或胃肠道的信号到胃肠道的内感受。 PFC.我们进一步假设，催产素通过增加内感受的敏感性来增强内感受。 迷走神经传入对心脏代谢改变的影响。我们将追求以下具体目标。Aim 1使用 神经解剖示踪，NDG的活体成像和具有生理和行为的体内光遗传学 记录以确定单独的NDGOxtr群体是否对血管或GI的刺激作出反应 引起明显的代偿反应。目的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是否支配血管系统或胃肠道 影响PFC神经元的兴奋-抑制平衡，以将行为导向稳态的纠正 需要的目的3利用组织特异性基因缺失、活体成像和药理学研究Oxtr（s） 由NDG表达的蛋白质影响心脏代谢内感受指数。总的来说，我们的实验将揭示， 在一个详细的和机械的水平，1）刺激，NDGOxtr，2）皮层神经元编码， 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.