Leveraging vagal oxytocin receptors to understand cardiometabolic interoception

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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.