Encoding of inflammatory mediators by vagal sensory neurons

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Project Summary The nervous system and immune system communicate with each other to respond to infections and maintain immune homeostasis. Work over the last two decades has shown that the vagus nerve is a critical pathway for neuro-immune communication carrying motor signals descending to the body, in addition to sensory signals ascending to the brain. These pathways comprise the two arcs in the neuro-immune reflex circuit termed the inflammatory reflex, in which neural activity on the vagus nerve regulates cytokine production in the spleen. While the functional and molecular mechanisms of the descending motor pathway to the spleen are well-established in this reflex, it is unclear how vagal sensory neurons detect and represent information about inflammation in situ. This unknown mechanism is a critical piece of the ascending sensory arc of the inflammatory reflex. Therefore, the goal of the proposed studies is to use large-scale calcium imaging to discover how vagal sensory neurons encode and represent information about specific inflammatory mediators. By monitoring vagal sensory neurons while they are presented with inflammatory mediators of the innate immune response (e.g. pro- and anti-inflammatory cytokines, DAMPs, PAMPs), we aim to uncover a neural code both at the population-level and at the level of individual sensory neurons. This new understanding will provide crucial mechanistic insights into the nervous system representation of immune signals as a general principle, which can be used to understand what goes wrong in a host of inflammatory disorders that involve immune dysregulation. With a team of experienced scientists who are experts in the neural regulation of immunity, we will use techniques and approaches adapted from sensory neuroscience to determine how vagal sensory neurons encode information about inflammatory mediators. This new fundamental understanding of neuro-immune communication will potentially provide new mechanistic insights about disorders of disrupted immune homeostasis. It may also lead to the identification of new targets and strategies for vagus nerve-based neuromodulation to treat a host of inflammatory disorders.