Tuesday, December 3, 2024
12/3/2024
Project Summary/Abstract Inflammation, the primary biological response to injury and infection, is essential for survival and under precise neuronal control. Sensory neurons, which densely innervate all bodily tissues, report the occurrence of inflammation to the brain, because cytokines and other inflammatory mediators stimulate action potentials. The arrival of incoming sensory signals stimulates brain neurons to send regulatory signals that return to the body and regulate cytokine production. The vagus nerve, a major conduit for body-brain signaling, inhibits inflammation and cytokine production in arthritis, colitis, ischemia, organ transplantation, anxiety-depression, diabetes, and other conditions. In preliminary studies, we (1) used optogenetics and functional mapping to reveal cholinergic neurons in the brain stem significantly increase splenic nerve activity and inhibit TNF production via a significantly specific neuronal pathway; (2) assembled a unique bioelectronic vagus nerve recording toolkit and nociceptor transgenic mouse colonies to reveal sensory vagus nerve pathways activated by IL-1 and TNF; and (3) adapted Cre-based mouse lines and virus constructs enabling the functional combination of mapping activated brain networks and subsequent targeted reactivation of these networks using pharmacogenetics. We identified brain neural networks that respond specifically to IL-1 and TNF, but the function of these networks on the development and progression of inflammation remain undefined. Our long-term goal is to reveal brain neural networks regulating the onset and progression of inflammation, particularly within the setting of inflammatory arthritis in which sensory neuron activation plays a key etiologic role. The objective of this grant is to characterize the role for brain neural network activity in arthritis onset and progression. The central hypothesis is that brain neural network activity plays a critical role in regulating inflammatory arthritis, and the activation of these neurons regulates inflammation. Despite the clinical relevance and the direct importance to understanding basic functional neurological mechanisms of inflammation, the role of brain networks controlling the onset and progression of inflammatory arthritis is completely understudied. Our rationale is that identification of the mechanism(s) to modulate brain neurons in the setting of inflammatory arthritis will reveal new therapeutic opportunities. Here, we will leverage powerful genetic, pharmacogenetic, optogenetic, and bioelectronic approaches for functional mapping and neural circuit analysis to unravel how brain networks are activated by peripheral signals and how they relay outputs to the vagus nerve to impact inflammatory physiological responses. We Aim to use (1) our recently developed genetic techniques which we have used to “trap” subsets of neurons during conditions of activity induced by exposure to cytokines to define brain neural network activity during the onset and progression of inflammatory arthritis and (2) our recently developed pharmacogenetic techniques to selectively “reactivate” these same brain network neurons to assess the mechanisms by which these networks modulate vagus nerve signaling, and therefore, the onset and progression of inflammatory arthritis. The proposed research is innovative because we investigate the effect of brain neural network activity on inflammatory arthritis, a previously unstudied mechanism. 1
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