"Functional gastrointestinal (GI) and motility disorders are the most common GI disorders, affecting as many as 1 in 4 persons worldwide. GI motility dysfunction presents as a symptom in a number of diseases including Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS) and as a secondary symptom in diseases such as Parkinson's disease (PD) and diabetes mellitus. Despite this, treatments for functional GI disorders are scarce. This may be due, in part, to a lack of understanding of the underlying mechanisms that regulate GI function and dysfunction. Normal GI functions are regulated by the enteric nervous system (ENS), an intrinsic neuronal network comprised of enteric neurons and enteric glia embedded in the gut wall. Enteric glia are a unique type of peripheral glial cell that play important roles in GI health and disease. Alterations in ENS control of GI function, underlie the pathology of many GI disorders. Indeed, enteric neuron death and subsequent disruption of the neuronal network causes motility dysfunction in a number of GI disorders. In addition, activation of enteric glia is a critical mediator of neurodegeneration during intestinal inflammation. In this dissertation, we investigate the physiological and pathophysiological roles of enteric glia in GI function regulation. The goal of this dissertation was to understand how glial activation modulates GI function and contributes to neuroinflammation. The work in this dissertation used a combination of transgenic animal strains, immunohistochemistry (IHC), selective drugs, Ca2+ imaging, motility assays, and in situ and in vivo models of colitis. We found that the tachykinin neurokinin A (NKA) contributes to neuroinflammation in the ENS through a multicellular signaling cascade involving enteric neurons, nociceptors and enteric glia. Importantly, activation of neurokinin-2 receptors (NK2Rs) on nociceptive neurons drove Ca2+ responses on enteric glia and antagonizing NK2R signaling prevented key aspects of neuroinflammation in the ENS such as reactive gliosis and neuron death. Further, we provide the first evidence that enteric glia express two subtypes of functional muscarinic receptors and direct activation of modified muscarinic receptors on enteric glia enhances GI motility. Lastly, we studied the effects of glial fibrillary acidic protein (GFAP) upregulation in inflammation and found that GFAP upregulation may contribute to neuroinflammation in colitis. Our data provide new evidence for an active role for enteric glial cells in GI physiology and pathophysiology. Specifically, we demonstrate that 1) communication between enteric neurons, glia and nociceptors underlies the effects of tachykinins in inflammation 2) cholinergic activation of enteric glia is a physiological mechanism that contributes to regulation of GI motility and 3) enteric glial reactivity characterized by morphological changes and GFAP upregulation drives enteric neuron death in colitis. Our findings propose new therapeutic targets for the treatment of GI motility disorders."--Pages ii-iii.
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