We have conducted preliminary work on the impact of proteinase-activated receptors [PAR] on hindbrain regulation of gastric function. The genesis of this work was the 70 year-old observation by Cushing that bleeding intracranial head injury produced a profound anorexia, nausea, gastric stasis, and accompanying ulcer. While Cushing's ulcer was, for many years, attributed to the effects of increased intracranial pressure on medullary neural circuits that control autonomic outflow to the gut, physiological studies in head injury patients reveal that there is no correlation between ventricular pressure and the degree of gastric stasis. The discovery of """"""""thrombin receptor"""""""" [proteinase activated receptor - PAR] in the brainstem led us to the hypothesis that proteinase action of thrombin [present as a function of bleeding] on PARs in the dorsal medulla could affect changes in autonomic control of the gut. Studies in intact, awake animals reveal that exposure of the 4th ventricle to the PAR1 agonist peptide SFLLRN [or thrombin] provokes a suppression of gastric transit similar to that seen with systemic CCK;a potent anorexic and inhibitor of gastric transit. Our preliminary attempts to understand the neural mechanisms behind the effects of thrombin and PAR activation have revealed a startling possibility. That is, the detection of thrombin action may be a primary function of astrocytes within the nucleus of the solitary tract [NST]. Changes in autonomic function that result from PAR activation could be due to glial interactions with brainstem neurons that control digestive functions and feeding behavior. Even more important is the possibility that glial-neural communication in the NST has wider significance as a general chemosensory mechanism ultimately responsible for significant modulation of autonomic functions. Our preliminary studies with live cell calcium imaging methods are the first to observe this phenomenon in the brainstem. We will use this technique, along with immunohistochemical, and in vivo neurophysiological methods to test the hypothesis that PAR action to change autonomic function is the result of a potent glial-neural interaction in the NST. These results will provide the basis for future studies of glial-neural interactions in brainstem autonomic and behavioral control. The way in which the brain detects nutrients, hormones, cytokines and other chemical stimuli is not well understood. The historical assumption has been that neurons within the CNS performed the detection. Recent work in cell culture and in slice preparations, in combination with our preliminary studies, suggests the possibility that glia (and not neurons) may be the principal detectors of many chemical stimuli. Furthermore, activated glia then communicate with neurons to induce the appropriate response to the chemical stimulus. A correct description of how the brain detects local and circulating chemical agents will have a significant impact on our understanding of brain regulation of autonomic and behavioral functions in health and disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Mitler, Merrill
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Lsu Pennington Biomedical Research Center
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Baton Rouge
United States
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Reiner, David J; Mietlicki-Baase, Elizabeth G; McGrath, Lauren E et al. (2016) Astrocytes Regulate GLP-1 Receptor-Mediated Effects on Energy Balance. J Neurosci 36:3531-40
Vance, Katie M; Rogers, Richard C; Hermann, Gerlinda E (2015) PAR1-activated astrocytes in the nucleus of the solitary tract stimulate adjacent neurons via NMDA receptors. J Neurosci 35:776-85
Vance, Katie M; Rogers, Richard C; Hermann, Gerlinda E (2015) NMDA receptors control vagal afferent excitability in the nucleus of the solitary tract. Brain Res 1595:84-91
Burke, Susan J; Stadler, Krisztian; Lu, Danhong et al. (2015) IL-1? reciprocally regulates chemokine and insulin secretion in pancreatic ?-cells via NF-?B. Am J Physiol Endocrinol Metab 309:E715-26
Hermann, Gerlinda E; Viard, Edouard; Rogers, Richard C (2014) Hindbrain glucoprivation effects on gastric vagal reflex circuits and gastric motility in the rat are suppressed by the astrocyte inhibitor fluorocitrate. J Neurosci 34:10488-96
Vance, Katie M; Ribnicky, David M; Hermann, Gerlinda E et al. (2014) St. John's Wort enhances the synaptic activity of the nucleus of the solitary tract. Nutrition 30:S37-42
Vance, Katie M; Ribnicky, David M; Rogers, Richard C et al. (2014) Artemisia santolinifolia enhances glutamatergic neurotransmission in the nucleus of the solitary tract. Neurosci Lett 582:115-9
Lukewich, Mark K; Rogers, Richard C; Lomax, Alan E (2014) Divergent neuroendocrine responses to localized and systemic inflammation. Semin Immunol 26:402-8
McDougal, David H; Viard, Edouard; Hermann, Gerlinda E et al. (2013) Astrocytes in the hindbrain detect glucoprivation and regulate gastric motility. Auton Neurosci 175:61-9
Rogers, Richard C; Viard, Edouard; Hermann, Gerlinda E (2013) CXCL12 sensitizes vago-vagal reflex neurons in the dorsal medulla. Brain Res 1492:46-52

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