Cytokine production by immune effector cells forms part of the host response to antigenic challenge, trauma or irradiation. Protection of the host relies on cytokine release to stimulate: immune attack on pathogens, wound healing, tissue remodeling and energy mobilization. However, elevation of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF], following these insults is also associated with the onset of gastric stasis, nausea, vomiting and anorexia. Degradation of the control of gastrointestinal, fluid and nutritional homeostasis causes significant morbidity and mortality apart from that caused by the primary disease process.Our work has shown that: a) initiation of gastric inhibition by peripheral immune challenge is dependent on TNF synthesis, b) peripherally generated cytokines suppress CNS-commanded, vagally mediated increases in gastric motility and c) TNF can operate directly on neurons of the dorsal vagal complex [DVC] of the brainstem to produce profound gastroinhibition. These results satisfied the initial goals of the project, i.e., the unambiguous demonstration of a role for the dorsal medulla and vagal control circuitry in TNF-mediated gastric stasis.Now we wish to investigate the physiological mechanisms by which TNF dramatically alters vagal control of the stomach. The present proposal focuses on three Specific Aims: 1) which vagal efferent pathway(s) are invoked by central TNF action, 2) the specific phenotype of brainstem neuron(s) activated by TNF and 3) the cellular mechanisms activated within the DVC by TNF. We expect that TNF suppresses gastric motility by acting at several sites within vago-vagal reflex circuits in the medulla. We predict that: 1) TNF enhances glutamate neurotransmission between vagal afferents and the solitary nucleus, 2) TNF directly affects the excitability of specific phenotypes of solitary neurons which control the activity of vagal efferent [DMN] neurons, and 3) these DMN neurons (which ultimately control gastric motility) are also likely to be under the direct influence of TNF. Perhaps TNF produces its profound and prolonged inhibition of gastric motility, (and, perhaps, the generation of nausea, emesis and suppression of feeding) by acting at several points in the DVC simultaneously. These hypotheses will be tested using a combination of in vivo and in vitro neurophysiological methods.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
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Hamilton, Frank A
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Lsu Pennington Biomedical Research Center
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Baton Rouge
United States
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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
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
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
Rogers, Richard C; Hermann, Gerlinda E (2012) Tumor necrosis factor activation of vagal afferent terminal calcium is blocked by cannabinoids. J Neurosci 32:5237-41
McDougal, David H; Hermann, Gerlinda E; Rogers, Richard C (2011) Vagal afferent stimulation activates astrocytes in the nucleus of the solitary tract via AMPA receptors: evidence of an atypical neural-glial interaction in the brainstem. J Neurosci 31:14037-45
Rogers, Richard C; McDougal, David H; Hermann, Gerlinda E (2011) Leptin amplifies the action of thyrotropin-releasing hormone in the solitary nucleus: an in vitro calcium imaging study. Brain Res 1385:47-55
Hermann, Gerlinda E; Rogers, Richard C (2009) TNF activates astrocytes and catecholaminergic neurons in the solitary nucleus: implications for autonomic control. Brain Res 1273:72-82

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