Stromal cell derived factor [SDF1;also referred to as CXCL12] is a pleiotropic chemokine that is essential for the normal development of neurons and glia but also functions in the initiation of glial metastasis. Neurons and glia release SDF1 not only as part of the metastatic process but also in response to head trauma and as a result of neuroinflammatory disorders and neuroinfection. The literature suggests that profound anorexia, gastric stasis, nausea and emesis are frequent complications of CNS pathology in which SDF1 release is prominent. Our previous published work with cytokine action in the brainstem and our preliminary data suggest a central hypothesis: that SDF1 generated within the CNS causes gastrointestinal dysfunction via action on CXCR4 receptors on neuronal elements of the gastric vago-vagal reflex control circuitry in the dorsal medulla. Hormonal, cytokine and neurotransmitter inputs to these brainstem circuit elements that significantly depress digestive functions also suppress feeding behavior by acting on the same circuit elements. Thus, an understanding of SDF1 effects on digestion control circuits in the brainstem can provide insight into the mechanisms responsible for visceral afferent control of feeding behavior. We will utilize a combination of in vitro live-cell calcium imaging, in vivo neurophysiological, and behavioral approaches to generate a comprehensive view of how this important chemokine affects change in autonomic and behavioral control circuitry in the brainstem.

Public Health Relevance

Chemokines are small protein-like molecules produced by immune and neural tissues. Their release is elevated as a consequence of cancer, trauma, or infection of the brain. These disease processes are always associated with severe disruption of feeding behavior and control of digestive functions. Disruption of gastrointestinal motility, nausea, emesis, and anorexia are common features of neurodegenerative disease. Our hypothesis is that chemokines released as a function of the disease process directly affect the activity of cells in the brainstem that are responsible for essential digestion and feeding behavior control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK052142-10A1
Application #
7882123
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Hamilton, Frank A
Project Start
1997-01-15
Project End
2014-03-31
Budget Start
2010-04-15
Budget End
2011-03-31
Support Year
10
Fiscal Year
2010
Total Cost
$370,000
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
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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