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 #
5R01DK052142-12
Application #
8241068
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
2012-04-01
Budget End
2013-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$304,029
Indirect Cost
$98,604
Name
Lsu Pennington Biomedical Research Center
Department
None
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
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; 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
Rogers, Richard C; Hermann, Gerlinda E (2008) Mechanisms of action of CCK to activate central vagal afferent terminals. Peptides 29:1716-25
Hermann, Gerlinda E; Rogers, Richard C (2008) TNFalpha: a trigger of autonomic dysfunction. Neuroscientist 14:53-67
Hermann, Gerlinda E; Van Meter, Montina J; Rogers, Richard C (2008) CXCR4 receptors in the dorsal medulla: implications for autonomic dysfunction. Eur J Neurosci 27:855-64
Rogers, Richard C; Van Meter, Montina J; Hermann, Gerlinda E (2006) Tumor necrosis factor potentiates central vagal afferent signaling by modulating ryanodine channels. J Neurosci 26:12642-6
Hermann, Gerlinda E; Barnes, Maria J; Rogers, Richard C (2006) Leptin and thyrotropin-releasing hormone: cooperative action in the hindbrain to activate brown adipose thermogenesis. Brain Res 1117:118-24

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