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.
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.
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