The mechanisms influencing the capacity of the olfactory nerve for ongoing replacement of olfactory sensory neuron axons is not well understood. Recent data, from our labs and others, emphasize the role of the glia that wrap axon fascicles in the nerve, the olfactory ensheathing cells/glia (OECs). We showed previously that OECs support axon outgrowth, described some of their basic molecular properties, and demonstrated their effectiveness as a transplant strategy in spinal cord injury. In the current application we propose a series of studies to examine mechanisms of communication among OECs and between the axons and OECs. Glia-neuron interactions being described elsewhere in the nervous system provide a mechanism for coordinating and synchronizing activity. In the olfactory pathway, neuron-glia interactions could provide a strategy for governing the release of growth factors or other molecules that may contribute to the trophic effect of OECs on axon extension. To pursue this overarching hypothesis we propose a series of 3 aims. First, we will test the hypothesis that glutamate mechanisms, including glutamate receptors and/or transporters, are expressed by the OECs. We will also quantify gap junction protein expression and their distribution in this pathway. Finally, the effects of synchronized loss and replacement of axons on these properties will be examined. Second, the basic biophysical properties of OECs and their response to glutamate released by axons has not been studied. Our preliminary data suggest a dynamic interaction may occur and that the OECs can support transient membrane currents in response to gluatamate. We will pursue this finding while also determining if these properties change during degenerative/regenerative events. Third, the mechanisms of OEC proliferation/turnover are unknown but may also be subject to influences from the olfactory nerve;there is preliminary data suggesting that OECs may increase proliferation during axon (re)generation raising the hypothesis that the ratio of OECs:axons may be a determinant of recovery. Collectively, these studies will have a significant impact on our understanding of the mechanisms of cell turnover and axon growth in the olfactory pathway;information critical to the treatment of patients with traumatic injury to the olfactory nerve as well as to the proposed use of OECs as a treatment strategy in spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007880-05
Application #
7860388
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Davis, Barry
Project Start
2006-07-01
Project End
2012-10-31
Budget Start
2010-07-01
Budget End
2012-10-31
Support Year
5
Fiscal Year
2010
Total Cost
$296,897
Indirect Cost
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Rodriguez-Gil, Diego J; Hu, Wilbur; Greer, Charles A (2013) Dishevelled proteins are associated with olfactory sensory neuron presynaptic terminals. PLoS One 8:e56561
Miller, Alexandra M; Treloar, Helen B; Greer, Charles A (2010) Composition of the migratory mass during development of the olfactory nerve. J Comp Neurol 518:4825-41
Rela, Lorena; Bordey, Angelique; Greer, Charles A (2010) Olfactory ensheathing cell membrane properties are shaped by connectivity. Glia 58:665-78
Miller, Alexandra M; Maurer, Lydia R; Zou, Dong-Jing et al. (2010) Axon fasciculation in the developing olfactory nerve. Neural Dev 5:20
Imamura, Fumiaki; Greer, Charles A (2009) Dendritic branching of olfactory bulb mitral and tufted cells: regulation by TrkB. PLoS One 4:e6729