During the previous funding period we demonstrated that diverse chemokine receptors are expressed by many cell types in the nervous system including neurons in both the central and peripheral nervous systems. Chemokine receptor expression is widespread in both the adult and during embryonic development. Chemokines appear to serve many roles both during development and in the adult. One of these appears to be coordinating the migration and proliferation of neural stem/progenitor cells. In keeping with this proposal we demonstrated that the chemokine SDF-1 and its receptor CXCR4 were important in the formation of both the dentate gyrus of the hippocampus and the dorsal root ganglia. We also demonstrated that neural progenitor cells cultured from both the embryonic and adult brain expressed a wide variety of chemokine receptors. In the current proposal we shall further investigate the role of chemokines in the regulation of neural progenitor cell function in the adult brain. We will attempt to demonstrate that the chemokine SDF-1 can be released from dentate granule neurons in an activity dependent manner and influence both synaptic transmission as well as the development of neural progenitor cells in the subgranular zone of the dentate gyrus. In addition, we will also attempt to demonstrate that chemokines are responsible for the """"""""homing"""""""" of neural progenitor cells to diseased areas of the brain in animal models of HIV-1 related dementia.. In order to achieve these aims we will perform studies using cultured hippocampal slices, electrophysiology, confocal microscopy and animal models of HIVE. It is likely that the results of these experiments will be of importance for our understanding of the mechanisms that control neurogenesis in the brain. Furthermore the CXCR4 chemokine receptor has frequently been shown to be involved in these effects, it is likely that HIV-1 may interfere with neurogenesis and that this may contribute to the neuropathological effects of the virus.
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