Our aim is to understand the role that serotonin ((5-HT) plays in the development of the architecture of the primary somatosensory cortex (S-I). Dense 5-HT immunoreactivity exactly matches the distribution of thalamocortical afferents in developng S-I for about the first two weeks of life and recent results from our laboratory have shown that more than 90% depletion of 5-HT from the developing cortex is assiciated with a 30% to 50% reduction in the cross-sectional areas of hte patches of thalamocortical axon arbors representing the mystacial vibrissae. This reduction is not associated with any significant decrease in either brain weight, cortical weight, or cortical volume. The experiments comprising this application will define the effects of 5-HT depletion and elevation on the morphology of individual thalamocortical axons and test a potential mechanism underlying this phenomenon. Our working hypothesis is that 5-HT influences thalamocortical development by acting at 5-HT 1B receptors located located on the terminals of thalamic axons to presynaptically inhibit thalamocortical synaptic transmission. This action modulates activity-dependent processes involved in the elaboration of thalamocortical axon arbors. If thalamocortical transmission is altered by abnormally high or low 5-HT levels in the developing cortex, it will interfere with the normal organization of these axons. We will test this hypothesis by answering the following questions; 1) How do increases or decreases in 5- HT levels in the developing cortex influence the arbors of individual thalamocortical axons: We will ansere this question by decreasing 5-HT levels in the developing cortex via systemic administration of the toxin 5,7-DHT and increasing levels of this amine by application of ELVAX implants impregnated with 5-HT to the developing cortex. Individual thalamocortical axons will be labelled with Di-I and reconstructed with a connfocal scanning laser microscope (CSLM). 2) Are the effects of increased 5-HT levels upon thalamocortical axon arbors mimicked by blocking activity with tetrodotoxin (TTX) and are the effects of decrease d 5-HT levels blocked by tetrodotoxin (TTX)? If increased 5-HT levels cause a reduction in the focussing of thalamocortical axon arbors and this effect is activity dependent, it should also be observed when thalamocortical activity is is disrupted with TTX. We will answer this question by applying TTX-impregnated ELVAX implant to the developing cortex, labelling thalamocortical axon with Di-I and reconstructing these fibers using the (CSLM). We will also combine TTX application with 5-HT depletion. If the effects observed whtn 5-HT is depleted from the developing cortex depend on enhancement of activity, then they should be blocked by co-administration of TTX. 3) Can 5-HT modify acitivity in the developing cortex: This proposal will be tested in a series of in vivo and in vitro recording experiments.
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