This application seeks funds for the continuation of a project aimed at studying the biological signals that induce a reactive state in astrocytes in vivo. The model system that has been exploited during the current funding period is primarily the hippocampal formation of the rat. Astrocytic responses are induced by lesions, either surgical (aspiration of entorhinal cortex) or electrical (seizures or spreading depression). The response that has been measured is the up-regulation of GFAP and GFAP mRNA. During the current funding period, the principal investigator has determined that electrolytic brain lesions lead to an astrocytic response, measured as a marked increase in GFAP.This increase is not attenuated by blocking all neuronal activity in the affected area (by injection of TTX), and the TTX block alone has no effect. At the same time """"""""intense stimulation"""""""" of entorhinal cortex (i.e., electrical activity) does lead to a modest increase in GFAP. The timing of the increase has been studied in detail as has its unilateral vs. bilateral nature. The role of """"""""diffusible gliotrophic substances"""""""" has been studied by placing gel plegets directly on the cerebral cortex of experimental animals. Pledgets that have been pretreated with saline (controls) induce no response. By contrast, the experimental gels that had undergone a 24 hr incubation in a lesion induced cavity in a donor rat induced a substantial GFAP response. The role of degeneration debris in stimulating astrocytic responses was measured in a clever system, the Ola mouse strain (an inbred strain in which Wallerian degeneration occurs on a much delayed time course). The GFAP response in the denervated region was delayed by the same degree as the degeneration. The role of high [K+] in the GFAP induction was investigated by putting K+-gelfoam on the cortex and getting a huge response. There was an increase in cerebral cortex as well, but on a slower time base. In each, the extent of the GFAP rise was related to whether the resulting seizures were accompanied by spreading depression.The sprouting of cholinergic afferents, a normal part of the hippocampal response to entorhinal cortex lesions was blocked by seizures induced in the early post-lesion period.
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