The experiments described in this application will determine the behavioral and anatomical sequelae of transplantation of fetal hippocampal or cerebellar tissue to the brains of adult rats suffering brain damage due to exposure to trimethyltin (TMT) a neurotoxin present in the environment. The long-term objective of this research is to refine the use of nerve cell implantation into the toxicant-damaged brain as a potential treatment for neural and behavioral dysfunction. Because the ability to use cell transplantation to normalize brain dysfunction depends to some degree on the ability of the host brain to exhibit neural plasticity another goal is to study neural plasticity endogenous to the brain of rats exposed to TMT. The first specific aim of this research is to determine the effects of four different types of fetal brain tissue transplanted into the damaged hippocampus or entorhinal cortex on behaviors disrupted by exposure to TMT. These behaviors are locomotor activity, responding on an operant task that requires low response rates, and performance in a maze. The tissue to be transplanted will be either the entire fetal hippocampus, the fetal entorhinal cortex, or anlage of pyramidal cells injected as a suspension into the adult hippocampus. In this way the ability to attenuate behavioral deficits by replacing increasingly more specific parts of the TMT-damaged hippocampal circuit will be tested. Fetal cerebellar tissue will be transplanted as a control for specificity of effect. The second specific aim of this research is to obtain as complete a description of the morphology and connectivity of the transplants as possible in order to develop hypotheses concerning the mechanism(s) of action of the transplants on neural and behavioral functioning. Both light and electron microscopy will ba used to accomplish this aim. The final specific aim of this research is to study reactive synaptogenesis (""""""""axon sprouting"""""""") produced in the cholinergic input to the hippocampus by TMT. This system will provide a model of endogenous neuroplasticity after systemic exposure to a neurotoxin. Light microscopic histochemical procedures will be used in this experiment. Completion of these experiments will provide data that will extend knowledge regarding the potential for neuroplasticity within the mammalian brain after exposure to a toxic environmental chemical and provide information concerning specificity of neural transplantation techniques in alleviating neurotoxicant-induced neural and behavioral dysfunction.
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