NEUROACTIVE SUBSTANCES, MOTONEURONS, AND ALS

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Neurotransmitter abnormalities have been considered in the probable etiology of ALS. Our conceptual position as to how neuroactive substances (neurotransmitters and neuromodulators) may be involved is that these substances (especially the neuropeptides) in neurons presynaptic to motoneurons may have "trophic" effects on the motoneuron, and selective loss of some of the presynaptic neurochemical systems may be the predisposing factor in the development of ALS. However, little is known about neuroactive substances contained within motoneurons or in neural systems innervating motoneurons. The proposed study principally aims at identifying the neuroactive substances, in particular neuropeptides and other neuromodulatory agents that are associated with spinal motoneurons in the monkey and human. Light microscopic immunohistochemical techniques will be employed to localize a wide range of neuroactive substances in all motoneuron columns of the human and monkey spinal cord. From such studies it will be ascertained if there are any significant differences in the patterns of distribution of neurochemicals in spinal motoneuron groups susceptible to motoneuron degeneration (e.g. Onuf's nucleus and phrenic nucleus) as compared to non-susceptible groups of motoneurons. Electron microscopic immunohistochemical analyses will determine the ultrastructural localization of neuroactive substances in various motoneuron columns, and the relationship of immunoreactive structures to motoneurons. The co-existence of neuroactive substances within terminals will be explored by double labeling immunocytochemical methods. Our conceptual position will be evaluated in part by studying the distribution of neuropeptides and monoamines in spinal cord tissue from deceased ALS patients.