We have shown in the previous grant period that fibers from the nucleus raphe obscurus (nRO) and nucleus paragigantocellularis lateralis (lPGi) contact the motoneurons that innervate the external anal sphincter (EAS MNs). The nRO and one of its neurotransmitters, serotonin (5-HT) may inhibit reflex activity of EAS. Spinal cord lesions, or lesions of the nRO result in hyperactivity of the EAS, similar to the spasticity seen in man after spinal cord injury (SCI). We know that after partial lesions of the cord, eliminative function gradually improves in our rat SCI model, and the hyperreflexia of the EAS declines. Since 5-HT has been shown to sprout after spinal cord lesions, we propose that the disruption of 5-HT inputs into the EAS motor nucleus or other regions of the cord, results in the release of the reflex from descending control, and that improvement in function is related to the re-establishment of connections that come from spared descending fibbers from the brainstem. We will use a number of interrelated measures to assess the role of sprouting and 5-HT on recovery after SCI. EAS hyperreflexia and its decline will be measured along with a standardized locomotor outcome measure. Sprouting of 5-HT fibers will be measured anatomically in the cord nuclei containing the MNs that produce EAS contractions. Fibers from the brainstem (nRO and lPGi) will be labeled with anterograde tracers and their projects will be quantified to test for sprouting. The effects of nRO stimulation and 5-HT agonists/antagonists on EAS reflexes will be tested in normal and spinal injured rats. The role of putative increases in 5-HT fibers in the recovery process will be measured by determining whether removal or blockade of 5-HT input reinstates hyperreflexia, and by determining whether increases in axons, and decreases in reflex activity, are correlated with an increased in the 5- HT released in the spinal cord by nRO stimulation. Together, these convergent tests of the central hypothesis should yield strong affirmation or denial of the role of 5-HT in changes in eliminative reflex function after SCI. The possible role of other descending systems will be considered. Together, the results may lead toward the identification of drugs that can enhance eliminative function after SCI in man.
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