CONTROL OF GI ELIMINATIVE REFLEXES AFTER SPINAL INJURY

我们在之前的研究中已经表明，来自中缝隐核（nRO）和副巨细胞外侧核（lPGi）的纤维与支配外肛门括约肌（EAS MNs）的运动神经元接触。nRO及其神经递质之一5-羟色胺（5-HT）可能抑制EAS的反射活性。脊髓病变或nRO病变导致EAS过度活跃，类似于脊髓损伤（SCI）后人类的痉挛。我们知道脊髓局部病变后，大鼠脊髓损伤模型的消除功能逐渐改善，EAS的高反射性下降。由于5-羟色胺已被证明在脊髓病变后会出现，我们认为，阻断进入EAS运动核或脊髓其他区域的5-羟色胺输入，会导致下行控制下的反射释放，而功能的改善与来自脑干的下行纤维的连接重建有关。我们将使用一些相关的措施来评估发芽和5-羟色胺在脊髓损伤后恢复中的作用。EAS高反射及其下降将与标准化运动结果测量一起测量。5-HT纤维的发芽将在含有产生EAS收缩的MNs的脐带核中进行解剖学测量。脑干纤维（nRO和lPGi）将被标记为顺行示踪剂，它们的项目将被量化以测试发芽。nRO刺激和5-HT激动剂/拮抗剂对正常和脊髓损伤大鼠EAS反射的影响将被测试。5-羟色胺纤维增加在恢复过程中的作用将通过确定去除或阻断5-羟色胺输入是否会恢复高反射性，以及通过确定轴突的增加和反射活动的减少是否与nRO刺激脊髓中释放的5-羟色胺增加相关来测量。综上所述，这些对中心假设的趋同性检验应该强烈肯定或否认5-HT在脊髓损伤后消除反射功能变化中的作用。将考虑其他下降系统可能起的作用。总之，这些结果可能会导致鉴定出能够增强人类脊髓损伤后消除功能的药物。

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.