SEROTONIN AND SPINAL REFLEX PLASTICITY

治疗脊髓损伤后的反射性亢进的一个重要目的是了解控制反射增益可塑性改变的机制。最近，我们发现5-羟色胺（5-HT）可以有效且可重复地促进脊髓反射数小时。这些动作类似于伤害性刺激后的持续屈曲反射反应，表明初级传入和下行系统都可以调节屈曲反射传入（FRA）通路中插入的脊髓中间神经元的增益。“不幸的是，人们对FRA中间神经元的了解比其他中间神经元要少得多。”因此，我们建议利用5-HT在FRA通路中易于诱导的增强，对控制屈肌退缩反射这一众所周知行为可塑性的网络、细胞和分子机制进行详细分析。我们提出表征参与5-HT诱导的反射促进的传入和间神经元群，以验证屈肌反射传入（FRA）中间神经元优先被5-HT促进的假设。损伤诱导的有害刺激导致蛋白激酶C （PKC）的激活和脊髓神经元的持久可塑性。由于5-HT2受体也激活PKC，我们提出验证5-HT2受体通过激活PKC介导5- ht诱导的脊髓反射持久促进的假设。然后，我们建议使用细胞/分子方法来识别选择性服务于促进反射的中间神经元的“分子标记”。我们假设pkcγ和/或PKCepsilon同工酶的膜易位将识别易化的中间神经元。使用类似的技术，我们还将验证慢性脊髓损伤后的高反射是由于组成活性PKC同工酶的新表达的假设。总之，本建议将采用多学科方法来表征脊髓反射通路中新发现的可塑性形式。从这些研究中获得的信息将为控制脊髓损伤后的高反射提供见解，以便屈曲反射其他利用相同脊髓回路的行为（例如运动）在正常的感觉-运动增益范围内发挥作用。

An important objective in the treatment of the hyperreflexia that follows spinal cord injury is to understand the mechanisms that control plastic alterations in reflex gain. Recently, we have discovered that serotonin (5-HT) can potently and reproducibly facilitate spinal reflexes for hours. These actions resemble persistent flexion reflex responses seen following nociceptive stimuli, and suggest that both primary afferents and descending systems can modulate the gain of the spinal interneurons interposed in flexor reflex afferent (FRA) pathways. "Unfortunately, much less is known about the FRA interneurons than other interneurons". Hence, we propose to use the easily- inducible augmentation in FRA pathways by 5-HT to undertake a detailed analysis of the network, cellular, and molecular mechanisms controlling plasticity of this well known behavior, the flexor withdrawal reflex. 1 We propose to characterize the afferent and interneuronal populations involved in the 5-HT-induced reflex facilitation to test the hypothesis that the flexor reflex afferent (FRA) interneurons are preferentially facilitated by 5-HT. 2 Injury- inducing noxious stimuli lead to the activation of protein kinase C (PKC) and a long-lasting plasticity in spinal neurons. Because 5-HT2 receptors also activate PKC, we propose to test the hypothesis that 5-HT2 receptors mediate the 5-HT-induced long- lasting facilitation of spinal reflexes via activation of PKC. 3 We then propose to use cellular/molecular approaches to identify `molecular markers' selective to interneurons serving facilitated reflexes. We hypothesize that membrane translocation of the PKCgamma and/or PKCepsilon isozymes will identify the facilitated interneurons. Using similar techniques, we will also test the hypothesis that the hyperreflexia that follows chronic spinal cord injury is due to a novel expression of constitutively active PKC isozymes. In summary, this proposal will use a multidisciplinary approach to characterize a newly-discovered form of plasticity in spinal cord reflex pathways. Information derived from these studies should provide insights into controlling the hyperreflexia that follows spinal cord injury so that the flexion reflex other behaviors that utilize the same spinal circuitry (e.g. locomotion) are allowed to function within a normal range of sensori-motor gain.