SEROTONIN AND SPINAL REFLEX PLASTICITY

治疗脊髓损伤后的反射亢进的一个重要目标是了解控制反射增益可塑性变化的机制。最近，我们发现5-羟色胺(5-羟色胺)可以有效地和可重复地促进脊髓反射数小时。这些行为类似于伤害性刺激后的持续性屈曲反射反应，提示初级传入系统和下行系统都可以调节插入屈肌反射传入通路的脊髓中间神经元的增益。不幸的是，与其他中间神经元相比，人们对FRA中间神经元的了解要少得多。因此，我们建议利用5-羟色胺容易诱导的FRA通路的增强来对控制屈肌收缩反射这一众所周知的行为的可塑性的网络、细胞和分子机制进行详细的分析。1我们建议对参与5-羟色胺诱导的反射易化的传入和神经元间群体进行表征，以验证5-羟色胺优先促进屈肌反射传入(FRA)中间神经元的假说。2损伤诱导的伤害性刺激导致蛋白激酶C(PKC)的激活和脊髓神经元的长期可塑性。由于5-HT2受体也激活PKC，我们建议验证5-HT2受体通过激活PKC介导5-HT2诱导的长时间脊髓反射易化的假说。3然后，我们建议使用细胞/分子方法来识别对服务于易化反射的中间神经元具有选择性的“分子标记”。我们假设，PKCGamma和/或PKCepsilon同工酶的膜易位将识别促进的中间神经元。使用类似的技术，我们还将检验这一假设，即慢性脊髓损伤后的反射亢进是由于一种新的结构性活性PKC同工酶的表达。总之，这项建议将使用多学科方法来描述一种新发现的脊髓反射通路中的可塑性形式。来自这些研究的信息应该为控制脊髓损伤后的反射亢进提供洞察力，以便屈曲反射和其他利用相同脊髓回路的行为(例如运动)可以在正常的感觉-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.