SEROTONIN AND SPINAL REFLEX PLASTICITY

治疗脊髓损伤后反射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）可以有效地和可重复地促进脊髓反射数小时。 这些行动类似于持续的屈曲反射反应，伤害性刺激后，并表明初级传入和下行系统可以调节插入屈肌反射传入（FRA）途径的脊髓中间神经元的增益。“不幸的是，对FRA interneurons的了解比其他interneurons少得多。 因此，我们建议使用5-HT在FRA通路中容易诱导的增强来对控制这种众所周知的行为（屈肌撤回反射）的可塑性的网络、细胞和分子机制进行详细分析。1我们提出了5-HT诱导的反射易化中涉及的传入和中间神经元群体的特征，以检验屈肌反射传入（FRA）中间神经元优先被5-HT易化的假设。 2.伤害性刺激可激活脊髓神经元蛋白激酶C（PKC），使脊髓神经元具有持久的可塑性。 因为5-HT 2受体也激活PKC，我们建议测试的假设，5-HT 2受体介导的5-HT诱导的脊髓反射的持久促进通过激活PKC。 [3]然后，我们建议使用细胞/分子方法来识别对易化反射服务的中间神经元有选择性的“分子标记”。 我们推测，PKC γ和/或PKC β同工酶的膜转位将确定促进的中间神经元。 使用类似的技术，我们也将测试的假设，反射亢进，以下慢性脊髓损伤是由于一种新的表达组成型活性PKC同工酶。总之，这项建议将使用多学科的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应该提供对控制脊髓损伤后的反射亢进的见解，以便允许利用相同脊髓回路（例如运动）的屈曲反射和其他行为在感觉运动增益的正常范围内发挥作用。

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.