Maladaptive Plasticity in Spinal Cord Injury: Cellular Mechanisms

项目摘要/摘要 脊髓损伤(SCI)会产生一种毁灭性的综合征，其特征是运动功能障碍，反射亢进， 痉挛和神经源性疼痛。脊髓损伤治疗的长期目标是促进脊髓损伤的适应性可塑性 在限制适应不良可塑性的同时恢复功能，导致反射亢进、痉挛和 顽固性疼痛。最近的研究表明，适应性和非适应性中枢神经系统的可塑性都可以发生在 脊髓的水平指示功能恢复的水平。然而，促进的具体条件 脊髓损伤的适应性和非适应性脊柱可塑性还没有被很好地理解。这一点的中心假设是 R01是脊髓可塑性是由脊髓损伤急性期异常的外周刺激所形成的。 对不适应形式的可塑性。这一假设具有很强的临床/翻译相关性，因为 流行病学研究表明，周围损伤和早期肢体停用是儿童常见的并存疾病 人体SCI。在到I级创伤中心就诊的SCI患者中，高达85%的人在 除了对中枢神经系统的损害。初步数据显示，外周伤害性刺激传递 完全性脊髓损伤的尾部会产生适应不良的脊柱可塑性，表现为触觉反射亢进。 和痉挛。在脊髓损伤以下的周围神经损伤或强迫后肢停用中也观察到了类似的效果， 在脊髓横断伤和挫伤模型中也是如此。我们的发现将这些影响与体内特定的改变联系在一起 谷氨酸受体介导的脊髓前角突触可塑性，提供了一个新的治疗靶点 以恢复脊髓损伤后的功能。R01的目的是在初步数据的基础上进行扩展：1)测试 脊髓损伤下异常伤害性刺激的机制基础(目标1)，2)评估是否相似 影响发生在异常本体感觉刺激驱动脊髓中枢神经元亢进 反射/痉挛(目标2)，以及3)测试对抗适应不良可塑性的新目标，以促进适应 利用转录和转基因技术恢复脊髓损伤(目标3)。拟议中的项目具有 在多发性创伤性脊髓损伤中形成急性神经元活动的意义--一种普遍的临床表现 中枢神经系统损害伴有外周损伤和卧床时间延长。

PROJECT SUMMARY/ABSTRACT Spinal cord Injury (SCI) produces a devastating syndrome characterized by motor dysfunction, hyper-reflexia, spasticity, and neurogenic pain. The long-term goal of SCI therapy is to promote adaptive plasticity for restoration of function while limiting maladaptive plasticity that results in hyper-reflexia, spasticity and intractable pain. Recent research has indicated that both adaptive and maladaptive CNS plasticity can occur at the level of the spinal cord to dictate recovery of function. However, the specific conditions that promote adaptive versus maladaptive spinal plasticity in SCI are not well-understood. The central hypothesis of this R01 is that spinal cord plasticity is shaped by aberrant peripheral stimulation in the acute phase of SCI that tips plasticity toward a maladaptive form. This hypothesis has strong clinical/translational relevance, as epidemiological studies indicate that peripheral injuries and early limb disuse are prevalent comorbidities in human SCI. Up to 85% of SCI individuals presenting to level I trauma centers have peripheral injuries in addition to CNS damage. Preliminary data demonstrate that peripheral nociceptive stimulation delivered caudal to a complete SCI lesion produces maladaptive spinal plasticity that manifests as tactile hyper-reflexia and spasticity. Similar effects are observed with peripheral nerve injury or forced hindlimb disuse below SCI, and in both transection SCI and contusion SCI models. Our findings link these effects to specific alterations in glutamate receptor-mediated synaptic plasticity in the spinal ventral horn, providing a novel therapeutic target for restoration of function after SCI. The Aims of this R01 expand on the preliminary data to: 1) test mechanistic underpinnings of aberrant nociceptive stimulation below SCI (Aim 1), 2) evaluate whether similar effects occur with aberrant proprioceptive stimulation driving spinal cord central neuronal hyper- reflexia/spasticity (Aim 2), and 3) test new targets for combating maladaptive plasticity to promote adaptive recovery in SCI using transcriptomic and transgenic technologies (Aim 3). The proposed project has implications for shaping acute neuronal activity in polytraumatic SCI—a prevalent clinical presentation where CNS lesions are accompanied with peripheral injuries and protracted bedrest.