Learning Within the Spinal Cord: Clinical Implications

描述(申请人提供)：先前的研究表明，脊髓内的神经元可以支持一些简单的学习形式。通过胸部横断切断与大脑的联系，可以研究在分离的脊髓中的学习。当一条后腿伸展时，电击一条后腿的横断大鼠很快就会学会将腿保持在一个弯曲的位置，以最大限度地减少净电击暴露，这是一种器质性条件反射。接受与腿部位置无关的电击(不可控电击)的大鼠不学习，当稍后用可控电击测试时，表现出学习缺陷。这种学习缺陷可以通过可控的冲击训练来预防和扭转。当受试者被测试时，工具性训练也使他们能够在更难的反应标准下学习。我们的假设是，工具性训练能够在脊髓内进行学习，并具有保护作用，因为它促进了神经营养因子BDNF的合成和释放。目的1利用药理学技术探索这一假说。使用干扰BDNF功能的药物操作来评估BDNF的必要性。通过人工将BDNF应用于脊柱组织来检查其充分性。如果脑源性神经营养因子发挥了关键作用，那么阻断脑源性神经营养因子应该会消除工具性训练的有益影响，而应用脑源性神经营养因子应该会起到保护作用。初步数据表明，可控性休克训练可上调BDNF mRNA的表达，而不可控刺激则下调其表达。AIM 2使用信使核糖核酸表达的分析来检测这些效应的持续时间和它们的解剖位置。蛋白质分析将评估这种表达如何影响BDNF水平和涉及的信号通路。先前的工作表明，不可控的刺激会扰乱脊柱挫伤后的恢复。我们概述了一种新的程序，以最大限度地发挥可控刺激的益处，并寻找证据表明工具性训练在挫伤模型中具有持久的效果。额外的工作将评估训练是否影响康复，因为它促进了BDNF的释放。这项研究的长期目标是在功能和神经生物学水平上表征脊柱可塑性的机制。器械训练提供了一种常见行为技术(功能电刺激[FES])的模型，用于促进人类脊柱损伤后的康复。通过确定关键的仪器关系和涉及的神经化学系统，我们希望开发更有效的程序来促进恢复。此外，旨在促进损伤后神经生长的程序需要技术来塑造适当的神经神经支配模式。工具性训练可以提供选择适应性神经连接所需的程序。

DESCRIPTION (provided by applicant): Prior research has shown that neurons within the spinal cord can support some simple forms of learning. Learning in the isolated spinal cord can be studied by cutting communication with the brain by means of a thoracic transection. Transected rats given shock to one hind leg whenever the leg is extended soon learn to maintain the leg in a flexed position that minimizes net shock exposure, a form of instrumental conditioning. Rats that receive shock independent of leg position (uncontrollable shock) do not learn and exhibit a learning deficit when later tested with controllable shock. This learning deficit can be prevented, and reversed, by training with controllable shock. Instrumental training also enables learning when subjects are tested with a more difficult response criterion. Our hypothesis is that instrumental training enables learning within the spinal cord, and has a protective effect, because it promotes the synthesis and release of the neurotrophin BDNF. Aim 1 explores this hypothesis using pharmacological techniques. The necessity of BDNF is evaluated using drug manipulations that disrupt BDNF function. Sufficiency is examined by artificially applying BDNF to the spinal tissue. If BDNF plays a key role, disrupting BDNF should eliminate the beneficial effect of instrumental training and the application of BDNF should have a protective effect. Preliminary data suggest that training with controllable shock up-regulates BDNF mRNA expression while uncontrollable stimulation down-regulates expression. Aim 2 uses assays for mRNA expression to examine the duration of these effects and their anatomical locus. Protein assays will evaluate how this expression affects BDNF levels and the signal pathways involved. Prior work has shown that uncontrollable, but not controllable, stimulation disrupts recovery after a spinal contusion injury. We outline a novel procedure to maximize the beneficial effect of controllable stimulation and seek evidence that instrumental training has a lasting effect in a contusion model. Additional work will evaluate whether training affects recovery because it promotes the release of BDNF. The long-term goal of this research is to characterize the mechanisms that underlie spinal plasticity at both a functional and neurobiological level. Instrumental training provides a model of a common behavioral technique (functional electrical stimulation [FES]) used to foster recovery after spinal injury in humans. By identifying key instrumental relations, and the neurochemical systems involved, we hope to develop more effective procedures to promote recovery. Further, procedures designed to promote neural growth across an injury require techniques to shape the appropriate pattern of neural innervation. Instrumental training could provide the procedure needed to select adaptive neural connections.