Learning Within the Spinal Cord: Clinical Implications

描述（由申请人提供）：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。在离体脊髓中的学习可以通过切断与大脑的交流来研究。横断的大鼠在一条后腿被电击时，只要腿被伸展，很快就学会了将腿保持在弯曲的位置，以最大限度地减少净电击暴露，这是一种工具性条件反射。接受与腿部位置无关的电击（不可控电击）的大鼠不学习，并且在随后进行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电击训练来预防和逆转。当受试者接受更难的反应标准测试时，仪器训练也能使他们学习。我们的假设是，器械训练使脊髓内的学习，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探讨这一假说，使用药理学技术。使用破坏BDNF功能的药物操作来评估BDNF的必要性。通过人工将BDNF应用于脊髓组织来检查是否充分。如果BDNF起着关键作用，那么破坏BDNF应该会消除器械训练的有益效果，而BDNF的应用应该会产生保护作用。初步的数据表明，训练与可控的冲击上调BDNF mRNA的表达，而不可控的刺激下调表达。目的2使用mRNA表达的测定来检查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水平和相关的信号通路。先前的工作已经表明，不可控的，但不可控的，刺激破坏脊髓挫伤后的恢复。我们概述了一种新的程序，以最大限度地提高可控刺激的有益效果，并寻求证据表明，工具训练有一个持久的影响，在挫伤模型。额外的工作将评估训练是否会影响恢复，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用于促进人类脊髓损伤后恢复的常见行为技术（功能性电刺激[FES]）的模型。通过确定关键的工具关系，以及所涉及的神经化学系统，我们希望开发出更有效的程序来促进康复。此外，旨在促进损伤处神经生长的程序需要技术来塑造神经支配的适当模式。仪器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.