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形式的学习。孤立脊髓的学习可以通过胸椎横断切断与大脑的联系来研究。横断的大鼠在一条后腿伸展时受到电击，很快就学会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。接受不依赖于腿部位置的电击（不可控电击）的大鼠不能学习，并且在随后的可控电击测试中表现出学习缺陷。这种学习缺陷可以通过可控冲击训练来预防和扭转。当受试者接受较难的反应标准测试时，工具性训练也有助于学习。我们的假设是，器械训练能够促进脊髓内的学习，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利用药理学技术探讨这一假设。通过破坏BDNF功能的药物操作来评估BDNF的必要性。通过人为地将BDNF应用于脊髓组织来检验是否充足。如果BDNF起关键作用，那么破坏BDNF就会消除工具性训练的有益效果，而BDNF的应用应该具有保护作用。初步数据表明，可控刺激训练上调BDNF mRNA表达，不可控刺激训练下调BDNF mRNA表达。目的2使用mRNA表达测定来检查这些影响的持续时间及其解剖位点。蛋白质分析将评估这种表达如何影响BDNF水平和所涉及的信号通路。先前的研究表明，不可控但不可控的刺激会破坏脊髓挫伤后的恢复。我们概述了一种新的程序，以最大限度地发挥可控刺激的有益效果，并寻求证据，证明器质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描述脊柱可塑性的机制。器械训练提供了一种常见的行为技术（功能性电刺激[FES]）的模型，用于促进人类脊髓损伤后的恢复。通过识别关键的工具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，旨在促进损伤神经生长的手术需要形成适当的神经支配模式的技术。仪器训练可以提供选择自适应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.