Learning Within the Spinal Cord: Clinical Implications

脊髓内的学习：临床意义

• 批准号: 7354777
• 负责人: James William Grau
• 金额: $ 35.07万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354777
• 关键词: Address; Adverse effects; Affect; Arts; Attenuated; Behavior Therapy; Behavioral; Behavioral Model; Biological Assay; Biological Models; Brain; Brain-Derived Neurotrophic Factor; Cellular Assay; Chest; Clinic; Clinical; Cognitive Therapy; Communication; Complement; Confocal Microscopy; Contusions; Coupled; Couples; Coupling; Data; Development; Drug usage; Effectiveness; Electric Stimulation; Environment; Enzyme-Linked Immunosorbent Assay; Equipment; Exercise; Exhibits; Exposure to; FPS-FES Oncogene; Fiber; Fostering; Goals; Grant; Hindlimb; Hippocampus (Brain); Human; Immunoglobulin G; In Situ Hybridization; Injury; Intractable Pain; Laboratories; Learning; Leg; Limb structure; Localized; Long-Term Potentiation; Mediating; Modeling; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Numbness; Operant Conditioning; Operative Surgical Procedures; Outcome; Paralysed; Patients; Pattern; Pharmacological Treatment; Physiological; Play; Positioning Attribute; Procedures; Proteins; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Relative (related person); Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Shapes; Shock; Signal Pathway; Spinal; Spinal Cord; Spinal Cord Plasticity; Spinal Injuries; Spinal cord injury; Stream; System; Techniques; Testing; Therapeutic Effect; Time; Tissues; Training; Translating; Treatment Effectiveness; Treatment Protocols; Western Blotting; Work; behavioral pharmacology; clinically significant; design; innovation; mRNA Expression; nerve supply; neural growth; neurobiological mechanism; neurochemistry; neurotrophic factor; novel; prevent; programs; protective effect; relating to nervous system; response

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.

描述（由申请人提供）：先前的研究表明，脊髓中的神经元可以支持一些简单的学习形式。可以通过通过胸腔横切来切割与大脑的通讯来研究孤立的脊髓中的学习。每当腿伸展时，横向大鼠都会对一条后腿进行冲击，以便很快学会将腿保持在弯曲的位置，以最大程度地减少净冲击曝光，这是一种器乐调节的一种形式。与腿部位置无关的震动（无法控制的冲击）的大鼠在以后进行可控的冲击测试时不会学习和表现出学习缺陷。可以通过可控制的冲击训练来防止和逆转这种学习不足。工具培训还可以在测试受试者时以更困难的响应标准进行学习。我们的假设是，工具训练可以在脊髓中学习，并具有保护作用，因为它促进了神经营养蛋白BDNF的合成和释放。 AIM 1使用药理学技术探讨了这一假设。使用破坏BDNF功能的药物操作评估BDNF的必要性。通过人为地将BDNF应用于脊柱组织来检查足够。如果BDNF起关键作用，那么破坏BDNF应消除仪器培训的有益效果，而BDNF的应用应具有保护作用。初步数据表明，可控休克的训练上调BDNF mRNA表达，而无法控制的刺激下调表达。 AIM 2使用测定mRNA表达来检查这些作用的持续时间及其解剖基因座。蛋白质测定将评估该表达如何影响BDNF水平和涉及的信号途径。先前的工作表明，无法控制但不可控制的刺激破坏了脊柱挫伤后的恢复。我们概述了一种新的程序，以最大程度地提高可控刺激的有益效果，并寻求证据表明工具训练在挫伤模型中具有持久作用。其他工作将评估培训是否会影响恢复，因为它促进了BDNF的释放。这项研究的长期目标是表征在功能和神经生物学水平上脊柱可塑性构成的机制。仪器训练提供了用于促进人类脊柱损伤后恢复的常见行为技术（功能电刺激[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，我们希望制定更有效的程序来促进恢复。此外，旨在促进跨损伤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。乐器训练可以提供选择自适应神经连接所需的过程。