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内的神经元可以支持一些简单形式的学习。可以通过胸椎横断切断与大脑的通讯来研究孤立脊髓的学习情况。每当一条后腿伸展时，横断的老鼠就会受到电击，很快就会学会将腿保持在弯曲位置，从而最大限度地减少净电击暴露，这是一种工具调节的形式。接受与腿部位置无关的电击（无法控制的电击）的大鼠不会学习，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休克训练来预防和逆转。当受试者接受更困难的反应标准测试时，仪器训练还可以使学习成为可能。我们的假设是，乐器训练能够促进脊髓内的学习，并具有保护作用，因为它促进神经营养蛋白 BDNF 的合成和释放。目标 1 使用药理学技术探索这一假设。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 应用于脊柱组织来检查充足性。如果 BDNF 发挥关键作用，那么破坏 BDNF 就会消除器械训练的有益效果，而 BDNF 的应用应该具有保护作用。初步数据表明，可控电击训练会上调 BDNF mRNA 表达，而不可控制的刺激会下调表达。目标 2 使用 mRNA 表达分析来检查这些效应的持续时间及其解剖位置。蛋白质检测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，无法控制但又无法控制的刺激会扰乱脊髓挫伤后的恢复。我们概述了一种新颖的程序，以最大限度地发挥可控刺激的有益效果，并寻求器械训练对挫伤模型具有持久效果的证据。额外的工作将评估训练是否会影响恢复，因为它会促进 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（功能性电刺激 [FES]）模型，用于促进人类脊柱损伤后的恢复。通过确定关键的工具关系和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，旨在促进损伤后神经生长的手术需要塑造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。