Robotic Training and the Modulation of BDNF Activity in Spinally Transected Rats

脊髓横断大鼠的机器人训练和 BDNF 活性调节

• 批准号: 7596431
• 负责人: RAY D DE LEON
• 金额: $ 28.24万
• 依托单位: CALIFORNIA STATE UNIVERSITY LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596431
• 关键词: Animals; Area; Boxing; Brain; Brain-Derived Neurotrophic Factor; Cyclic AMP-Responsive DNA-Binding Protein; Drug usage; Exercise; Family; Figs - dietary; Glutamate Receptor; Hindlimb; Human; Immunoglobulin G; In Situ Hybridization; K 252a; Label; Left; Locomotion; Locomotor Recovery; Lumbar spinal cord structure; Medial; Mediating; Messenger RNA; Motor Neurons; Motor output; Muscle; N-Methyl-D-Aspartate Receptors; NR1 gene; Neuraxis; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Pharmaceutical Preparations; Phase; Physical activity; Play; Proteins; Rattus; Recovery; Research Personnel; Right-On; Robotics; Role; Sensory; Side; Signal Transduction; Spinal; Spinal Cord; Spinal cord injury; Synapses; Synapsin I; Synaptic plasticity; Techniques; Testing; Training; Transcription factor genes; Weight-Bearing state; Work; base; calmodulin-dependent protein kinase II; experience; improved; insight; member; neural circuit; neurotransmitter release; neurotrophic factor; programs; receptor; receptor binding; research study; response; robotic device

DESCRIPTION (provided by applicant): The recovery of hindlimb stepping in complete spinally transected (ST) animals is improved by treadmill training. Little is known about the mechanisms by which treadmill training improves stepping, but our studies suggest that training enhances plasticity in the neurons of the lumbar spinal cord that generate stepping. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family and has been shown to play a crucial role in activity-dependent plasticity in the central nervous system. We propose to study the role of BDNF in activity-dependent plasticity in the spinal cord of ST rats that undergo hindlimb treadmill training. Our overall hypothesis is that endogenously-produced BDNF improves the ability of ST rats to generate hindlimb stepping by strengthening synapses within the neural circuits that control stepping. In the first experiment, we will first determine the extent that BDNF synthesis by lumbar spinal neurons is dependent on the amount of treadmill training imposed on the ST rats. We will use a robotic device that, unlike conventional treadmills, allows precise control over the amount of hindlimb activity during treadmill stepping. Using a combination of in situ hybridization and immunohistochemical techniques, we will then examine the expression of BDNF mRNA and protein, TrkB (the receptor for BDNF) and plasticity-related molecules, synapsin I, CREB, CaMKII and NMDA receptor subunits in lumbar spinal neurons following 1 day, 4 or 12 weeks of treadmill training. In our second experiment, we will selectively enhance the activity of extensor neurons in one hindlimb using the robotic device to apply a force during treadmill training. After 4 weeks, we will compare the expression of BDNF mRNA and protein to determine if the more active neurons have higher BDNF expression. In our third experiment, we will administer drugs that block BDNF activity in the spinal cord to determine if the effects of treadmill training require BDNF action. Thus, at the end of the project, we will know the extent that BDNF synthesis in lumbar spinal neurons is dependent on the levels of hindlimb activity and we will know if BDNF activity is crucial for the recovery of stepping in ST rats. These studies will provide some important insight into the mechanisms by which treadmill training improves stepping after spinal cord injury. In addition, the findings may suggest a role for activity-based strategies in neurotrophin treatments for spinal cord injury.

描述(申请人提供)：通过跑步机训练，可改善完全脊椎横断(ST)动物后肢踏步的恢复。跑步机训练改善步态的机制知之甚少，但我们的研究表明，训练增强了腰椎脊髓中产生步态的神经元的可塑性。脑源性神经营养因子(BDNF)是神经营养因子家族的一员，已被证明在中枢神经系统的活性依赖性可塑性中起着关键作用。我们建议研究脑源性神经营养因子在接受后肢跑步机训练的ST大鼠脊髓活动依赖性可塑性中的作用。我们的总体假设是，内源性产生的BDNF通过加强控制步进的神经回路中的突触来提高ST大鼠产生后肢步进的能力。在第一个实验中，我们将首先确定腰椎脊髓神经元合成BDNF的程度取决于施加在ST大鼠身上的跑步机训练量。我们将使用一种机器人设备，与传统的跑步机不同，它可以精确控制跑步机踏步过程中后肢的活动量。采用原位杂交和免疫组织化学技术相结合的方法，检测1天、4周或12周跑台训练后大鼠腰段脊髓神经元BDNF、TrkB和可塑性相关分子、突触素I、CREB、CaMKII和NMDA受体亚单位的表达。在我们的第二个实验中，我们将使用机器人设备在跑步机训练期间有选择地增强一侧后肢伸展神经元的活动。4周后，比较脑源性神经营养因子的mRNA和蛋白的表达，以确定越活跃的神经元是否有更高的脑源性神经营养因子的表达。在我们的第三个实验中，我们将给脊髓注射阻断脑源性神经营养因子活性的药物，以确定跑步机训练的效果是否需要脑源性神经营养因子作用。因此，在项目结束时，我们将知道腰椎脊髓神经元中BDNF合成的程度取决于后肢活动的水平，我们将知道BDNF活性是否对ST大鼠步态的恢复至关重要。这些研究将对跑步机训练改善脊髓损伤后步幅的机制提供一些重要的见解。此外，这一发现可能表明基于活动的策略在神经营养素治疗脊髓损伤中的作用。