ACTIVITY REFINES CORTICOSPINAL TERMINATIONS

活动改善皮质脊髓终止

• 批准号: 6970108
• 负责人: John H Martin
• 金额: $ 35.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970108
• 关键词: axon; behavior test; behavioral /social science research tag; cats; confocal scanning microscopy; developmental neurobiology; early experience; electron microscopy; immunocytochemistry; limb movement; microelectrodes; motor cortex; neuronal transport; neuropharmacology; neurotrophic factors; psychomotor function; pyramidal tracts; sensorimotor system; spinal cord; synapses; synaptogenesis

DESCRIPTION (provided by applicant): Our overall goal is to identify the mechanisms underlying postnatal development of connectional specificity and function in the corticospinal (CS) system. During the present funding period we found that CS terminals can activate spinal neurons early during postnatal development, before the system's limb motor functions are expressed, and that the transition from development to function involves strong facilitation of CS postsynaptic responses. We found that without activity or normal limb use, CS axons develop an anomalous projection pattern and their terminals have fewer branches and varicosities than normals. These impaired axons have little or no capacity to re-grow lost terminations later in development. The lack of compensation is not because there is only a brief window for axon growth (i.e., critical period), since we found that CS axon terminals normally are capable of abundant growth later in development. Our studies show that CS system activity and forelimb use radically transform the distribution and morphology of CS axon terminals, which is established by intrinsic spinal neurotrophic factors and guidance cues, into the mature pattern. We also found that augmenting CS activity by stimulating axons in the medullary pyramid promotes the growth of developing CS terminations and enhances their capacity to compete for synapses with spinal neurons. This finding not only is important for understanding the mechanisms of CS system development but also presents a way to harness activity-dependent processes to re-shape CS system development experimentally. The present application has 3 aims. First, we will determine how activity modifies the anatomical and physiological characteristics of the CS synapse with spinal neurons during early postnatal development. Second, we will determine the differential contributions of neurotrophic and activity-dependent interactions in developing the topographic distribution and morphology of CS terminations. Third, we will develop ways to enhance the long-term survival of CS terminations that have been promoted by early postnatal stimulation and to determine their capacity to activate spinal motor circuits. With these experiments we expect to gain insight into how early development of the corticospinal system sets the stage for its motor control functions later in life. Through this understanding we hope to learn how perinatal damage to the CS system, which typically produces cerebral palsy, can be averted.

描述（由申请人提供）：我们的总体目标是确定皮质脊髓（CS）系统中连接特异性和功能产后发展的基础机制。在目前的资金期间，我们发现CS终端可以在产后发育期间早期激活脊柱神经元，然后在系统的肢体运动功能表达之前，并且从发育到功能的过渡涉及强大的促进CS突触后反应。我们发现，如果没有活性或正常的肢体使用，CS轴突就会发展出异常的投影模式，其末端的分支和静脉曲张比正常性较少。这些受损的轴突几乎没有或没有能力重新生长在后来发展的终止。缺乏补偿不是因为轴突生长（即关键时期）只有一个简短的窗口，因为我们发现CS轴突终端通常能够在后来发育中具有丰富的生长。我们的研究表明，CS系统活性和前肢使用从根本上将CS轴突末端的分布和形态转化为固有的脊柱神经营养因子和指导线索，从而将其建立为成熟的模式。我们还发现，通过刺激髓质金字塔中的轴突来增强CS活性会促进开发CS终止的生长，并增强其与脊柱神经元争夺突触的能力。这一发现不仅对于理解CS系统开发的机制很重要，而且还提出了一种利用活动依赖性过程以通过实验重新塑造CS系统开发的方法。本应用程序有3个目标。首先，我们将确定活性如何修饰产后早期发育期间CS突触与脊柱神经元的解剖学和生理特征。其次，我们将确定神经营养和活动依赖性相互作用在开发CS终止的地形分布和形态方面的差异贡献。第三，我们将开发方法来增强CS终止的长期存活，这些终止是通过早期产后刺激促进的，并确定它们激活脊柱运动电路的能力。 通过这些实验，我们希望深入了解皮质脊髓系统的早期发展如何为其运动控制功能奠定了阶段。通过这种理解，我们希望了解如何避免对通常产生大脑麻痹的CS系统的围产期损害。