ACTIVITY REFINES CORTICOSPINAL TERMINATIONS

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的出生后发育的潜在机制。在目前的资助期间，我们发现，CS终端可以激活脊髓神经元早期在出生后的发展，系统的肢体运动功能表达之前，从发展到功能的过渡涉及CS突触后反应的强烈促进。我们发现，没有活动或正常的肢体使用，CS轴突开发一个异常的投影模式和他们的终端有较少的分支和静脉曲张比正常。这些受损的轴突几乎没有或没有能力在发育后期重新生长失去的终止。缺乏补偿并不是因为轴突生长只有一个短暂的窗口（即，关键期），因为我们发现CS轴突终末通常能够在发育后期大量生长。我们的研究表明，CS系统的活动和前肢的使用从根本上改变了CS轴突终末的分布和形态，这是由内在的脊髓神经营养因子和指导线索建立到成熟的模式。我们还发现，通过刺激脊髓锥体中的轴突来增强CS活性，可以促进发育中的CS末端的生长，并增强它们与脊髓神经元竞争突触的能力。这一发现不仅是重要的CS系统的发展机制的理解，但也提出了一种方法来利用活动依赖的过程来重塑CS系统的发展实验。本申请具有三个目的。首先，我们将确定如何活动修改的解剖和生理特征的CS突触与脊髓神经元在出生后的早期发展。其次，我们将确定不同的贡献神经营养和活动依赖性的相互作用，在发展的地形分布和形态的CS终端。第三，我们将开发方法，以提高长期生存的CS终止已促进出生后早期刺激，并确定其激活脊髓运动回路的能力。 通过这些实验，我们希望能够深入了解皮质脊髓系统的早期发育如何为其以后的运动控制功能奠定基础。通过这种理解，我们希望了解如何避免围产期对CS系统的损害，这通常会导致脑瘫。

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.