PREVENTION OF DENDRITIC ATROPHY AFTER MOTONEURON INJURY

描述（由申请人提供）：神经退行性疾病或神经损伤可导致脊髓运动神经元的丧失。然而，在这种损伤后，剩余的运动神经元表现出各种形态和功能变化。由于一些运动神经元的丧失和其他剩余运动神经元的继发性变化，功能恢复很差，并且恢复的时间过程充其量是延长的。动物模型的发展，例如涉及直接脊髓损伤或周围神经损伤，已经开始为运动神经元病理和潜在治疗方法的机制提供线索。我们的工作将集中在运动神经元树突上，它对信息的接收和整合至关重要。神经损伤或相邻运动神经元死亡后运动神经元的树突萎缩，防止运动神经元的萎缩或促进其恢复，对脊髓功能的恢复具有重要影响。我们已经开始在成年大鼠脊髓中开发两种模型，利用诱导运动神经元死亡或周围神经切断，这将使我们能够研究预防或加速剩余运动神经元树突状萎缩的潜在方法。在我们的第一个模型中，我们发现邻近运动神经元的死亡会导致剩余运动神经元的树突树突萎缩，但类固醇激素的操纵，特别是睾丸激素，可以防止或逆转这种萎缩。使用形态学方法，我们将确定睾酮和树突保护是否存在剂量/效应关系，如果存在，则确定所需的最低睾酮量。我们还将使用电生理方法测试这些操作所产生的功能恢复程度。使用形态学方法，我们将确定是否存在保护树突萎缩治疗窗口的临界时间限制，以及雄激素是否会阻止或加速树突萎缩的恢复。在我们的第二个模型中，我们发现睾酮与脑源性神经营养因子（BDNF）在预防周围运动神经切断后树突萎缩方面具有相互作用。我们将利用原位杂交和免疫组织化学技术来测试BDNF在肌肉或运动神经元或其受体中的表达是否可以受到雄激素的调节。总之，使用这两种模型的研究结果将为类固醇激素在治疗脊髓疾病或神经损伤中的治疗作用提供信息。

DESCRIPTION (provided by applicant): Neurodegenerative diseases or nerve injury can result in the loss of spinal motoneurons. However, remaining motoneurons after such insults show a variety of morphological and functional changes. As a consequence of both the loss of some motoneurons and the secondary changes in other, remaining motoneurons, functional restoration is poor, and the time course of recovery is protracted at best. The development of animal models, for example involving direct spinal cord damage or peripheral nerve injury, have begun to yield clues to both the mechanisms involved in motoneuron pathology and potential therapeutic approaches. Our work will concentrate on motoneuron dendrites, which are essential for the reception and integration of information. Dendrites in motoneurons atrophy after nerve injury or the death of neighboring motoneurons, and preventing that atrophy, or improving its recovery, in motoneurons that survive the initial insult will have a major impact on the restoration of spinal function. We have begun to develop two models in the adult rat spinal cord, utilizing induced motoneuron death or peripheral nerve cuts that will allow us to examine potential ways of preventing, or accelerating recovery from, dendritic atrophy in remaining motoneurons. In our first model, we found that the death of neighboring motoneurons causes the dendritic arbor of the remaining motoneurons to atrophy, but that manipulation of steroid hormones, specifically testosterone, can prevent or reverse that atrophy. Using morphological methods, we will determine if there is a dose/effect relationship for testosterone and dendritic protection, and if so, establish the minimum amount of testosterone required. We will also test the degree of functional recovery produced by these manipulations using electrophysiological methods. Using morphological methods, we will determine if there are critical temporal limits to the therapeutic window for protection from dendritic atrophy, and whether androgen prevents or accelerates recovery from dendritic atrophy. In our second model, we found an interactive effect of testosterone with brain-derived neurotrophic factor (BDNF) in preventing dendritic atrophy after cutting peripheral motor nerves. We will test whether the expression of BDNF in muscle or motoneurons, or its receptors, could be regulated by androgens, utilizing in situ hybridization and immunohistochemical techniques Together, results from studies using these two models will be informative about the therapeutic role for steroid hormones in treating spinal cord disease or nerve injury.