GROWTH FACTORS IN THE ADULT AND AGING BRAIN

帕金森氏病的特征是神经元过早变性， 黑质纹状体多巴胺神经元 为了发现可能导致这种情况的原因 这种细胞损失或提供一种治疗， 疾病的进展，我们实验室的研究一直集中在 确定对生存和可塑性重要的因素， 多巴胺神经元 为了实现这一目标，我们一直在利用 三种小鼠模型。 第一种是韦弗突变小鼠， 多巴胺能黑质纹状体纤维的异常发育首先是 观察到，随后在类似的多巴胺能神经元变性， 在帕金森氏病中发现的模式，TGF-α， 多巴胺能神经元变性的时间。 此外，我们还发现， 这些小鼠的甲状腺激素水平也有所下降， 大脑发育的调节器。 因此，我们提出了旨在 发现TGF-α或甲状腺激素的减少 激素负责多巴胺神经元的神经变性， 韦弗突变小鼠 最近，另一种突变小鼠被 发现了waved-1，它缺乏TGF-α表达。 的 第二种突变小鼠的可用性，使我们能够专门测试 TGF-α单独缺乏是否会导致 多巴胺神经元或增加其对神经毒素的敏感性，1- 甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）。 有证据表明 中脑边缘多巴胺能神经元越有弹性 侧支轴突发芽的退化的反应， 黑质纹状体神经元 因此，这些多巴胺能神经元代表了 刺激侧支轴突发芽的潜在靶点， 黑质多巴胺神经元的神经变性。 然而，在这方面， 这些神经元的能力会随着年龄的增长而下降， 自发发芽 因此，在最后一个小鼠模型系统中， 研究哪些内源性因素可能导致损伤诱导的 可塑性的多巴胺神经元在年轻的动物，他们的诱导， 对损伤的反应受到调节，损伤诱导的激活是否 成为与年龄相关的多巴胺能神经递质丧失的限制因素 可塑性 这些研究的结果可能揭示治疗 增强多巴胺神经元恢复的可能性， 神经退行性疾病，其中自发恢复通常不能 发生.

Parkinson's disease is characterized by the premature neurodegeneration of nigrostriatal dopamine neurons. In order to discover what may be causing this cellular loss or provide a treatment that may decrease the progression of the disease, studies in our laboratory have been focused on identifying factors that are important for the survival and plasticity of dopamine neurons. In order to carry out this goal, we have been utilizing three mouse models. The first, is the weaver mutant mouse in which abnormal development of the dopaminergic nigrostriatal fibers is first observed followed by degeneration of dopaminergic neurons in a similar pattern to what is found in Parkinson's disease, TGF-alpha, during the time of dopaminergic neuronal degeneration. In addition, we have found that these mice also have decreased levels of thyroid hormone, a potent regulator of brain development. Therefore, we have proposed studies aimed at discovering whether the decreases in either TGF-alpha or thyroid hormone are responsible for the neurodegeneration of dopamine neurons in the weaver mutant mouse. Recently, another mutant mouse has been discovered, waved-1, which has a deficiency in TGF-alpha expression. The availability of this second mouse mutant, allows us to specifically test whether a deficiency in TGF-alpha alone results in the degeneration of dopamine neurons or increase their sensitivity to the neurotoxin, 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). There is evidence that the more resilient mesolimbic dopaminergic neurons are able to undergo collateral axonal sprouting in response to degeneration of the nigrostrital neurons. Thus, these dopaminergic neurons represent a potential target to stimulate collateral axonal sprouting after neurodegeneration of dopamine neurons in the substantia nigra. However, there is an age-related loss in the capacity of these neurons to spontaneously sprout. Therefore, in the last mouse model system we investigate what endogenous factors may be responsible for lesion-induced plasticity of dopamine neurons in young animals, how their induction in response to injury is regulated, and whether lesion-induced activation becomes the limiting factor in the age-related loss of dopaminergic plasticity. The results of these studies may reveal therapeutic possibilities for enhancing the recovery of dopamine neurons in neurodegenerative diseases in which spontaneous recovery does not normally occur.