GROWTH FACTORS IN THE ADULT AND AGING BRAIN

帕金森氏病的特点是过早的神经变性 黑质纹状体多巴胺神经元。为了找出可能导致 这种细胞损失或提供一种治疗方法可能会减少 随着疾病的发展，我们实验室的研究一直集中在 确定对生物多样性的生存和可塑性至关重要的因素 多巴胺神经元。为了实现这一目标，我们一直在利用 三只老鼠模型。第一种是织布工突变小鼠， 多巴胺能黑质纹状体纤维发育异常是第一例 观察到随之而来的多巴胺能神经元变性 在帕金森氏病中发现的转化生长因子-α的模式，在 多巴胺能神经元变性时间。此外，我们还发现， 这些小鼠的甲状腺激素水平也降低了，这是一种有效的 大脑发育的调节器。因此，我们提出了旨在 在发现转化生长因子-α或甲状腺的下降 激素与脑内多巴胺神经元的神经变性有关 织布变种小鼠。最近，另一只突变的小鼠被 发现了Waved-1，它在转化生长因子-α的表达上存在缺陷。这个 这第二个小鼠突变体的可用性使我们能够专门测试 转化生长因子-α缺乏是否单独导致血管退行性变 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的弹性越强 侧枝轴突出芽对退行性变的反应 黑质回神经元。因此，这些多巴胺能神经元代表一种 刺激侧枝轴突萌发的潜在靶点 黑质内多巴胺神经元的神经变性。然而， 这些神经元的能力随着年龄的增长而丧失 自发地发芽。因此，在最后一个小鼠模型系统中，我们 调查哪些内源性因素可能导致病变 幼年动物多巴胺神经元的可塑性，它们是如何诱导的 对损伤的反应是受调控的，损伤诱导的激活 成为与年龄相关的多巴胺能丧失的限制因素 可塑性。这些研究的结果可能揭示出治疗 促进脑内多巴胺神经元恢复的可能性 自然恢复不正常的神经退行性疾病 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.