GDNF AND BDNF EFFECTS ON AGED DOPAMINE NEURONS

年龄相关性神经退行性变的病因至今尚不清楚，但多项研究结果表明，在早期发育过程中的特定事件（如突变和/或损伤）可能会导致特别脆弱的神经元群体（如中脑黑质的多巴胺能系统）终身存在被掩盖的缺陷。这种缺乏症在儿童和成年早期可能没有症状，因为单胺系统非常适应变化。然而，当保护机制在自然老化过程中失效时，次优系统的增加的灵敏度可能会引起不足 功能，导致氧化应激，表型损失，最后，细胞死亡。多巴胺能神经元依赖于神经营养因子的发育和持续的神经可塑性。特别是，胶质细胞系源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）已被证明对这些神经元具有强大的作用，无论是在发育中的神经系统还是在成年个体中。选择性多巴胺损伤后，纹状体中的GDNF和BDNF都不受调节，并且这种生长因子反应在衰老过程中减弱，这表明生长因子的丧失可能是由于生长因子的缺乏而导致的。 刺激可能是导致与年龄相关的神经变性过程的因素之一。我们建议利用GDNF（GDNF+/-）和BDNF（BDNF+/-）无效突变的杂合子动物来研究运动行为、多巴胺形态和多巴胺神经传递的年龄相关改变（目的1）。此外，我们建议利用产前暴露于内毒素脂多糖（LPS）作为产前多巴胺神经元减少的模型，以确定这种减少是否也会引起以后生活中DA功能的改变（目标#2），最后，我们建议将这种产前暴露于内毒素与GDNF+/-或BDNF+/-小鼠中两种生长因子的部分丧失相结合（目标#3）。这些研究旨在确定这两种DA功能障碍的触发因素是否对整个多巴胺功能具有协同或相加作用， 衰老项目0001的总体目标是确定更少的多巴胺神经元（LPS治疗）和生长因子（BDNF+/-或GDNF+/-）的终身减少的组合是否在衰老期间对多巴胺神经元特别有害。项目0001将向项目0003和0004提供脑组织，分别用于神经炎症和神经传递研究，并向项目0005提供脑组织，用于检测黑质DA神经元亚群。所有动物均由Animal Core生成。

The etiology of age-related neurodegeneration is largely unknown to date, but multiple findings suggest that specific events (such as mutations and/or injury) during early development may give rise to life-long, masked deficiencies in especially vulnerable neuronal populations, such as the dopaminergic system of the midbrain substantia nigra. This deficiency may not be symptomatic during childhood and early adulthood, since the monoamine systems are extremely adaptive to change. However, when protection mechanisms fail during the natural aging process, the added sensitivity of a sub-optimal system may then give rise to deficient functioning, leading to oxidative stress, phenotypic loss, and, finally, cell death. Dopaminergic neurons are dependent upon neurotrophic factors for their development and continued neuroplasticity throughout life. In particular, glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF), have both been shown to have powerful effects on these neurons, both in the developing nervous system and in the adult individual. Both GDNF and BDNF are unregulated in the striarum following a selective dopamine lesion, and this growth factor response is diminished during aging, suggesting that a loss of growth factor stimulation may be one of the factors leading to age-related neurodegenerative processes. We propose to utilize animals heterozygous to a GDNF (GDNF+/-) and BDNF (BDNF+/-) null mutation to study age-related alterations in motor behavior, dopamine morphology, and dopamine neurotransmission (Aim 1). In addition, we propose to utilize prenatal exposure to the endo toxin lipopolysaccharide (LPS) as a model for prenatal reduction in dopamine neurons, to determine if this reduction also gives rise to altered DA function later in life (Aim #2), and, finally, we propose to combine this prenatal exposure to endotoxins with a partial loss of the two growth factors in GDNF+/- or BDNF+/- mice (Aim #3). These studies are aimed to determine if these two triggers of DA dysfunction have synergistic or additive effects on overall dopamine function during aging. The overall goal of Project 0001 is to determine if a combination of fewer dopamine neurons (LPS treatment) and a life-long reduction in growth factors (BDNF+/- or GDNF+/-) is especially deleterious to dopamine neurons during aging. Project 0001 will provide brain tissues to Project 0003 and 0004, for studies of neuroinflammation and neurotransmission, respectively, and to Project 0005 for detection of subpopulations of nigral DA neurons. All animals will be generated by the Animal Core.