PHARMACOLOGY OF NGF FOR FOREBRAIN CHOLINERGIC NEURONS

拟议的研究旨在表征功能 基底前脑胆碱能神经元对NGF的重要反应。期间 上一个资助期确定了NGF促进生存， 轴突生长和胆碱能神经元的生化分化 体外发育在成年大鼠部分伞横断， 脑室内注射神经生长因子可以防止 损伤引起的隔区胆碱能细胞体的消失， 单次注射或给药长达五个月， 导致细胞的永久拯救，并且NGF同样有效 在中年和年轻的成年大鼠中。本建议的第一部分 解决了关于细胞反应的具体剩余问题， 在我们的损伤范例中（神经元的死亡或萎缩， 神经生长因子在大脑中的渗透）。第二部分论述了功能性 成年胆碱能神经元对NGF的反应。在突触前水平， NGF对胆碱乙酰转移酶（ChAT）表达的作用，高 亲和力胆碱摄取，乙酰胆碱合成和释放将是 探讨了为了评估突触前的变化是否会对神经元的活动产生影响， 突触后水平，卡巴胆碱刺激的磷脂酰肌醇分解 将受到监控。第三部分探讨了bFGF和 胰岛素（类似于NGF，刺激培养的ChAT活性） 胆碱能神经元）对胆碱能神经元产生相似或不同的作用。 神经元将对培养的胆碱能神经元进行研究， 对成年大鼠部分伞切断。这些发现将有助于 了解NGF在发育和成年功能中的生理作用 基底前脑胆碱能神经元。这项研究的主要目标是 了解神经生长因子的药理学管理的后果 局这些发现与潜在的 神经生长因子在阿尔茨海默病和将有助于开发神经药理学 神经营养因子的应用。

The proposed studies are aimed at the characterization of functionally important responses of basal forebrain cholinergic neurons to NGF. During the previous funding period it was established that NGF promotes survival, neurite growth, and biochemical differentiation of cholinergic neurons developing in vitro. In adult rats with partial fimbrial transections, it was shown that intraventricular administration of NGF prevents the lesion-induced disappearance of cholinergic cell bodies in the septal area, that single injections or administration for up to five months does not result in permanent rescue of the cells, and that NGF is equally effective in middle-aged as in young adult rats. The first part of this proposal addresses specific remaining questions regarding the response of cell bodies to NGF in our lesion paradigm (death or shrinkage of neurons, penetration of NGF in the brain). The second part deals with the functional response of adult cholinergic neurons to NGF. At the presynaptic level the actions of NGF on choline acetyltransferase (ChAT) expression, high affinity choline uptake, acetylcholine synthesis and release will be explored. To assess whether presynaptic changes have consequences at the postsynaptic level, carbachol-stimulated breakdown of phosphatidylinositol will be monitored. The third part addresses the question whether bFGF and insulin (which, similar to NGF, stimulate ChAT activity of cultured cholinergic neurons) produce similar or different actions on cholinergic neurons. Studies will be carried out on cholinergic neurons in culture and on adult rats with partial fimbrial transection. The findings will help to understand the physiological role of NGF in development and adult function of basal forebrain cholinergic neurons. The major goal of the study is to understand the consequences of pharmacological administration of NGF administration. The findings have direct relevance for the potential use of NGF in Alzheimer's disease and will help to develop neuropharmacological applications of neurotrophic factors.