PHARMACOLOGY OF NGF FOR FOREBRAIN CHOLINERGIC NEURONS

所提出的研究是针对功能的表征 基底前脑胆碱能神经元对神经生长因子的重要反应。在.期间 在上一个资助期，确定了NGF促进生存， 胆碱能神经元的轴突生长和生化分化 在体外发育。在部分切断海马伞的成年大鼠中，它 研究表明，脑室内注射NGF可防止 病变导致隔区胆碱能细胞体消失， 单次注射或给药长达五个月并不 导致永久挽救细胞，而NGF同样有效 在中年，就像年轻成年大鼠一样。这项提案的第一部分 解决与细胞响应有关的特定剩余问题 在我们的损伤范式中，身体到NGF(神经元死亡或萎缩， NGF在大脑中的渗透)。第二部分是关于功能 成年胆碱能神经元对神经生长因子的反应。在突触前水平， NGF对胆碱乙酰转移酶(ChAT)表达的作用 亲和力胆碱摄取、乙酰胆碱的合成和释放 探索过了。为了评估突触前变化是否在 突触后水平，卡巴胆碱刺激的磷脂酰肌醇的分解 将会受到监控。第三部分探讨了碱性成纤维细胞生长因子和 胰岛素(与NGF类似，可刺激培养的 胆碱能神经元)对胆碱能产生相似或不同的作用 神经元。将对培养的胆碱能神经元和 在部分切断海马伞的成年大鼠上。这些发现将有助于 了解NGF在发育和成人功能中的生理作用 基底前脑胆碱能神经元。研究的主要目标是 了解NGF药理学给药的后果 行政管理。这些发现与潜在的使用有直接关系。 神经生长因子在阿尔茨海默病中的作用，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.