ANALYSIS OF FACTORS PREVENTING CNS NEURON DEATH IN VIVO

隔基底区胆碱能和非胆碱能神经元的变性 前脑区域在许多疾病状态下都被观察到，例如 阿尔茨海默病和帕金森氏症--痴呆症。虽然还不确定 是什么因素导致了这种细胞死亡，有人提出 中枢神经系统损伤或与之相关的神经退行性改变 一些衰老障碍，如阿尔茨海默病，是由于缺乏 靶向神经营养因子。这一假设与 最近的研究表明，神经营养因子在体内释放 对成年哺乳动物中枢神经系统选择性损伤的反应促进 CNS和PNS神经元在培养中的存活及其对存活的影响 移植的神经元。因此，这一提议的长期目标 研究目的是开发体内实验制剂，为 特定营养物质和细胞环境的鉴定 防止与年龄相关的细胞死亡并影响神经元存活 在成熟的哺乳动物中枢神经系统中的损伤之后。实验模型 在这些研究中使用的系统是间隔投射到 海马体结构。本提案的具体目标是 利用脑内神经移植与各种 病变范例与脑室或全身给药 建议的营养物质，以确定实验操作 即：1)防止胆碱能逆行变性 完全性双侧大脑中隔神经切断后的非胆碱能隔神经元 穹隆/海马伞和2)促进这些神经元的存活 老年个体中的人口。脑内特定的神经元群体 间隔区域及其传入投射将使用 采用逆行和顺行的多种神经解剖学技术 轴突追踪程序，乙酰胆碱酯酶组织化学， 胆碱能和GABA能神经元的免疫细胞化学鉴定 生化分析程序。拟议研究的数据将提供 洞察影响细胞生长的分子因素和细胞环境 隔区胆碱能和非胆碱能神经元的存活 成熟和老年哺乳动物中枢神经系统。这些结果应该被证明是有益的 评估靶向衍生营养因子的损失是否可能 与神经损伤后观察到的神经元变性有关 在中枢神经系统老化的过程中。此外，这些结果将提供洞察力 转化为可能的治疗方法，可能促进细胞存活 成年哺乳动物中枢神经系统。

Degeneration of cholinergic and non-cholinergic neurons in the septal-basal forebrain region has been observed in a number of disease states such as Alzheimer's disease and Parkinsonism-dementia. Although it is uncertain what factors are responsible for this cell death, it has been proposed that neurodegenerative changes resulting from CNS injuries or associated with some aging disorders, such as Alzheimer's disease, result from the loss of target-derived neuronotrophic factors. This hypothesis is consistent with recent studies which indicate that neuronotrophic factors released in response to selective lesions of the adult mammalian CNS promote the survival of CNS and PNS neurons in culture and influence the survival of transplanted neurons. Thus, the long-term objectives of this proposed research are to develop in vivo experimental preparations for the identification of specific trophic substances and cellular environments that prevent age related cell death and influence neuronal survival following lesions in the mature mammalian CNS. The experimental model system to be employed in these studies is the septal projection to the hippocampal formation. The specific aims of the present proposal are to utilize intracephalic neural transplants in conjunction with a variety of lesion paradigms and the intraventricular or systemic administration of proposed trophic substances in order to identify experimental manipulations that: 1) prevent retrograde degeneration of cholinergic and non-cholinergic septal neurons following complete bilateral transections of the fornix/fimbria and 2) promote the survival of these neuronal populations in aged individuals. Specific neuronal populations within the septal region and their afferent projections will be identified using a variety of neuroanatomical techniques employing retrograde and anterograde axonal tracing procedures, acetylcholinesterase histochemistry, immunocytochemical identification of cholinergic and gabaergic neurons, and biochemical assay procedures. Data from the proposed research will provide insight into molecular factors and cellular environments that influence the survival of cholinergic and non-cholinergic septal neurons within the mature and aged mammalian CNS. These results should prove beneficial for evaluating whether the loss of target-derived trophic factors may be involved in the neuronal degeneration observed following neural injuries and during aging of the CNS. Moreover, these results will provide insight into possible treatment therapies that may promote cell survival in the adult mammalian CNS.