CHOLINERGIC CIRCUITS AND HIPPOCAMPAL FUNCTION IN AGING

衰老过程中的胆碱能回路和海马功能

基本信息

批准号：
3122717
负责人：
GREGORY M ROSE
金额：
$ 7.91万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-29 至 1996-06-30
项目状态：
已结题

项目摘要

Severe deterioration in the ability to learn and remember is a hallmark of patients with Alzheimer's disease. Foremost among the neuropathological changes that occur in the brains of the victims of Alzheimer's disease is a loss of basal forebrain cholinergic neurons. The loss of cholinergic innervation to the hippocampal formation, a brain region known to be necessary for the formation of new long-term memories, is thought to be major contributor to memory loss. The objective of the experiments described in this proposal is to understand the contributions of muscarinic and nicotinic cholinergic function in the hippocampus to hippocampus-dependent learning and memory. A rodent model will be used to determine the relationship between age-related alterations in cholinergic neurotransmission in the hippocampus and the mnemonic deficits with aging. Experimental measures of cholinergic function will be assessed in rats of different ages after their learning ability has been evaluated using the Morris water maze, a place learning task known to depend upon intact cholinergic input to the hippocampus, and for which age-related decrements have been well documented. Subsequently, several measures of cholinergic function will be evaluated: 1) the responsiveness of hippocampal neurons to local application of muscarine and nicotine; 2) the capacity of intrinsic hippocampal connections to demonstrate long-lasting synaptic plasticity, and the ability of muscarinic and nicotinic drugs to modulate this phenomenon; and 3) biochemical measures of the status of the cholinergic projection to the hippocampus, including measures of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity, the status of pre- and post-synaptic nicotinic receptors. A key element of the experimental design is that ages of the rats to be tested will be selected so that the influences of aging and cholinergic system function upon learning ability can be independently evaluated. Thus, in addition to using young (3 months old; learning unimpaired) and aged (24 months old; learning impaired) rats in the experiments, a third group (20 months old) be used. In this latter population, some animals will have intact learning ability, while others will be learning impaired. Within-subject comparisons of learning ability and measures of hippocampal cholinergic function can be made in this group independent of age, and will provide the strongest test of correlations between physiological/biochemical parameters and learning ability. Finally, the effect of chronic infusion of nerve growth factor (NGF), a trophic substance which is necessary for the survival of central cholinergic neurons, upon the above described behavioral and electrophysiological/biochemical measures will be evaluated.

学习和记住的能力严重恶化是阿尔茨海默氏病的患者。神经病理学阿尔茨海默氏病受害者的大脑发生的变化是基础前脑胆碱能神经元的丧失。胆碱能的丧失对海马形成的神经，一个已知的大脑区域形成新的长期记忆所必需的，被认为是记忆丧失的主要贡献者。实验的目的该提议中描述的是了解毒蕈碱的贡献海马中的烟碱胆碱能功能海马依赖的学习和记忆。啮齿动物模型将用于确定与年龄相关的胆碱能改变之间的关系随着衰老的形式，海马和助记符缺陷中的神经传递。将在大鼠中评估胆碱能功能的实验度量在学习能力之后的不同年龄已通过莫里斯水迷宫，一项已知依赖完整的地方学习任务海马的胆碱能输入，以及与年龄相关的降低已经有充分的记录。随后，胆碱能的几种测量将评估功能：1）海马神经元的反应性局部应用毒arine和尼古丁； 2）能力内在的海马连接以证明长期突触可塑性，以及毒蕈碱和烟碱药物调节的能力这种现象； 3）地位的生化措施胆碱能投射到海马，包括胆碱的测量乙酰转移酶（CHAT）和乙酰胆碱酯酶（ACHE）活性，前和突触后烟碱受体的状态。一个关键要素实验设计是选择要测试的大鼠的年龄因此，衰老和胆碱能系统的影响对可以独立评估学习能力。因此，除了使用年轻人（3个月大；学习不受影响）和老化（24个月大；在实验中学习受损的大鼠，第三组（20个月大）被使用。在后一个人群中，有些动物将完整学习能力，而其他人将学习受损。主题内比较学习能力和海马胆碱能的测量可以在这个组中独立于年龄来发挥功能，并将提供生理/生化参数之间的相关性最强测试和学习能力。最后，神经慢性输注的影响生长因子（NGF），一种营养物质，是必需的上述中央胆碱能神经元的生存将评估行为和电生理/生化措施。