MECHANISMS OF NGF-INDUCED COGNITIVE IMPROVEMENT IN AGING

描述(改编自申请者摘要)：最近的研究表明 神经生长因子(NGF)的应用，这是一种神经营养因子 对胆碱能神经元的存活和表型维持至关重要， 改善老年大鼠的认知能力。提出了工作的目标 在这项建议中是为了探索基本的神经生物学机制负责 用于NGF诱导的老年受试者的认知增强。引路人 假说是NGF起作用使长期突触可塑性正常化 机制和蛋白激酶C活性。此外，还提出了一种新的检测方法 将外周给药的NGF输送到大脑将是其特征。 幼年(4月龄)和老年(22月龄)雄性Fischer 344只大鼠 在优先涉及海马体的行为任务中进行评估， 额叶皮质，或基底前脑胆碱能系统。海马区突触 可塑性将被测量为与认知状态相关。之后 基线评估，动物将接受NGF或适当的 控制解决方案。外周给药的NGF与一种 转铁蛋白受体抗体允许转运生物活性 神经生长因子进入大脑。在四周的治疗后，这些老鼠将会 在行为和电生理测试中重新评估，然后 牺牲以评估蛋白激酶C(PKC)的活性，该酶 已被证明与学习和大脑的调节有关 可塑性，在海马体、额叶皮质和隔区。其他内容 将进行实验，直接评估两者之间的关系 NGF、PKC、海马可塑性与空间学习。总而言之，这是 这项工作将提供有关以下方面的重要信息 与年龄相关的学习障碍，以及潜在的电生理 以及解决这些问题的生化底物。此外，这项工作将 确定与年龄相关的认知问题可以减少的程度 神经生长因子的治疗，并提供了对神经生长因子的作用机制的洞察(S 能够达到它的效果。最后，这项工作将对 一种将NGF输送到脑内的新方法的疗效 与传统技术相比在潜在临床上的优势 申请。

DESCRIPTION (Adapted from Applicant's Abstract): Recent work has shown that administration of nerve growth factor (NGF), a neurotrophin which is critical for the survival and phenotypic maintenance of cholinergic neurons, improves cognitive performance in aged rats. The goal of the work presented in this proposal is to explore basic neurobiological mechanisms responsible for NGF-induced enhancement of cognition in aged subjects. The guiding hypotheses are that NGF acts to normalize long-term synaptic plasticity mechanisms and protein kinase C activity. In addition, a novel method for delivering peripherally administered NGF to the brain will be characterized. Young (4 month old) and aged (22 month old) male Fischer 344 rats will be evaluated in behavioral tasks which preferentially involve the hippocampus, frontal cortex, or basal forebrain cholinergic system. Hippocampal synaptic plasticity will be measured to correlate with cognitive status. After baseline evaluation, the animal will receive either NGF or appropriate control solution. Peripherally administered NGF is conjugated to a transferrin receptor antibody to allow the transport of biologically active NGF into the brain. After four weeks of treatment, the rats will be re-evaluated in the behavioral and electrophysiological tests, then sacrificed to assess the activity of protein kinase C (PKC), an enzyme which has been shown to be involved in the regulation of both learning and brain plasticity, in the hippocampus, frontal cortex and septal area. Additional experiments will be performed to directly evaluate the relationship between NGF, PKC, hippocampal plasticity and spatial learning. Taken together, this work will provide important information concerning the extent and degree of age-related learning impairments, as well as potential electrophysiological and biochemical substrates for these problems. In addition, the work will determine the extent to which age-related cognitive problems can be reduced with NGF treatment, and provide insight into the mechanism(s) by which NGF is able to achieve its effects. Finally, this work will evaluate the efficacy of a novel means of delivering NGF to the brain which has clear advantages over conventional techniques in terms of potential clinical application.