Hippocampal Synaptic Plasticity and Aging

描述：(改编自申请者摘要)：衰老和痴呆症通常 伴随着学习和记忆新信息的能力减弱。 重要的是，记忆缺陷在造成脑部损伤中起主要作用。 日常生活和功能独立性的丧失。改善环境质量的一个策略 老年人的生活质量是开发改善记忆的治疗方法 功能。要实现这一目标，需要更好地理解细胞 涉及记忆的机制，以及这些机制如何随着年龄的增长而变化。 尽管学习所涉及的机制尚不确定，但人们相信 记忆的形成涉及突触的持续使用依赖的变化 功能和突触传递的长时程增强(LTP) 这发生在短暂的高频使用兴奋性突触之后 代表了与记忆相关的突触可塑性的模型。它还显示， 诱导LTP能力随着年龄的增长和早期使用的机制而减弱 在生活中产生LTP在衰老的大脑中可能不那么有效。在这 建议，我们将使用从不同种类的大鼠海马片制备的体外脑片 从青春期到成年后期的出生后年龄决定了 LTP的诱导和表达随年龄的变化而变化。初步研究 提示CA1区N-甲基-D-天冬氨酸受体(NMDAR)依赖LTP 海马区随着年龄的增长而下降，而LTP依赖于 电压激活的钙通道(VACCs)持续存在。此外，NMDAR依赖 在适当的能量条件下，可以在老化的海马区诱导LTP 提供来源和/或神经调节剂。这个项目将建立在这些基础上 初步观察，并将涉及两个具体目标：1.审查 LTP诱导阈值的变化及NMDAR和VAC的作用 2.研究葡萄糖、替代能源底物和 胰岛素在调节LTP诱导衰老中的作用。希望能更好地 了解LTP与年龄相关的变化，并找出提高LTP的方法 NMDAR依赖的LTP在成年海马区将导致更有效的 年龄相关性认知功能减退的治疗。

DESCRIPTION: (Adapted from applicant's abstract): Aging and dementia are often accompanied by diminished ability to learn and remember new information. Importantly, defects in memory play major roles in producing impairments in daily living and loss of functional independence. One strategy to improve the quality of life for the elderly is to develop treatments that improve memory function. Achieving this goal will require better understanding of cellular mechanisms involved in memory and how these mechanisms change with aging. Although the mechanisms involved in learning are not certain, it is believed that memory formation involves persistent use-dependent changes in synaptic function and that the long-term potentiation (LTP) of synaptic transmission that occurs following brief high-frequency use of excitatory synapses represents a model for memory-related synaptic plasticity. It also appears that the ability to induce LTP diminishes with aging and that mechanisms used early in life to generate LTP may not be as effective in the aged brain. In this proposal, we will use in vitro hippocampal slices prepared from rats of various postnatal ages ranging from adolescence through late adulthood to determine how LTP induction and expression change as a function of aging. Preliminary studies suggest that N-methyl-D-aspartate receptor (NMDAR)-dependent LTP in the CAl hippocampal region declines with aging, while LTP dependent upon voltage-activated Ca2+ channels (VACCs) persists. Furthermore, NMDAR-dependent LTP can be induced in the aging hippocampus provided that appropriate energy sources and/or neuromodulators are supplied. This project will build upon these preliminary observations and will address two specific aims: 1. To examine changes in LTP induction threshold and the role of NMDARs and VACCs during aging; 2. To examine the role of glucose, alternative energy substrates and insulin in modulating LTP induction with aging. It is hoped that better understanding of age-related changes in LTP and identifying ways to enhance NMDAR-dependent LTP in the adult hippocampus will lead to more effective treatments for age-related cognitive decline.