Hippocampal Synaptic Plasticity and Aging

描述：（改编自申请人的摘要）：衰老和痴呆症往往是 伴随着学习和记忆新信息的能力下降。 重要的是，记忆缺陷在产生记忆障碍方面起着重要作用。 日常生活和功能独立性的丧失。一种改善 提高老年人生活质量的方法是开发改善记忆力的治疗方法 功能实现这一目标需要更好地理解细胞 以及这些机制如何随着年龄的增长而变化。 虽然学习的机制还不确定，但人们相信， 记忆的形成涉及突触的持续使用依赖性变化， 突触传递的长时程增强（LTP） 兴奋性突触的短暂高频率使用 代表了记忆相关突触可塑性的模型。似乎也 诱导LTP能力随着年龄的增长和早期使用的机制而减弱 在老年人的大脑中产生LTP可能不那么有效。在这 建议，我们将使用从各种大鼠制备的体外海马切片， 从青春期到成年晚期的出生后年龄， LTP的诱导和表达随着年龄的变化而变化。初步研究 表明CA 1中N-甲基-D-天冬氨酸受体（NMDAR）依赖性LTP 海马区随着年龄的增长而下降，而LTP依赖于 电压激活的Ca 2+通道（VACCs）持续存在。此外，NMDAR依赖 在适当的能量条件下，衰老海马可诱导LTP 源和/或神经调节剂。该项目将建立在这些 初步意见，并将处理两个具体目标：1。审查 LTP诱导阈值的变化以及NMDARs和VACCs在LTP诱导过程中的作用 老化; 2.研究葡萄糖、替代能源底物和 胰岛素调节LTP诱导与衰老。希望能更好地 了解LTP中与年龄相关的变化，并确定如何提高 NMDAR依赖的LTP在成年海马会导致更有效的 治疗与年龄相关的认知能力下降。

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.