Synaptic Substrates of Age-Dependent Memory Deficits

学习和记忆障碍往往伴随着年龄的增长。通常，这种损伤与年龄相关。 痴呆症。然而，其中很大一部分可归因于所谓的正常衰老。 正常的年龄相关认知功能障碍在海马体依赖行为中最为明显。有趣的是， 然而，一些老年人表现出完整的记忆功能，而另一些人则严重受损， 尽管他们的年龄是一样的。尽管与年龄相关的行为和生理缺陷 尽管认知能力下降的特征已经得到很好的描述，但这种个体差异的基础仍不清楚。 这项拟议研究的目的是评估老年受损患者海马区突触的可能性。 动物逐渐被削弱，以至于远端突触不再对神经元产生同样的影响 输出为更接近的那些。老年人距离依赖突触伸缩功能退化的研究进展 受损的动物会严重扰乱突触整合，从而损害海马区 功能。拟议研究的基本策略是将衰老的大鼠诊断为受损或 使用两个海马区依赖任务未受损，然后检查形态、受体表达、 它们在海马CA1区锥体神经元中的突触功能和可塑性。老鼠会在行为上 使用Morris水迷宫和痕迹眨眼条件作用，分析空间和时间 学习，分别。对突触的分析将通过结合常规和 CA1锥体全细胞膜片钳记录的免疫金连续切片电子显微镜 神经元。主要的预测是老年受损大鼠穿孔突触的比例或数量 相对于衰老的未受损的大鼠，会减少，这将伴随着表达的减少 突触的AMPA型和NMDA型受体，特别是在远端突触之间。全细胞膜片钳 录音将确定远端突触和近端突触是否对 老年未受损大鼠的神经元输出，以及这种位置独立性在老年大鼠中是否被破坏 受损的对应者。最后，对长时程增强的诱导和逆转进行了考察。 行为学特征的老年大鼠的抑郁将为了解突触功能障碍提供线索 调节有助于减少距离依赖的突触伸缩，以及它是否 与年龄相关的认知能力下降有关。综上所述，该提案中的实验将提供 对老化大脑中突触的基本见解，以及它们的形式和功能是否与认知有关 容量。此外，确定老年动物突触功能缺陷的性质和位置将 促进预防措施的设计，旨在使老龄化更“成功”。

Learning and memory impairments often accompany aging. Frequently, such impairments are related to agerelated dementias. A substantial proportion of these, however, are attributable to so-called normal aging. Normal age-related cognitive dysfunction is most apparent in hippocampus-dependent behaviors. Interestingly, however, some aged individuals exhibit intact mnemonic function, whereas others are severely impaired, despite being the same chronologic age. Though the behavioral and physiological deficits associated with agerelated cognitive decline are well characterized, the substrates for such individual variability remain unknown. The aim of the proposed research is to evaluate the possibility that hippocampal synapses in aged impaired animals are gradually weakened such that distal synapses no longer have the same influence on neuronal output as more proximal ones. The proposed degradation of distance-dependent synaptic scaling in aged impaired animals would significantly disrupt synaptic integration and consequently impair hippocampal function. The basic strategy of the proposed research is to diagnose aged rats as either impaired or unimpaired using two hippocampus-dependent tasks, and then examine the morphology, receptor expression, function, and plasticity of their synapses in hippocampal CA1 pyramidal neurons. Rats will be behaviorally characterized using the Morris water maze and trace eyeblink conditioning, which assay spatial and temporal learning, respectively. The analyses of synapses will be accomplished by combining conventional and immunogold serial section electron microscopy with whole-cell patch-clamp recordings from CA1 pyramidal neurons. The major prediction is that the proportion or number of perforated synapses in aged impaired rats relative to aged unimpaired rats will be reduced, and this will be accompanied by a reduction in the expression of synaptic AMPA-type and NMDA-type receptors, particularly among distal synapses. The whole-cell patchclamp recordings will determine whether distal synapses and proximal synapses have the same influence on neuronal output in aged unimpaired rats, and whether such location-independence is disrupted in their aged impaired counterparts. Finally, an examination of the induction and reversal of long-term potentiation and depression in behaviorally characterized aged rats will provide insight into whether dysfunctional synaptic regulation contributes to the proposed reduction in distance-dependent synaptic scaling, and whether it correlates with age-related cognitive decline. All together, the experiments in this proposal will provide fundamental insights into synapses in the aging brain, and whether their form and function relate to cognitive capacity. Additionally, determining the nature and locus of deficient synaptic function in aged animals will facilitate the design of preventative measures intended to make aging more "succesful".