Synaptic Substrates of Age-Dependent Memory Deficits

学习和记忆障碍往往伴随着衰老。通常，这种损害与年龄有关 痴呆症然而，其中很大一部分可归因于所谓的正常衰老。 正常的年龄相关的认知功能障碍最明显的是依赖校园的行为。有趣的是， 然而，一些老年人表现出完整的记忆功能，而其他人则严重受损， 尽管他们的年龄相同尽管与年龄相关的行为和生理缺陷 虽然认知能力下降的特征得到了很好的描述，但这种个体差异的基质仍然未知。 本研究的目的是评估老年人海马突触受损的可能性， 动物逐渐变弱，使得远端突触不再对神经元具有相同的影响。 输出为更近端的输出。提出的老年人距离依赖性突触缩放的退化 受损的动物将显著破坏突触整合， 功能这项研究的基本策略是将老年大鼠诊断为受损或 未受损的使用两个依赖于海马区的任务，然后检查形态，受体表达， 海马CA1区锥体神经元突触的功能和可塑性。老鼠的行为 其特征在于使用Morris水迷宫和跟踪眨眼条件反射，其分析空间和时间 学习，分别。突触的分析将通过结合常规和 CA1锥体细胞免疫金连续切片电镜全细胞膜片钳记录 神经元主要的预测是老年受损大鼠中穿孔突触的比例或数量 相对于未受损的老年大鼠， 突触AMPA型和NMDA型受体，特别是在远端突触。全细胞膜片钳 记录将确定远端突触和近端突触是否对神经元有相同的影响。 老年未受损大鼠的神经元输出，以及这种位置独立性是否在老年大鼠中被破坏。 受损的同行最后，研究了长时程增强的诱导和逆转， 行为特征的老年大鼠的抑郁症将提供对功能障碍的突触是否 调节有助于减少距离依赖性突触缩放，以及是否 与年龄相关的认知能力下降有关。总之，本提案中的实验将提供 对衰老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功能有关。 容量此外，确定老年动物中突触功能缺陷的性质和部位将有助于 促进旨在使老龄化更“成功”的预防措施的设计。

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".