Nicolle Michelle M., Zhang Hai-Yan, Bizon Jennifer L.
The hippocampus is an anatomical region that is critical for certain types of learning and memory that are vulnerable to the effects of normal aging. Early data indicated that these cognitive deficits could be attributed to age-related neuronal loss. However, in the mid-1990s, it was discovered that frank neural degeneration was not a consequence of the normal aging process. First observed in rodents, this finding has since been replicated in primates, including humans (reviewed in [1] and [2]). Given the fact that hippocampal neuronal number is relatively preserved, even at very advanced ages, dysfunctions associated with neuronal integrity (e.g., proper encoding, gene expression and cell signaling) have become an important avenues of exploration as causative factors of age-related mnemonic impairment [3–5]). Indeed, as this chapter discusses in detail, age-related deficits in signal transduction do occur and are presumed to reflect deficient transfer of information both within the hippo-campal formation and between the hippocampus and other brain structures critical for proper cognitive function (e.g., [6–8]). The animal model that we have used to investigate the behavioral relevance of age-related changes in signal transduction mechanisms is reliable and well-established [9, 10]. Briefly, hippocampal-dependent spatial memory is assessed in young and aged male Long-Evans rats in the Morris water maze. Using data from probe trials that are interpolated throughout our training protocol, an individual measure of spatial learning ability is derived for each rat (i.e., a “spatial learning index”). As shown in Figure 9.1, plotting individual young and aged rat spatial performance using the spatial learning index reveals that this measure reliably distinguishes two groups of aged rats: (1) those that learn on par with the young cohorts (i.e., aged-unimpaired rats) and (2) those that perform outside the range of young rats, demonstrating impairment on the task (i.e., aged-impaired rats) [9]. The variability in spatial learning performance observed in this population of aged rats both mimics that observed in humans and affords investigators the opportunity to not only compare neurobiological factors that change as a function of age but, also, to directly link such changes to a functional behavioral measure of hippocampal integrity. Among aged rats, the correlation between individual learning indices and neurobiological measures related to the efficacy of signal transduction mechanisms is the primary methodology used in our studies. Although all data in this chapter are related to this one particular model, both the neurobiological and behavioral changes have been replicated in other strains of rodents and even primates. The approaches and techniques described here should be useful and applicable to other animal models of cognitive aging.
海马体是一个解剖学区域，对于某些类型的学习和记忆至关重要，而这些学习和记忆容易受到正常衰老的影响。早期数据表明，这些认知缺陷可归因于与年龄相关的神经元损失。然而，在20世纪90年代中期，人们发现明显的神经退行性变并非正常衰老过程的结果。这一发现首先在啮齿动物中观察到，此后在包括人类在内的灵长类动物中也得到了证实（见[1]和[2]中的综述）。鉴于即使在非常高龄时海马体神经元数量相对保持不变，与神经元完整性相关的功能障碍（如正确编码、基因表达和细胞信号传导）已成为作为与年龄相关的记忆障碍病因的重要探索途径[3 - 5]）。事实上，正如本章详细讨论的那样，与年龄相关的信号转导缺陷确实存在，并被认为反映了海马结构内以及海马体与对正常认知功能至关重要的其他脑结构之间信息传递的不足（如[6 - 8]）。我们用于研究信号转导机制中与年龄相关变化的行为相关性的动物模型是可靠且成熟的[9, 10]。简而言之，在莫里斯水迷宫中评估年轻和老年雄性Long-Evans大鼠的海马体依赖性空间记忆。使用在我们整个训练方案中插入的探测试验数据，为每只大鼠得出空间学习能力的个体测量值（即“空间学习指数”）。如图9.1所示，使用空间学习指数绘制年轻和老年大鼠的个体空间表现图，结果表明该测量方法能够可靠地区分两组老年大鼠：（1）那些与年轻组表现相当的大鼠（即未受损的老年大鼠）和（2）那些表现超出年轻大鼠范围、在任务中表现受损的大鼠（即受损的老年大鼠）[9]。在这群老年大鼠中观察到的空间学习表现的变异性既模仿了在人类中观察到的情况，又为研究人员提供了机会，不仅可以比较随年龄变化的神经生物学因素，还可以将这些变化直接与海马体完整性的功能性行为测量联系起来。在老年大鼠中，个体学习指数与与信号转导机制功效相关的神经生物学测量之间的相关性是我们研究中使用的主要方法。尽管本章中的所有数据都与这一特定模型相关，但神经生物学和行为变化在其他啮齿动物甚至灵长类动物品系中也得到了重复验证。这里描述的方法和技术应该对其他认知衰老动物模型有用且适用。
